Testosterone metabolization, autism, male brain, and female identity

I began this post intending to write about testosterone metabolization in autism and possible connections with transgender identity, but realized halfway through that I didn’t actually know whether the autist-trans connection was primarily male-to-female or female-to-male. I had assumed that the relevant population is primarily MtF because both autists and trans people are primarily male, but both groups do have female populations that are large enough to contribute significantly. Here’s a sample of the data I’ve found so far:

A study conducted by a team of British scientists in 2012 found that of a pool of individuals not diagnosed on the autism spectrum, female-to-male (FTM) transgender people have higher rates of autistic features than do male-to-female (MTF) transgender people or cisgender males and females. Another study, which looked at children and adolescents admitted to a gender identity clinic in the Netherlands, found that almost 8 percent of subjects were also diagnosed with ASD.

Note that both of these studies are looking at trans people and assessing whether or not they have autism symptoms, not looking at autists and asking if they have trans symptoms. Given the characterization of autism as “extreme male brain” and that autism is diagnosed in males at about 4x the rate of females, the fact that there is some overlap between “women who think they think like men” and “traits associated with male thought patterns” is not surprising.

If the reported connection between autism and trans identity is just “autistic women feel like men,” that’s pretty non-mysterious and I just wasted an afternoon.

Though the data I have found so far still does not look directly at autists and ask how many of them have trans symptoms, the wikipedia page devoted to transgender and transsexual computer programmers lists only MtFs and no FtMs. Whether this is a pattern throughout the wider autism community, it definitely seems to be a thing among programmers. (Relevant discussion.)

So, returning to the original post:

Autism contains an amusing contradiction: on the one hand, autism is sometimes characterized as “extreme male brain,” and on the other hand, (some) autists (may be) more likely than neurotypicals to self-identify as transwomen–that is, biological men who see themselves as women. This seems contradictory: if autists are more masculine, mentally, than the average male, why don’t they identify as football players, army rangers, or something else equally masculine? For that matter, why isn’t a group with “extreme male brains” regarded as more, well, masculine?

(And if autists have extreme male brains, does that mean football players don’t? Do football players have more feminine brains than autists? Do colorless green ideas sleep furiously? DO WORDS MEAN?)

*Ahem*

In favor of the “extreme male brain” hypothesis, we have evidence that testosterone is important for certain brain functions, like spacial recognition, we have articles like this one: Testosterone and the brain:

Gender differences in spatial recognition, and age-related declines in cognition and mood, point towards testosterone as an important modulator of cerebral functions. Testosterone appears to activate a distributed cortical network, the ventral processing stream, during spatial cognition tasks, and addition of testosterone improves spatial cognition in younger and older hypogonadal men. In addition, reduced testosterone is associated with depressive disorders.

(Note that women also suffer depression at higher rates than men.)

So people with more testosterone are better at spacial cognition and other tasks that “autistic” brains typically excel at, and brains with less testosterone tend to be moody and depressed.

But hormones are tricky things. Where do they come from? Where do they go? How do we use them?

According to Wikipedia:

During the second trimester [of pregnancy], androgen level is associated with gender formation.^[13] This period affects the femininization or masculinization of the fetus and can be a better predictor of feminine or masculine behaviours such as sex typed behaviour than an adult’s own levels. A mother’s testosterone level during pregnancy is correlated with her daughter’s sex-typical behavior as an adult, and the correlation is even stronger than with the daughter’s own adult testosterone level.^[14]

… Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–6 months of age.^[15][16] The function of this rise in humans is unknown. It has been theorized that brain masculinization is occurring since no significant changes have been identified in other parts of the body.^[17] The male brain is masculinized by the aromatization of testosterone into estrogen, which crosses the blood–brain barrier and enters the male brain, whereas female fetuses have α-fetoprotein, which binds the estrogen so that female brains are not affected.^[18]

(Bold mine.)

Let’s re-read that: the male brain is masculinized by the aromatization of testosterone into estrogen.

If that’s not a weird sentence, I don’t know what is.

Let’s hop over to the scientific literature, eg, Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines:

Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry.

Hypothesis: the way testosterone works in the brain (where we both do math and “feel” male or female) and the way it works in the muscles might be very different.

Do autists actually differ from other people in testosterone (or other hormone) levels?

In Elevated rates of testosterone-related disorders in women with autism spectrum conditions, researchers surveyed autistic women and mothers of autistic children about various testosterone-related medical conditions:

Compared to controls, significantly more women with ASC [Autism Spectrum Conditions] reported (a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle, (d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g) epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and prostate cancers, tumors, or growths. Compared to controls, significantly more mothers of ASC children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths.

Androgenic Activity in Autism has an unfortunately low number of subjects (N=9) but their results are nonetheless intriguing:

Three of the children had exhibited explosive aggression against others (anger, broken objects, violence toward others). Three engaged in self-mutilations, and three demonstrated no aggression and were in a severe state of autistic withdrawal. The appearance of aggression against others was associated with having fewer of the main symptoms of autism (autistic withdrawal, stereotypies, language dysfunctions).

Three of their subjects (they don’t say which, but presumably from the first group,) had abnormally high testosterone levels (including one of the girls in the study.) The other six subjects had normal androgen levels.

This is the first report of an association between abnormally high androgenic activity and aggression in subjects with autism. Although a previously reported study did not find group mean elevations in plasma testosterone in prepubertal autistic subjects (4), it appears here that in certain autistic individuals, especially those in puberty, hyperandrogeny may play a role in aggressive behaviors. Also, there appear to be distinct clinical forms of autism that are based on aggressive behaviors and are not classified in DSM-IV. Our preliminary findings suggest that abnormally high plasma testosterone concentration is associated with aggression against others and having fewer of the main autistic symptoms.

So, some autists have do have abnormally high testosterone levels, but those same autists are less autistic, overall, than other autists. More autistic behavior, aggression aside, is associated with normal hormone levels. Probably.

But of course that’s not fetal or early infancy testosterone levels. Unfortunately, it’s rather difficult to study fetal testosterone levels in autists, as few autists were diagnosed as fetuses. However, Foetal testosterone and autistic traits in 18 to 24-month-old children comes close:

Levels of FT [Fetal Testosterone] were analysed in amniotic fluid and compared with autistic traits, measured using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in 129 typically developing toddlers aged between 18 and 24 months (mean ± SD 19.25 ± 1.52 months). …

Sex differences were observed in Q-CHAT scores, with boys scoring significantly higher (indicating more autistic traits) than girls. In addition, we confirmed a significant positive relationship between FT levels and autistic traits.

I feel like this is veering into “we found that boys score higher on a test of male traits than girls did” territory, though.

In Polymorphisms in Genes Involved in Testosterone Metabolism in Slovak Autistic Boys, researchers found:

The present study evaluates androgen and estrogen levels in saliva as well as polymorphisms in genes for androgen receptor (AR), 5-alpha reductase (SRD5A2), and estrogen receptor alpha (ESR1) in the Slovak population of prepubertal (under 10 years) and pubertal (over 10 years) children with autism spectrum disorders. The examined prepubertal patients with autism, pubertal patients with autism, and prepubertal patients with Asperger syndrome had significantly increased levels of salivary testosterone (P < 0.05, P < 0.01, and P < 0.05, respectively) in comparison with control subjects. We found a lower number of (CAG)_n repeats in the AR gene in boys with Asperger syndrome (P < 0.001). Autistic boys had an increased frequency of the T allele in the SRD5A2 gene in comparison with the control group. The frequencies of T and C alleles in ESR1 gene were comparable in all assessed groups.

What’s the significance of CAG repeats in the AR gene? Apparently they vary inversely with sensitivity to androgens:

Individuals with a lower number of CAG repeats exhibit higher AR gene expression levels and generate more functional AR receptors increasing their sensitivity to testosterone…

Fewer repeats, more sensitivity to androgens. The SRD5A2 gene is also involved in testosterone metabolization, though I’m not sure exactly what the T allele does relative to the other variants.

But just because there’s a lot of something in the blood (or saliva) doesn’t mean the body is using it. Diabetics can have high blood sugar because their bodies lack the necessary insulin to move the sugar from the blood, into their cells. Fewer androgen receptors could mean the body is metabolizing testosterone less effectively, which in turn leaves more of it floating in the blood… Biology is complicated.

What about estrogen and the autistic brain? That gets really complicated. According to Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism:

Here, we show that male and female hormones differentially regulate the expression of a novel autism candidate gene, retinoic acid-related orphan receptor-alpha (RORA) in a neuronal cell line, SH-SY5Y. In addition, we demonstrate that RORA transcriptionally regulates aromatase, an enzyme that converts testosterone to estrogen. We further show that aromatase protein is significantly reduced in the frontal cortex of autistic subjects relative to sex- and age-matched controls, and is strongly correlated with RORA protein levels in the brain.

If autists are bad at converting testosterone to estrogen, this could leave extra testosterone floating around in their blood… but doens’t explain their supposed “extreme male brain.” Here’s another study on the same subject, since it’s confusing:

Comparing the brains of 13 children with and 13 children without autism spectrum disorder, the researchers found a 35 percent decrease in estrogen receptor beta expression as well as a 38 percent reduction in the amount of aromatase, the enzyme that converts testosterone to estrogen.

Levels of estrogen receptor beta proteins, the active molecules that result from gene expression and enable functions like brain protection, were similarly low. There was no discernable change in expression levels of estrogen receptor alpha, which mediates sexual behavior.

I don’t know if anyone has tried injecting RORA-deficient mice with estrogen, but here is a study about the effects of injecting reelin-deficient mice with estrogen:

The animals in the new studies, called ‘reeler’ mice, have one defective copy of the reelin gene and make about half the amount of reelin compared with controls. …

Reeler mice with one faulty copy serve as a model of one of the most well-established neuro-anatomical abnormalities in autism. Since the mid-1980s, scientists have known that people with autism have fewer Purkinje cells in the cerebellum than normal. These cells integrate information from throughout the cerebellum and relay it to other parts of the brain, particularly the cerebral cortex.

But there’s a twist: both male and female reeler mice have less reelin than control mice, but only the males lose Purkinje cells. …

In one of the studies, the researchers found that five days after birth, reeler mice have higher levels of testosterone in the cerebellum compared with genetically normal males³.

Keller’s team then injected estradiol — a form of the female sex hormone estrogen — into the brains of 5-day-old mice. In the male reeler mice, this treatment increases reelin levels in the cerebellum and partially blocks Purkinje cell loss. Giving more estrogen to female reeler mice has no effect — but females injected with tamoxifen, an estrogen blocker, lose Purkinje cells. …

In another study, the researchers investigated the effects of reelin deficiency and estrogen treatment on cognitive flexibility — the ability to switch strategies to solve a problem⁴. …

“And we saw indeed that the reeler mice are slower to switch. They tend to persevere in the old strategy,” Keller says. However, male reeler mice treated with estrogen at 5 days old show improved cognitive flexibility as adults, suggesting that the estrogen has a long-term effect.

This still doesn’t explain why autists would self-identify as transgender women (mtf) at higher rates than average, but it does suggest that any who do start hormone therapy might receive benefits completely independent of gender identity.

Let’s stop and step back a moment.

Autism is, unfortunately, badly defined. As the saying goes, if you’ve met one autist, you’ve met one autist. There are probably a variety of different, complicated things going on in the brains of different autists simply because a variety of different, complicated conditions are all being lumped together under a single label. Any mental disability that can include both non-verbal people who can barely dress and feed themselves and require lifetime care and billionaires like Bill Gates is a very badly defined condition.

(Unfortunately, people diagnose autism with questionnaires that include questions like “Is the child pedantic?” which could be equally true of both an autistic child and a child who is merely very smart and has learned more about a particular subject than their peers and so is responding in more detail than the adult is used to.)

The average autistic person is not a programmer. Autism is a disability, and the average diagnosed autist is pretty darn disabled. Among the people who have jobs and friends but nonetheless share some symptoms with formally diagnosed autists, though, programmer and the like appear to be pretty popular professions.

Back in my day, we just called these folks nerds.

Here’s a theory from a completely different direction: People feel the differences between themselves and a group they are supposed to fit into and associate with a lot more strongly than the differences between themselves and a distant group. Growing up, you probably got into more conflicts with your siblings and parents than with random strangers, even though–or perhaps because–your family is nearly identical to you genetically, culturally, and environmentally. “I am nothing like my brother!” a man declares, while simultaneously affirming that there is a great deal in common between himself and members of a race and culture from the other side of the planet. Your  coworker, someone specifically selected for the fact that they have similar mental and technical aptitudes and training as yourself, has a distinct list of traits that drive you nuts, from the way he staples papers to the way he pronounces his Ts, while the women of an obscure Afghan tribe of goat herders simply don’t enter your consciousness.

Nerds, somewhat by definition, don’t fit in. You don’t worry much about fitting into a group you’re not part of in the fist place–you probably don’t worry much about whether or not you fit in with Melanesian fishermen–but most people work hard at fitting in with their own group.

So if you’re male, but you don’t fit in with other males (say, because you’re a nerd,) and you’re down at the bottom of the highschool totem pole and feel like all of the women you’d like to date are judging you negatively next to the football players, then you might feel, rather strongly, the differences between you and other males. Other males are aggressive, they call you a faggot, they push you out of their spaces and threaten you with violence, and there’s very little you can do to respond besides retreat into your “nerd games.”

By contrast, women are polite to you, not aggressive, and don’t aggressively push you out of their spaces. Your differences with them are much less problematic, so you feel like you “fit in” with them.

(There is probably a similar dynamic at play with American men who are obsessed with anime. It’s not so much that they are truly into Japanese culture–which is mostly about quietly working hard–as they don’t fit in very well with their own culture.) (Note: not intended as a knock on anime, which certainly has some good works.)

And here’s another theory: autists have some interesting difficulties with constructing categories and making inferences from data. They also have trouble going along with the crowd, and may have fewer “mirror neurons” than normal people. So maybe autists just process the categories of “male” and “female” a little differently than everyone else, and in a small subset of autists, this results in trans identity.*

And another: maybe there are certain intersex disorders which result in differences in brain wiring/organization. (Yes, there are real interesx disorders, like Klinefelter’s, in which people have XXY chromosomes instead of XX or XY.) In a small set of cases, these unusually wired brains may be extremely good at doing certain tasks (like programming) resulting people who are both “autism spectrum” and “trans”. This is actually the theory I’ve been running with for years, though it is not incompatible with the hormonal theories discussed above.

But we are talking small: trans people of any sort are extremely rare, probably on the order of <1/1000. Even if autists were trans at 8 times the rates of non-autists, that’s still only 8/1000 or 1/125. Autists themselves are pretty rare (estimates vary, but the vast majority of people are not autistic at all,) so we are talking about a very small subset of a very small population in the first place. We only notice these correlations at all because the total population has gotten so huge.

Sometimes, extremely rare things are random chance.