Sex and Sensibility

The State of the Art - Gender Identity and the Brain

European Society for Endocrinology Conference 2018

Symposium S30.3

Abstract : Brain structure and function in gender dysphoria

The concept of gender identity is uniquely human. Hence we are left with the phenomenon of men and women suffering from Gender Dysphoria (GD) also known as transsexualism to study the origins of gender identity in humans.
It has been hypothesized that atypical levels of sex steroids during a perinatal critical period of neuronal sexual differentiation may be involved in the development of GD. In order to test this hypothesis, we investigated brain structure and function in individuals diagnosed with GD using magnetic resonance imaging (MRI). Since GD is often diagnosed in childhood and puberty has been proposed to be an additional organizational period in brain differentiation, we included both prepubertal children and adolescents with GD in our studies.
First, we measured brain activation upon exposure to androstadienone, a putative male chemo-signal which evokes sex differences in hypothalamic activation (women > men). We found that hypothalamic responses of both adolescent girls and boys diagnosed with GD were more similar to their experienced gender than their birth sex, which supports the hypothesis of a sex-atypical brain differentiation in these individuals.
 At the structural level, we analyzed both regional gray matter (GM) volumes and white matter (WM) microstructure using diffusion tensor imaging. In cis-gender girls, larger GM volumes were observed in the bilateral superior medial frontal and left pre/postcentral cortex, while cis-gender boys had more volume in the bilateral superior-posterior cerebellum and hypothalamus. Within these regions of interest representing sexually dimorphic brain structures, GM volumes of both GD groups deviated from the volumetric characteristics of their birth sex towards those of individuals sharing their gender identity. Furthermore, we found intermediate patterns in WM microstructure in adolescent boys with GD, but only sex-typical ones in adolescent girls with GD.
These results on brain structure are thus partially in line with a sex-atypical differentiation of the brain during early development in individuals with GD, but might also suggest that other mechanisms are involved. Indeed, using resting state MRI, we observed GD-specific functional connectivity in the visual network in adolescent girls with GD. The latter is in support of a more recent hypothesis on alterations in brain networks important for own body perception and self-referential processing in individuals with GD.

Professor Julie Bakker, who led the research at the University of Liege in Belgium, said: “Although more research is needed, we now have evidence that sexual differentiation of the brain differs in young people with GD, as they show functional brain characteristics that are typical of their desired gender.”

“We will then be better equipped to support these young people, instead of just sending them to a psychiatrist and hoping that their distress will disappear spontaneously.”

Transsexualism as an Intersex Condition

Transsexualism as an Intersex Condition, M.Diamond. Transsexuality in Theology and Neuroscience: Findings, Controversies and Perspectives), ed. by Gerhard Schreiber, Berlin and Boston: De Gruyter 2016.

While more conclusive experimental data in support of the thesis presented is desirable, two recent publications have appeared that amplify and review much of the material discussed above, a paper entitled “Evidence Supporting the Biologic Nature of Gender Identity” and Bevan’s book with the title “The Psychobiology of Transsexualism and Transgenderism” (Bevan, 2015; Saraswat, Weinand, & Safer, 2015). To this investigator there seems evidence enough to consider trans persons as individuals intersexed in their brains and scant evidence to think their gender transition is a simple and unwarranted social choice.

An Issue Whose Time Has Come: Sex/Gender Influences on Nervous System Function

An Issue Whose Time Has Come: Sex/Gender Influences on Nervous System Function
Journal of Neuroscience Research, vol 95 1-2, Jan/Feb 2017

"Be careful, it's the third rail.” I received this strong advice to steer clear of studying sex differences from a senior colleague around the year 2000 when my research into brain mechanisms of emotional memory began drawing me into the issue of sex differences—or better yet, sex influences—on brain function. And in a way, he was right. For the vast majority of his long and distinguished neuroscience career, exploring sex influences was indeed a terrific way for a brain scientist not studying reproductive functions to lose credibility at best, and at worst, become a pariah in the eyes of the neuroscience mainstream......

Yup.

Theory Predicts....

Something that I think will stretch everyone's boundaries.

"Brain Sex" theory says the following -
1. The human brain is not homogenous
2. Some bits are sexually dimorphic - though they may also conform to neither stereotype
3. Some of the sexual dimorphism is due to current hormone levels
4. Some of the sexual dimorphism is set before birth, and will develop within narrow bounds later
5. Sexual dimorphism is anything but binary
6. Certain parts of the brain determine gender identity (by organisation-activation)
7. Certain parts of the brain determine body map, in particular, appropriate genitalia
8. Certain parts of the brain determine sexual orientation - gynephillic, androphillic, both, neither.
9. Certain parts of the brain determine sense of smell,  dichotic hearing etc
10. Certain parts of the brain determine play patterns as children
11. Certain parts of the brain determine interests and talents as adults

Now for some crucial bits

13. If some sexually dimorphic parts of the body are masculinised, usually most other bits are too to some degree. This applies to the body as a whole, but also the different parts of the brain. But, and this cannot be emphasised too highly, there are degrees, correlation is statistical not absolute, it's usual for some parts to be closer to a male rather than female stereotype, and other parts the reverse. There's no such thing as a "male brain" or "female brain". "Male" and "Female" don't refer to Platonic Ideals, just patterns found more commonly in one sex or the other.

What this means - some predictions.

Lots of men where everything lines up - male gender identity, male genitalia, gynephilia, male play patterns when young, "typically masculine interests" as adults, typically male senses of smell and hearing, and so on, with female equivalents.

Non-op trans women.

Girls with CAH who show male-typical play patterns and later often gynephillia (but female gender identity)

Boys who show female-typical play patterns and later often androphilia (but male gender identity)

And men like this. Male gender identity, usually androphilia, and non-masculine genital body map. "Nullos".

Limits on Neuroplasticity - and the infamous BSTc layer

I found a wonderfully informative site I wasn't aware of, by an author whose talents at conveying complex concepts to a lay audience exceed my own. Even though I'm the one who's supposed to have a Grad Cert in Science Communication from the ANU.

It's Liz - Day by Day, a blog that apparently started as a record of Transition, but has since become an excellent resource on the science of Sex and Gender.

A bit like this blog, though I started it many years before my own atypical and non-volitional transition. (Zoe kicks herself again for not doing it earlier, not having the courage to).

Anyway, from this site, a graphic illustration of one area of the brain where women tend to have one structural pattern (OK, we've not found any exceptions, just degrees) and men another.

As they say, sometimes a picture is worth a thousand words.

Now onto Neuroplasticity - the quality of the brain to change its structure due to environment.

A good article on the limits to it is Equal ≠ The Same: Sex Differences in the Human Brain

"But wait," argue the anti-sex difference authors, "the brain is plastic"-that is, molded by experience. One group of authors uses the word plasticity in the title of their paper three times to make sure we understand its importance.²⁹ (As someone who has studied brain plasticity for more than 35 years, I find the implication that it never occurred to me amusing.) By the plasticity argument-also made explicitly by neuroscientist Lise Eliot in her book Pink Brain Blue Brain-small sex differences in human brains at birth are increased by culture's influence on the brain's plasticity.³⁰ Eliot further argues that we can avoid "troublesome gaps" between the behaviors of adult men and women (a curious contradiction, by the way, of the view that there are no behavioral differences between the sexes) by encouraging boys and girls to learn against their inborn tendencies.

It is critical to understand where the fallacies in this argument lie. First, it is false to conclude that because a particular behavior starts small in children and grows, that behavior has little or no biological basis. One has only to think of handedness, walking, and language to see the point. Second, this argument presupposes that human "cultural" influences are somehow formed independent of the existing biological predispositions of the human brain. But third, and most important, is the key fallacy in the plasticity argument: the implication that the brain is perfectly plastic. It is not. The brain is plastic only within the limits set by biology.

To understand this critical point, consider handedness. It is indeed possible, thanks to the brain's plasticity, to force a child with a slight tendency to use her left hand to become a right-handed adult. But that does not mean that this practice is a good idea, or that the child is capable of becoming as facile with her right hand as she might have become with her left had she been allowed to develop her natural tendencies unimpeded. The idea that we should use the brain's plasticity to work against inborn masculine or feminine predispositions in the brains of children is as ill conceived as the idea that we should encourage left-handed children to use their right hand.

29 Fine, C. et al. Plasticity, plasticity, plasticity. . . and the rigid problem of sex, Trends in Cognitive Sciences November 2013, Vol. 17, No. 11.
30 Eliot, L., Pink Brain, Blue Brain: How Small Differences Grow Into Troublesome Gaps -- And What We Can Do About It, 2009; HMH Publishing.

Sex differences in the structural connectome of the human brain

Sex differences in the structural connectome of the human brain Ingalhalikar et al PNAS ; published ahead of print December 2, 2013

Sex differences in human behavior show adaptive complementarity: Males have better motor and spatial abilities, whereas females have superior memory and social cognition skills. Studies also show sex differences in human brains but do not explain this complementarity. In this work, we modeled the structural connectome using diffusion tensor imaging in a sample of 949 youths (aged 8–22 y, 428 males and 521 females) and discovered unique sex differences in brain connectivity during the course of development. Connection-wise statistical analysis, as well as analysis of regional and global network measures, presented a comprehensive description of network characteristics. In all supratentorial regions, males had greater within-hemispheric connectivity, as well as enhanced modularity and transitivity, whereas between-hemispheric connectivity and cross-module participation predominated in females. However, this effect was reversed in the cerebellar connections. Analysis of these changes developmentally demonstrated differences in trajectory between males and females mainly in adolescence and in adulthood. Overall, the results suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes. 

Scientists Discover Children’s Cells Living in Mothers’ Brains - Scientific American

Scientists Discover Children’s Cells Living in Mothers’ Brains - Scientific American

Women may have microchimeric cells both from their mother as well as from their own pregnancies, and there is even evidence for competition between cells from grandmother and infant within the mother.

It's more complicated than most people think. Our bodies are not static, they are performance art. We are not defined completely by our DNA.

Restoring Natural Sensory Feedback in Real-Time Bidirectional Hand Prostheses

Restoring Natural Sensory Feedback in Real-Time Bidirectional Hand Prostheses Raspopovic et al Sci Transl Med 5 February 2014:

More please, and faster.

Hand loss is a highly disabling event that markedly affects the quality of life. To achieve a close to natural replacement for the lost hand, the user should be provided with the rich sensations that we naturally perceive when grasping or manipulating an object. Ideal bidirectional hand prostheses should involve both a reliable decoding of the user’s intentions and the delivery of nearly “natural” sensory feedback through remnant afferent pathways, simultaneously and in real time. However, current hand prostheses fail to achieve these requirements, particularly because they lack any sensory feedback. We show that by stimulating the median and ulnar nerve fascicles using transversal multichannel intrafascicular electrodes, according to the information provided by the artificial sensors from a hand prosthesis, physiologically appropriate (near-natural) sensory information can be provided to an amputee during the real-time decoding of different grasping tasks to control a dexterous
hand prosthesis.
This feedback enabled the participant to effectively modulate the grasping force of the prosthesis with no visual or auditory feedback. Three different force levels were distinguished and consistently used by the subject. The results also demonstrate that a high complexity of perception can be obtained, allowing the subject to identify the stiffness and shape of
three different objects by exploiting different characteristics of the elicited sensations. This approach could improve the efficacy and “life-like” quality of hand prostheses, resulting in a keystone strategy for the near-natural replacement of missing hands. 

Another piece of the puzzle

Yet more evidence that MtoF and FtoM are not mirror-images, and that while saying "Trans women have female brains" captures the essence, and is useful as an initial step towards understanding, the reality is more complex than that. For that matter, cis women don't have female brains as such, yet men and women have statistical differences in neuro anatomy that correlate well with statistical differences in behaviour - such as sense of smell.

Cortical activation during mental rotation in male-to-female and female-to-male transsexuals under hormonal treatment. Carillo et al, Psychoneuroendocrinology. 2010 Sep;35(8):1213-22

There is strong evidence of sex differences in mental rotation tasks. Transsexualism is an extreme gender identity disorder in which individuals seek cross-gender treatment to change their sex. The aim of our study was to investigate if male-to-female (MF) and female-to-male (FM) transsexuals receiving cross-sex hormonal treatment have different patterns of cortical activation during a three-dimensional (3D) mental rotation task. An fMRI study was performed using a 3-T scan in a sample of 18 MF and 19 FM under chronic cross-sex hormonal treatment. Twenty-three males and 19 females served as controls. The general pattern of cerebral activation seen while visualizing the rotated and non-rotated figures was similar for all four groups showing strong occipito-parieto-frontal brain activation. However, compared to control males, the activation of MF transsexuals during the task was lower in the superior parietal lobe. Compared to control females, MF transsexuals showed higher activation in orbital and right dorsolateral prefrontal regions and lower activation in the left prefrontal gyrus. FM transsexuals did not differ from either the MF transsexual or control groups. Regression analyses between cerebral activation and the number of months of hormonal treatment showed a significant negative correlation in parietal, occipital and temporal regions in the MF transsexuals. No significant correlations with time were seen in the FM transsexuals. In conclusion, although we did not find a specific pattern of cerebral activation in the FM transsexuals, we have identified a specific pattern of cerebral activation during a mental 3D rotation task in MF transsexuals under cross-sex hormonal treatment that differed from control males in the parietal region and from control females in the orbital prefrontal region. The hypoactivation in MF transsexuals in the parietal region could be due to the hormonal treatment or could reflect a priori cerebral differences between MF transsexual and control subjects.

The Gender Similarities Hypothesis

The Gender Similarities Hypothesis Hyde, Janet Shibley American Psychologist, Vol 60(6), Sep 2005

The differences model, which argues that males and females are vastly different psychologically, dominates the popular media. Here, the author advances a very different view, the gender similarities hypothesis, which holds that males and females are similar on most, but not all, psychological variables. Results from a review of 46 meta-analyses support the gender similarities hypothesis. Gender differences can vary substantially in magnitude at different ages and depend on the context in which measurement occurs. Overinflated claims of gender differences carry substantial costs in areas such as the workplace and relationships.

It's a meta-meta analysis - a summary of summaries of experiments - and later work has shown rather more differences than the early metastudies would imply. About the only glaringly obvious ones visible here are those determined not by gender as such, but purely by testosterone levels.

Nonetheless, it supports two contentions that later work has shown to be well evidenced. First, that genuine innate (albeit statistical) differences exist. Second, that men and women are far more similar than different.

Historically, it's been the differences that have been overblown due to ideological belief, with no evidentiary basis. These days, it's the differences that have been minimised or even denied, again due to ideological belief, and against the evidence. Throughout, the statistical nature of the differences, that one can make no claims at all about individuals in any one area, have been completely ignored. Men and women differ from each other. Men differ from other men too, and women from other women. Both men and women as individuals can be more or less stereotypically masculine or feminine in different areas, gender is not a binary but a complex multivariant.

Open Minded Health

Open Minded Health - Results of Transsexual Brain Studies (as at 2011)

Recommended.

Conclusion
The amount of research that has been completed on the differences between transsexual and cissexual brains is small, but suggestive. Some areas of the brain appear to be sexually dimorphic irrespective of genetics or hormones (e.g., BSTc), whereas others appear to be more dependent upon sex hormones (e.g., brain volume). From the results of these studies, one may infer that pre-transition transsexual women’s brains are feminine in the BSTc and INAH3, partially feminine in their white matter tracts, and masculine in total brain and hypothalamic volume. Data in transsexual men is rarer because these studies are conducted in the western world, where transsexual women outnumber transsexual men (Gooren, 2006). However, studies of transsexual men appear to imply that the reverse is true for them.
These studies have numerous limitations. First, they have yet to be replicated. Replication is needed to ensure reliability and generalizability of these results. Second, these studies (especially those involving deceased brains) have small numbers of subjects, especially for the transsexual subjects. Studies involving brains from the Netherlands Brain Bank typically had fewer than 10 transsexual brains to study, and the latter two (Kruijver et al, Chung et al) only had a single transsexual male brain. Although fewer numbers of subjects are generally more acceptable in biological research than in psychological research, it is still a potential source of error.
Potentially the most glaring limitation in these studies is their conflation of sexual orientation and gender identity. Berglund et al (2008), for example, only compared heterosexual cissexual women and men with gynephilic/homosexual transsexual women. While they could not include androphilic/heterosexual transsexual women in their study because of rarity, they failed to include homosexual cissexual men and women as comparison groups. This introduces a potentially confounding variable.
Despite these limitations, evidence so far is suggestive of a biological influence in transsexuality. More research is needed to confirm and expand these preliminary findings.

Some of these criticisms have been met - at least partially - since 2011. Others remain. As a summary of the state-of-the-art back then, I could only improve on it marginally.

Stanford: Gender Orientation: IS Conditions Within The TS Brain

Another part of the puzzle

Increased Cortical Thickness in Male-to-Female Transsexualism Luders et al, Journal of Behavioral and Brain Science, 2011

Abstract:

Background: The degree to which one identifies as male or female has a profound impact on one’s life.
Yet, there is a limited understanding of what contributes to this important characteristic termed gender identity.
In order to reveal factors influencing gender identity, studies have focused on people who report strong feelings of being the opposite sex, such as male-to-female (MTF) transsexuals.

Method: To investigate potential neuroanatomical variations associated with transsexualism, we compared the regional thickness of the cerebral cortex between 24 MTF transsexuals who had not yet been treated with cross-sex hormones and 24 age-matched control males.

Results: Results revealed thicker cortices in MTF transsexuals, both within
regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus).

Conclusion: These findings provide further evidence that brain anatomy is associated with gender identity, where measures in MTF transsexuals appear to be shifted away from gender-congruent men.

HOW many sexes?

A comment on Billions of Sexes (Part 1) by Martine Rothblatt, on the Institute for Ethics & Emerging Technologies site

I differ from the author only on emphasis, and degree. However, these differences have important effects.

Let's start with the idea that there are male and female brains. They differ anatomically, and these differences correspond to different stereotyped behaviours, regardless of upbringing. This is most obvious in girls who have CAH, masculinised brains, and a male preference in play patterns, even though they have a normal female upbringing.

Now that we've established that idea, that it's objectively observable.. we have to tear it down. It's just the first step in Wittgenstein's ladder.

The brain is a complex structure, not a simple one. Any particular individual can have a more masculine anatomy in one area, a more feminine anatomy in others. The sexually dimorphic features have considerable overlap. Within any one area, few are unambiguously male or unambiguously female. The difference is statistical. Moreover, in the higher brain, hormonal balance plays a role in changing the brain's physical anatomy. Treat a male with female hormones, some of his brain structures will feminise. The brain is plastic in many areas, experiences and social environment causes physical changes, and much of what we call "gendered behaviour" is as the result of arbitrary socially constructed factors.

OK, understood that? Now discard it, it's the second step on the ladder.

The brain is not homogenous; different parts have different effects, and while some parts are plastic, others are not. While much "gendered behaviour" is a social construct, some is not, and is remarkably resistant to change. This is most obvious in Transsexual people, whose neuro-anatomy is female in some areas, male in others, and corresponds to neither in yet others. When the Lymbic nucleus is feminised, typically feminine emotional patterns are found, and these lead to a feminine gender identity. When the Superior Parietal Lobule (SPL) is feminised as well - as it often is - the "body map" is for female primary and secondary sex characteristics - breasts, vagina etc - and any mismatch with reality causes immense distress.

This also explains such observed phenomena as "phantom limb syndrome", and the widely variable emotional response to hysterectomy or mastectomy. Also too the variable response to any natural masculinisation of a female-at-birth body due to 5ARD or 17BHSD syndromes, which can cause a superficial "natural sex change".

What this means is that a binary model of sex and gender is merely a rough approximation. A better one is a trinary one, with male, female, and bigendered (approximately 1/3 in each category). But that still doesn't capture the multi-variance and fuzziness of the situation adequately. A small percentage won't fit either model, or indeed, any such gross over-simplification.

References (to substantiate my assertions):

Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation. Swaab Gynecol Endocrinol (2004) 19:301–312.

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study. - Rametti et al, J Psychiatr Res. 2010 Jun 8.

Prenatal hormones versus postnatal socialization by parents as determinants of male-typical toy play in girls with congenital adrenal hyperplasia” Pasterski VL, Geffner ME, Brain C, Hindmarsh P, Brook C, Hines M Child Dev 76(1):264-78 2005

Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure by Pol et al, Europ Jnl Endocrinology, Vol 155, suppl_1, S107-S114 2006

Biased-Interaction Theory of Psychosexual Development: “How Does One Know if One is Male or Female?” M.Diamond Sex Roles (2006) 55:589–600

Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Cohen-Kettenis PT. Arch Sex Behav. 2005 Aug;34(4):399-410.

I'm including this as a post because it summarises and encapsulates my conclusions so far. It's a bit more complex than this, but the 3 steps on Wittgenstein's ladder are enough.

The Biology of Sexual Orientation

My family health issues have subsided, though I'm still swamped with teaching and compiling my thesis.

It's been a month without blogging - the longest gap so far. All I can say is that writing up a PhD thesis will do that to you.

Blogging will continue to be light, but at least won't be non-existent. Hopefully things will be back to normal before Christmas.

In the meantime, for your edification and enjoyment, The Biology of Sexual Orientation - a presentation in 9 parts.

Part I: Introduction:


Part II: Biological Concepts


Part III: A Scientific Approach


Part IV: Family Studies and Birth Order


Part V: Molecular Studies


Part VI: A Neurohormonal Model


Part VII: Functional Cerebral Asymmetry


Part VIII: Hypothalamic Activation


Part IX: Conclusion

Sex on the brain

From New Scientist : Sex on the brain: What turns women on, mapped out

It's what women have been telling men for decades: stimulating the vagina is not the same as stimulating the clitoris. Now brain scan data has added weight to their argument.

The precise locations that correspond to the vagina, cervix and female nipples on the brain's sensory cortex have been mapped for the first time, proving that vaginal stimulation activates different brain regions to stimulation of the clitoris. The study also found a direct link between the nipples and the genitals, which may explain why some women can orgasm through nipple stimulation alone.
...
Some have argued that women who derive pleasure from vaginal stimulation do so because their clitoris is being indirectly stimulated, but the current findings contradict this. "They support the reports of women that they experience orgasm from various forms of stimulation," says Beverly Whipple, also of Rutgers University, who was not involved in the current study.

Komisaruk also checked what happened when women's nipples were stimulated, and was surprised to find that in addition to the chest area of the cortex lighting up, the genital area was also activated. "When I tell my male neuroscientist colleagues about this, they say: 'Wow, that's an exception to the classical homunculus,'" he says. "But when I tell the women they say: 'Well, yeah?'" It may help explain why a lot of women claim that nipple stimulation is erotic, he adds.

Something that tends to cheese women off : having male doctors tell them what they must be feeling, when said male doctors have no actual evidence to back up what they say.

Next time, believe her, OK doc? Because the MRI images show that your arrogant ideas aren't actually true, as any woman could have told you - and female medical professionals probably did, you just ignored them.

On a personal note, it's obvious my neural anatomy (in this area at least) is strongly female, and always has been. It's good to have the peripherals match the device drivers at last. That's all I'm saying on the subject.

Simon Lewis: Don't take consciousness for granted

Simon Lewis: Don't take consciousness for granted

After a catastrophic car accident that left him in a coma, Simon Lewis found ways to recover -- physically and mentally -- beyond all expectations. At the INK Conference he tells how this remarkable story led him to concern over all threats to consciousness, and how to overcome them.

More Parts of the Puzzle- Grey Matter

Prenatal Exposure to Female Hormones: Effect on Psychosexual Development in Boys Arch Gen Psychiatry, April 1973, Yalom et al. 28 (4): 554 :

Two groups of boys exposed prenatally to exogenously administered estrogen and progesterone were studied on several parameters of psychosexual development. Subjects were twenty 6-year-olds and twenty 16-year-olds whose diabetic mothers received these hormones to prevent pregnancy complication. Hormone-exposed boys were compared with same-aged boys whose mothers had not received exogenous hormones and matched for age and socioeconomic class.

Sixteen-year-olds exposed to estrogen and progesterone were rated lower on several variables related to general "masculinity," assertiveness and athletic ability. Six-year-olds exposed to estrogen and progesterone were rated lower on aggressivity and athletic ability. There were two cases of hypospadias among experimental subjects. While it was not possible to rule out influences other than hormonal which may have influenced results, data suggest that prenatal sex hormone levels may influence some aspects of postnatal psychosexual development in boys.

From mygenes.co.nz, a non-peer-reviewed religious site, that nonetheless at least gives its references:Are transssexual brains different?:

The answer is probably yes, but not because of innateness. The altered brain microstructure is probably due to years of repetitive thinking, fantasy and preoccupation with body image.

Thereby ignoring the work by Yalom above, and others.

However the results of studies on transsexuals may be better established than those on homosexual people showing somewhat more reproducible differences in the brains, though still with large overlap. This note argues these differences can be explained by preoccupied thinking and imagination alone.

Recently a paper by Savic and Arver (Savic and Arver, 2011) has appeared. Their innovation is to take a study group composed only of male-to-female gynephiles (i.e. those attracted sexually to women). Previous male-to-female studies mixed gynephiles and androphiles. The authors find that the brains in their study group were not feminised. There was no evidence for female brains in a male body; the brains were male-typical. This is contrary to many of the previous research studies on mixed groups, but the study is thorough. They also found that there were differences in the brains of their study groups which were not found in either heterosexual male or female brains. These regions have been identified as those possibly associated with bodily self-perception (they are also enlarged in those who do lots of meditation, focusing partly on body state).

The authors say this is a “highly speculative” interpretation, but it’s possible they are actually underestimating how much support it has. It is very clear that repeated patterns of mental exercise alone, as seen for example in navigation (London taxi drivers) and internet addiction (Maguire et al. 2006; Zhou et al. 2009) changes significantly the microstructure of the brain. Thinking, particularly repeated thinking, changes brain microstructure.

OK, let's look at these papers. First the Macguire paper, London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Maguire, E.A., Woollett, K. and Spiers, H.J. (2006) Hippocampus 16, 1091-101.

Licensed London taxi drivers show that humans have a remarkable capacity to acquire and use knowledge of a large complex city to navigate within it. Gray matter volume differences in the hippocampus relative to controls have been reported to accompany this expertise. While these gray matter differences could result from using and updating spatial representations, they might instead be influenced by factors such as self-motion, driving experience, and stress. We examined the contribution of these factors by comparing London taxi drivers with London bus drivers, who were matched for driving experience and levels of stress, but differed in that they follow a constrained set of routes. We found that compared with bus drivers, taxi drivers had greater gray matter volume in mid-posterior hippocampi and less volume in anterior hippocampi. Furthermore, years of navigation experience correlated with hippocampal gray matter volume only in taxi drivers, with right posterior gray matter volume increasing and anterior volume decreasing with more navigation experience. This suggests that spatial knowledge, and not stress, driving, or self-motion, is associated with the pattern of hippocampal gray matter volume in taxi drivers. We then tested for functional differences between the groups and found that the ability to acquire new visuo-spatial information was worse in taxi drivers than in bus drivers. We speculate that a complex spatial representation, which facilitates expert navigation and is associated with greater posterior hippocampal gray matter volume, might come at a cost to new spatial memories and gray matter volume in the anterior hippocampus.

OK, so we're talking about the hippocampus, and only the hippocampus. Furyhermore, we're only looking at grey matter distribution within that particular part of the brain.

Now let's look at the Zhou paper : Gray matter abnormalities in Internet addiction: A voxel-based morphometry study. Zhou et al, Eur J Radiol. 2011 Jul;79(1):92-5. :

BACKGROUND:This study aims to investigate brain gray matter density (GMD) changes in adolescents with Internet addiction (IA) using voxel-based morphometry (VBM) analysis on high-resolution T1-weighted structural magnetic resonance images.

METHODS:Eighteen IA adolescents and 15 age- and gender-matched healthy controls took part in this study. High-resolution T1-weighted magnetic resonance imaging scans were performed on the two groups. VBM analysis was used to compare the GMD between the two groups.

RESULTS:Compared with healthy controls, IA adolescents had lower GMD in the left anterior cingulate cortex, left posterior cingulate cortex, left insula, and left lingual gyrus.

CONCLUSIONS: Our findings suggested that brain structural changes were present in IA adolescents, and this finding may provide a new insight into the pathogenesis of IA.

This time, we're looking at other parts of the brain : the left anterior cingulate cortex, left posterior cingulate cortex, left insula, and left lingual gyrus. And again, only grey matter distribution.

I've blogged about the Savic paper before, and that post is worth re-visiting.

MtF-TR 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.

I'll add another paper to the mix : Regional gray matter variation in male-to-female transsexualism. by Luders et al Neuroimage. 2009 Jul 15;46(4):904-7.

Results revealed that regional gray matter variation in MTF transsexuals is more similar to the pattern found in men than in women. However, MTF transsexuals show a significantly larger volume of regional gray matter in the right putamen compared to men.

Altogether, females had the largest gray matter volumes in all but two significant clusters, which were located in the left and right putamen. Here, MTF transsexuals had the largest gray matter volumes (see Fig. 1). For the remaining clusters, MTF transsexuals had the smallest gray matter volumes, but their data spectrum largely overlapped with that of males.

OK, let's put this in a table:\

Organ	hippocampus	Left cingulate cortex	Left Insula	Left lingual gyrus	thalamus	putamen	Right insula	Inferior frontal cortex	Right angular gyrus
London Taxi Drivers	+ Posterior - Anterior	no data	no data	no data	no data	no data	no data	no data	no data
Japanese Internet Addicts	no data	-	-	-	no data	no data	no data	no data	no data
MtoF Luders	no data	no data	no data	no data	no data	+	no data	no data	no data
MtoF Savic	no data	no data	no data	no data	no data	no data	+	+	+

What conclusions can we draw from this, in terms of cause and effect? Well, the London Taxi Driver paper is pretty good evidence of neuroplaticity at work. The ratio of grey matter in the hippocampus changes as the result of repeated actions and thoughts. This is only to be expected, as the hippocampus is both one of the simplest neurological structures, and also known to be associated with laying down long-term memory. Total amount doesn't change, but distribution changes.

Regarding the Japanese Intersex Internet Addicts... we can't be sure. Is it that having a particular neurological structure makes one susceptible to Internet Addiction (whatever that may be, the definition isn't agreed upon). Or does Internet Addiction cause neurological changes in distribution of grey matter in specific areas? Moreover, we're talking about a decrease in grey matter, not an increase.

In both these cases, the repetitive physical and mental actions occur for significant periods of the day, totalling half the waking hours or more. It's difficult imagining what repetitive action is involved in being MtoF, male or female for that matter.

In summary, the case for neuroplasticity as regards grey matter distribution is very strong. As regards grey matter total, less strong, but still stronger than I'd thought in certain areas. Regarding the putamen though, very weak or non-existent.

Sexual differentiation of human behavior: Effects of prenatal and pubertal organizational hormones

Sexual differentiation of human behavior: Effects of prenatal and pubertal organizational hormones Sheri A. Berenbaum, Adriene M. Beltz Frontiers in Neuroendocrinology 32 (2011) 183–200

A key question concerns the extent to which sexual differentiation of human behavior is influenced by sex hormones present during sensitive periods of development (organizational effects), as occurs in other mammalian species. The most important sensitive period has been considered to be prenatal, but there is increasing attention to puberty as another organizational period, with the possibility of decreasing sensitivity to sex hormones across the pubertal transition. In this paper, we review evidence that sex hormones present during the prenatal and pubertal periods produce permanent changes to behavior.
There is good evidence that exposure to high levels of androgens during prenatal development results in masculinization of activity and occupational interests, sexual orientation, and some spatial abilities; prenatal androgens have a smaller effect on gender identity, and there is insufficient information about androgen effects on sex-linked behavior problems. There is little good evidence regarding long-lasting behavioral effects of pubertal hormones, but there is some suggestion that they influence gender identity and perhaps some sex-linked forms of psychopathology, and there are many opportunities to study this issue.

TLDR version - it's complicated. Here, let me give an example:

Sex matters for human behavior as it does for behavior in other species. Human males and females differ in many ways, including their appearance, their social identity, their social partners, the activities that interest them, how they present themselves to others, their aspirations and values, the likelihood of experiencing psychological and physical health problems, and the specific form in which those problems are manifested (reviewed in [20]). A key question concerns the causes of those differences, particularly the ways in which they are shaped by genes, physiology, and socialization.
The focus of this paper – in line with the other papers in this special issue of Frontiers of Neuroendocrinology – concerns the extent to which human behavioral sex differences are influenced by sex hormones present during sensitive periods of development acting to organize the brain.
More than 50 years ago, Phoenix et al. [130] provided an experimental demonstration in female guinea pigs that early exposure to androgens masculinized sexual behavior. This revolutionary work opened a new era in understanding sexual differentiation of behavior and led to thousands of studies in many species showing
unequivocally that sex hormones present early in development affect sexual differentiation of behavior as well as reproductive anatomy and function [166]. These hormones are said to have ‘‘organizational’’ effects because they produce permanent changes to brain structures and the behaviors they subserve. They are contrasted with ‘‘activational’’ effects, that is, hormones acting later in life to produce temporary alterations to the brain and behavior (through ongoing changes to neural circuitry) as the hormones circulate in the body throughout adolescence and adulthood. The main distinctions between organizational and activational effects concern timing and permanence, although these distinctions are not absolute [3].
Organizational effects have generally been considered to occur early in life when the brain is undergoing rapid change, but there has always been consideration of potential other sensitive periods of brain development when sex hormones again act to induce permanent changes [166].
Recent work in nonhuman animals has focused attention on other particular periods when there are substantial – and relatively abrupt – changes in levels of sex hormones, and that might serve as additional opportunities for hormones to sculpt brain structure: puberty and pregnancy (e.g., [91,149]). In this paper, we consider how human psychological sex differences are influenced by organizational hormones during prenatal development and again during puberty. We consider the foundations of the work, the methods used to study the question, the evidence that prenatal and pubertal hormones produce longterm behavioral changes, and directions for future research.

[20] J.E.O. Blakemore, S.A. Berenbaum, L.S. Liben, Gender Development, Psychology Press/Taylor & Francis, New York, 2009.
[91] C.H. Kinsley, L. Madonia, G.W. Gifford, K. Tureski, G.R. Griffin, C. Lowry, J. Williams, J. Collins, H. McLearie, K.G. Lambert, Motherhood improves learning and memory: neural activity in rats is enhanced by pregnancy and the demands of rearing offspring, Nature 402 (1999) 137–138.
[130] C.H. Phoenix, R.W. Goy, A.A. Gerall, W.C. Young, Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig, Endocrinology 65 (1959) 369–382.
[149] C.L. Sisk, J.L. Zehr, Pubertal hormones organize the adolescent brain and behavior, Front. Neuroendocrinol. 26 (2005) 163–174.
[166] K. Wallen, The organizational hypothesis: reflections on the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young (1959), Horm. Behav. 55
(2009) 561–565.

So far, so good. Relatively simple. But when you get further into it...

Data confirming the importance of pubertal hormones in gender identity comes from outcome studies of children with gender identity disorder, showing that the majority develop gender typical identity in adolescence and adulthood, although many continue to display sex-atypical characteristics. An early study of extremely feminine boys showed that most developed a homosexual orientation without gender dysphoria [64]. Two recent studies confirm that most children with gender dysphoria do not remain dysphoric after puberty. In one follow-up study of girls with gender identity disorder in childhood, only 12% were found to have gender dysphoria in adulthood; most developed a heterosexual orientation without gender dysphoria, although there were elevated rates of nonheterosexual orientation [48]. In another study of boys and girls with gender dysphoria in childhood, 27% of boys and 64% of girls were still gender dysphoric, and most had nonheterosexual orientation [167]. Both studies showed evidence of a ‘‘dosage’’ effect: children with more childhood cross-sex behavior or gender dysphoria were more likely to be gender dysphoric at follow up.
(This may explain why girls were more likely than boys in the second study to persist in dysphoria; they probably had to be more extreme to receive a diagnosis in the first place.) Additional evidence for the importance of puberty in gender identity comes from data showing reduced plasticity with age: individuals diagnosed with gender identity disorder in adolescence are more likely than those diagnosed in childhood to have persistent dysphoria into adulthood [172].
Nevertheless, testosterone at puberty is not essential for male gender identity. There are cases of male gender identity in individuals with male-typical chromosomes and prenatal androgen exposure who were castrated in early life and reared as girls because of genital defects (such as cloacal exstrophy or penile ablation [44,111,133]). Some typical girls develop gender dysphoria or male identity at puberty without any obvious exposure to testosterone [174].

[44] M. Diamond, H.K. Sigmundson, Sex reassignment at birth: long-term review and clinical implications, Arch. Pediatr. Adolesc. Med. 151 (1997) 298–304
[48] K.D. Drummond, S.J. Bradley, M. Peterson-Badali, K.J. Zucker, A follow-up study of girls with gender identity disorder, Dev. Psychol. 44 (2008) 34–45
[64] R. Green, The ‘‘Sissy Boy Syndrome’’ and the Development of Homosexuality, Yale University Press, New Haven, CT, 1987.
[111] H.F.L. Meyer-Bahlburg, Gender identity outcome in female-raised 46,XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation, Arch. Sex. Behav. 34 (2005) 423–438.
[133] W.G. Reiner, J.P. Gearhart, Discordant sexual identity in some genetic males with cloacal exstrophy assigned to female sex at birth, New Engl. J. Med. 350 (2004) 333–341.
[167] M.S. Wallien, P.T. Cohen-Kettenis, Psychosexual outcome of gender-dysphoric children, J. Am. Acad. Child Adolesc. Psychiat. 47 (2008) 1413–1423.
[172] K.J. Zucker, Gender identity development and issues, Child Adolesc. Psychiat. Clin. N. Am. 13 (2004) 551–568.
[174] K.J. Zucker, S.J. Bradley, Gender Identity Disorder and Psychosexual Problems in Children and Adolescents, Guilford, New York, 1995.

Paper [48] is flawed because the definition of "Gender Dysphoria" was far too relaxed; few met the actual criteria, and many were Intersex. Paper [64] is currently enmeshed in the controversy about the aversion therapy techniques used at UCLA - torturing children, basically - and the revelation that much of George Reckers work there was grossly flawed or even fraudulent. Green seems to have taken a second look at the subject though, to try to report on the actual situation rather than one seen through ultra-conservative fundamentalist eyes.

Doing good Science is hard enough without such complications, especially in an area so complex.

Summary: Post-natal hormones do have an effect on gender identity. Sometimes. Not always. And pre-natal hormones have an effect on gender identity. Sometimes. Possibly always. And it's dosage-dependant, and associated with other neural circuitry (usually) and sexual orientation (sometimes). I'd quote more, but I'm already close to the limits of "fair use" of a copyrighted article.

Yes, I'd like it to be nice and simple, a binary, boy brain or girl brain, always set before birth, not mutable in the slightest afterwards... but that's not what the evidence says.

I suppose this should have been obvious to me. Picking the name "Zoe" at age 10 (establishing gender identity well before puberty). Feeling my brain re-wire, the increased sense of smell, the acquisition of a sexual orientation etc in 2005-2006, some effects long before HRT, and due to a female hormone balance. The male-typical play patterns in my childhood, just to make things even more obscure, I was anything but a "sissy boy" - yet my emotional responses were female, even as a child.

It's complicated.