Bizarre Things Purported to Cause Autism: Hormonal Contraceptives

EXECUTIVE SUMMARY: An article published last winter in Medical Hypotheses suggests that long-term use of hormonal contraceptives might raise the likelihood of one's future children being born autistic. There is no good reason to believe this; the only things the article offers as potential reasons for it are 1) a very tenuous temporal relationship between widespread contraceptive use and a later (much later) rise in autism prevalence; 2) a misinterpreted bit of information largely pertaining to fertility testing; and 3) "What If?" scenarios involving epigenetics. I am worried about potential political fallout, to the further detriment of children and teenagers' sex education in the US, should this idea be uncritically popularized.
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Of all the myriad forms anti-feminist backlash can take, anti-contraceptive fearmongering is probably the most irritating to me.

So when I stumbled across this appalling article in Medical Hypotheses while I was casting about for items to populate my list of proposed causes of autism, I knew I would have to write a post specifically addressing this one.

The author, Kim Strifert, says that it may be possible that taking combined oral contraceptives (the ones that include both an estrogen, typically ethinyl estradiol, and a progestin, like levonorgestrel, norethindrone, or any of these others) over a long period* of time can change the conditions inside the ova and perhaps trigger epigenetic modification of genomic DNA.

I'd love to go into more detail about how this is supposed to work, but I can't, because no such detail is provided in the article:

Given the lack of research on the effects of oral contraceptive use on progeny, it is impossible at this point to specify a mechanistic link between oral contraceptives and autism. This fact represents a meaningful limitation to the hypothesis presented in this review. However, recent research already suggests that the current understanding of the pharmacology of oral contraceptives may be over-simplified. It has been proposed, for example, that epigenetic side-effects of pharmaceuticals may be involved in the etiology of cancer, heart disease, neurological and cognitive disorders, obesity, infertility, and sexual dysfunction [7][PDF]. It has also been suggested that epigenetic assays be incorporated into the safety assessment of all pharmaceutical drugs, which might lead to new mechanistic insights in the future [7]. Finally, new evidence is emerging that oral contraceptive use directly and deleteriously affects both the ovaries and the ova [8]. Thus, we are at a point where some concrete mechanistic hypotheses may be achievable in the near future.

What she does offer in support of her hypothesis is summarized here:

• Temporal correlation between use of oral contraceptives and increased prevalence of ASD.

• To date no definitive cause or contributing factors for increase in ASD prevalence has been established.

• Oral contraceptives disrupt the endocrine system -- COC's are endocrine disruptors.

• Oral contraceptives directly and deleteriously affect both the ovaries and ova.

• Likely effects of oral contraceptives on progeny are an open question.

• The called-for [by Dr. Roy Hertz**] further study and controlled follow-up of the possible transgenerational effects of oral contraceptive use has not been executed.

I will address these one at a time.

The first bullet point, the temporal correlation between use of oral contraceptives and autism prevalence, is true enough, but there are temporal correlations between lots of unrelated things. There's a whole mess of 'em archived for educational and comedic effect at Tyler Vigen's website Spurious Correlations. A cursory look at that website should be all the explanation you need of why this is not very good evidence that the two variables actually have anything to do with one another.

And even if we ignore that aspect of it, the time frames of the two trends -- increasing oral contraceptive use over time and increasing prevalence of autism over time -- don't quite overlap the way we would expect them to if there really were any sort of cause-and-effect relationship between them.

If there were such a relationship, we would expect a graph showing autism prevalence rates to be sort of a muted echo of a graph showing oral contraceptive use -- lower numbers overall, and trailing by maybe 5-10 years, but roughly the same shape, with peaks corresponding to peaks in the contraceptive-use graph.

Instead of that, we see two graphs of very different shapes, with their peaks separated by a much wider margin than would be possible if Strifert's hypothesis were true.

I cannot find comprehensive data on how many women used The Pill for every year between 1960, when it was approved, and now, but I can cobble together enough information from several different places to sketch a rough outline.

A very, very loose sketch of oral contraceptive usage in the US between 1960 and 2010, stitched together from numbers provided by PBS, the CDC (PDF, PDF), the Kaiser Family Foundation and the Guttmacher Institute

I can't vouch for the strictest accuracy of this picture, but the overall shape -- up, up, up, then slowing down, then a dip, then holding steady at about 10 million -- I'm reasonably confident in. 

By way of contrast, here is a graph of autism prevalence rates from 1985 to 2012 that Emily Willingham made:

Autism prevalence, 1985-2012, by Emily Willingham

As you can see, the shapes are very, very, very different! The graph of oral contraceptive use starts shooting upwards immediately, and then slows down its rate of increase, and then hits its peak and flattens out, while the graph of autism prevalence rises very slowly before it finally begins to build up steam. Like a logarithmic vs. an exponential*** curve...

They both trend upward, but other than that, they have little in common.

Even more important than the shape is the timing. Oral contraceptive use seems to hit its peak around the mid-to-late-1970s, while autism prevalence has perhaps not even peaked yet. It has a long, slow rise with what appear to be two inflection points, one around 2001 and another at about 2005.

Twenty-five years is an awfully long lag time between getting on the Pill and having young children. My mom could easily have been taking the Pill in the mid-1970s, and she had me thirty years ago! And I was diagnosed in 1989 or 1990, when the graph of autism prevalence was still hugging the x-axis.

The women making up that first big wave of oral contraceptive users are probably more likely to be the grandmothers of the children making up the present Autism Epidemic than they are to be their mothers.

The second bullet point is not really an argument in support of a causal relationship between contraceptive use and autism in progeny -- it's just saying, "Well, we don't know what causes autism, so why not entertain my idea?"

The third bullet point -- that hormonal contraceptives are endocrine disruptors -- is kind of a tautology. Of course they are endocrine disruptors -- they wouldn't be able to suppress ovulation if they were not.

Pointing out that hormonal contraceptives are endocrine disruptors is about as helpful as running up to someone and announcing that the Tylenol they are about to take will interfere with their body's natural warning system by dulling their sensations of pain. They know that; that is why they're taking the pill in the first place!

Finally, let's return to the first passage I quoted, which is the first mention of bullet point #4, "[o]ral contraceptives directly and deleteriously affect both the ovaries and ova." The source Strifert gives for this statement -- the "new evidence" that is "emerging" -- is this article on the biotechnology news website BioscienceTechnology.com.

What that article says is very different from what Strifert seems to think it says.

Prolonged hormonal contraceptive use does indeed shrink the ovaries, lower the levels of anti-Müllerian hormone in the blood, and reduce the number of ovarian follicles at a certain stage of maturation. Those two things are considered reliable indicators of how many egg cells might be left within the ovary.

(Here is a literature review comparing the relative merits of those two biomarkers)

However, the researchers who discovered this -- Dr. Kathrine Birch Petersen and her team -- do not think these effects are permanent, and are mostly concerned with making sure people getting their fertility tested after just coming off of birth control get an accurate estimate of their ovarian reserves. Dr. Birch Petersen is especially worried that this temporary suppression of ovarian-reserve markers by long-term contraceptive use might mask a naturally low ovarian reserve, something a person wishing to become pregnant would want to know about.

Here she is, quoted in the Bioscience Technology article:

Birch Petersen's team does not believe these changes [decreased ovarian volume, lower AMH levels, lower antral follicle count] are permanent. But as a result of the study, she said, women in the Pre-conceptional Care Program who have been on the contraceptive pill are now advised that their ovaries may look older and smaller, and may possess only a few small antral follicles, with low levels of AMH for a time after stopping. They are told this likely does not affect future fertility for most women. 

But it could matter for women undergoing premature menopause. Naturally diminished ovarian reserves could be masked by the above. It is therefore possible ovarian reserve assessment should be repeated after stopping birth control pills. 

"Worldwide, 160 million women are on the pill," Birch Petersen told Bioscience. "One percent will go into early menopause before the age of 40. The pill can mask the symptoms of early menopause, and this is why women should consider repeating the tests after six months [off the pill], if they have a low ovarian reserve." 

Next up, says Birch Petersen: "To examine what happens with the ovarian reserve parameters after one, three, and six months."

And here is a short press release published last year on the Clinical Endocrinology News website:

Oral contraceptives do more than prevent unwanted pregnancy. They also make it harder to gauge a woman's ovarian reserve, based on data from 833 women aged 19-46 years seen at a single Danish fertility clinic. 

Study findings suggested that an accurate measure of a woman's ovarian reserve can occur only after she has been off an estrogen-containing [oral contraceptive], probably for at least 3 months, Dr. Kathrine Birch Petersen reported at the annual meeting of the European Society of Human Reproduction and Embryology. 

The impact of estrogen-containing OC use on reducing ovarian volume was especially pronounced in women under 30, the reduction increased with longer durations of OC use, and the ability of OC's to mask a woman's actual ovarian reserve was strong enough to potentially conceal a true case of premature ovarian insufficiency, said Dr. Birch Petersen, an ob.gyn. at the Fertility Assessment and Counseling Clinic at Righospitalet in Copenhagen. 

"When we see a woman on an OC with impaired ovarian reserve, we would presume [based on these new findings] that her real ovarian reserve was about 30% higher than what we measure. We would advise her to be retested after she was off her OC for about 3 months," Dr. Birch Petersen said during a press conference before her presentation at the meeting. 

The study included the first women seen at the clinic since it opened in 2011, excluding those who were pregnant or failed to supply adequate information. The cross-sectional cohort included 240 women on estrogen-containing OC and 593 women with natural cycles. 

The analysis focused on three parameters: blood level of anti-Müllerian hormone (AMH), antral follicle count (AFC), and ovarian volume. The multivariate, linear regression analysis adjusted for age, body mass index, smoking, age of maternal menopause, maternal smoking during pregnancy, preterm birth, and duration of OC use. 

The analysis showed that compared with the women with natural cycles, those on an OC had a 19% relative reduction in their average blood level of AMH, a 16% reduction in average AFC, and a 47% relative reduction in average ovarian volume. The women on an OC also had smaller antral follicles. All three differences were statistically significant. 

Seeing an effect from an estrogen-containing OC on all three measures makes sense because of their interrelatedness. The antral follicles produce AMH, and a reduction in antral follicle number as well as size would shrink the ovarian contents and result in reduced volume. These results would not occur in women on a progestin-only OC, she said.

This additional context makes it clear to me that the changes wrought on the ovary by estrogen-containing contraceptives are indeed temporary.

And here is one more thing I wonder -- why autism? Why would the kind of epigenetic interference Strifert seems to be postulating only result in one type of developmental disability? I know autism is a broad category, but still -- why would only development of the nervous system be affected? Why not all aspects of fetal development?

(A cynic's response to that question would be, because autism is the biggest cultural bogeyman with which to threaten prospective parents. See also: the anti-vaccine movement.)

I would not be opposed to any of the further research into contraceptive safety, uterine and ovarian physiology, or potential alternative methods for contraception!

Even though I do not think it likely at all that what she suspects is true, I think that only good could come of additional efforts to develop even safer methods of contraception that work in multiple different ways.

But what I do not want to happen, which I strongly suspect would be a more likely near-term consequence of Strifert's article gaining widespread attention, is for her warnings to be hyperbolized (instead of the question "what is the effect of long-term hormonal contraceptive use on the ova?" it would become the statement "using hormonal contraceptives means that your children will be born with developmental disabilities later on") and be taught to teenagers in sex education classes as yet another reason they should eschew any and all birth control methods. Sex education classes in the US already lie to children about the efficacy of condoms and tell them that total sexual abstinence is the only way to protect themselves, so adding one more lie to the list is hardly unthinkable.

And looking at the path Strifert's ideas have taken into the blogosphere, this impression -- that, far from echoing her call for more research and development of new contraceptive methods and for improved safety of existing methods, the blogs reporting on her article merely urge their readers to eschew hormonal methods of contraception entirely.

The only blog post I could find dealing with this specific article is this one, by Dr. Kelly Brogan, MD, who despite her medical training seems to reject all of modern, conventional medicine in favor of diet and lifestyle changes.

There are other posts that express a similar idea -- that birth control pills can cause autism in one's future children -- but credit a different source and propose a different mechanism by which it happens (usually gut bacteria rather than the epigenetic explanation loosely sketched by Strifert); those blogs are about an even mix of anti-vaccine, alternative medicine blogs that advocate rejection of all conventional medicine and Catholic blogs that reject all methods of contraception except Natural Family Planning and abstinence.

I do not think it is irrelevant that those are the types of the blogs on which this particular Bizarre Autism Hypothesis has appeared.


*Pun intended

**In a 1966 report by the U.S. Food and Drug Administration's Advisory Committee on Obstetrics and Gynecology; that report, physically archived at the University of Michigan, has been digitized and can be viewed online here.

***Or, what is more likely, a logistic curve. Populations cannot grow indefinitely.

Testosterone and Estrogen Have Opposite Effects on Expression of a Gene Thought to be Underexpressed in Autism

Kev at Left Brain/Right Brain linked to this press release describing a new study published last week in PLoS ONE, that builds on several previous studies comparing gene expression in autistic people and their non-autistic siblings.

This study focuses on one gene, RORA, whose product is a steroid hormone receptor that also acts as a transcription factor. Previous studies had identified this gene as one that is expressed to a lesser degree in autistic people than in their non-autistic siblings; two studies compared the amount of mRNA (the product of DNA transcription, which serves as a template for protein synthesis) corresponding to certain genes that was present in cells taken from autistic people and their siblings, while a third study compared levels of DNA methylation (i.e., inactivation; methylated DNA is harder to transcribe) between those two groups. Only the third study mentions RORA, but the other two identify clusters of genes whose products do similar things, and are involved in similar processes, to RORA.

This study looks at the regulation of RORA by steroid hormones; its authors --- Drs. Valerie Hu and Ray-Chang Wu, along with grad students Terawit Sarachana and Minyi Xu --- found that both estrogen and testosterone affect its functioning (as assessed by bathing cultures of cells with solutions of varying strengths of either hormone, and then using qRT-PCR to determine how much RORA mRNA was produced under each condition), and that their effects are directly opposed to one another: testosterone suppresses the transcription of RORA, while estrogen enhances it.

They also found sequences within another gene --- that for aromatase, an enzyme that converts testosterone into estrogen --- that are the same as those making up RORA binding sites in other genes, which indicates that RORA might be involved in regulating the production of aromatase.

Given this, Sarachana and colleagues see the potential for a feedback loop: in the presence of testosterone, RORA is less active, which could mean that less aromatase is produced, which would mean more testosterone accumulates, leading to even more suppression of RORA.

Figure 5, in Sarachana et al., 2011 --- diagram showing the up- or down-regulation of RORA by the steroid hormones estrogen and testosterone, and the regulation of aromatase, and therefore estrogen synthesis, by RORA

(There's also a potential feedback loop involving estrogen, which up-regulates RORA, which up-regulates aromatase, which in turn produces more estrogen).

There was an upper limit to the dose-response effect of either hormone, though: for both, it was the 1-nanomole/L solution that had the strongest effect on RORA transcription, which seems to suggest that at very high concentrations of testosterone, RORA transcription might creep back upward.
Figure 1, in Sarachana et al., 2011; graphs showing the relative amounts of RORA expressed when cells are treated with three different strengths of a solution of either dihydrotestosterone (C) or 17-beta-estradiol (A), and also changes in expression of RORA over time following treatment with 1-nM solution of DHT (D) or estradiol (B)

Given that RORA has already been found to be less active in autistic people than it is in their non-autistic siblings, the suppression of RORA by testosterone provides a possible biological mechanism underpinning the greater prevalence of autism among males than females, and also associations found between higher levels of testosterone exposure in utero and later development of autistic traits.

There is some evidence for this proposed relationship; Sarachana and colleagues also assayed(post-mortem) brain tissue from autistic (n = 12) and non-autistic donors (n = 22), measuring both RORA and aromatase levels by immunofluorescence. They found two things that would tend to support their low RORA --> low aromatase --> more testosterone hypothesis: RORA is indeed present in smaller amounts in the brain tissue from autistic donors, and aromatase levels are strongly correlated with RORA levels in all the brains that were analyzed.
Figure 4A, in Sarachana et al., 2011; comparison between representative samples of brain tissue labeled to show either RORA (red) or aromatase (blue) expression. The top two samples come from female donors; the bottom two come from male donors. The second and fourth sample (one male, one female) come from autistic donors; the first and third come from age-matched non-autistic donors. You can see that the samples from the autistic donors are dimmer than the control samples; less color indicates less of the compound being assayed for, since the fluorescent molecule is attached to an antibody that will only bind to the protein of interest (RORA or aromatase, in this case).
Figure 4C, in Sarachana et al, 2011; graph showing the relationship, R², between the concentration of RORA and the concentration of aromatase present in tissue samples from both autistic and non-autistic donors

Now, if you're like me, you'll be wondering how strong the evidence is that a non-trivial proportion of autistic people actually do underexpress RORA. While the immunofluorescence assay of the tissue samples didn't falsify the hypothesis that autistic people's brain cells would produce less RORA and aromatase, because it involved only 34 brains, its findings can't be extrapolated to autistic people in general (or even to a specific subgroup of autistic people in general) without gene-expression data from a larger, more representative autistic sample.

In this article, Valerie Hu and her co-author Mara Steinberg describe a new method for sorting autistic study participants into subgroups based on how they scored on individual questions on the Autism Diagnostic Interview (ADI-R). The rationale for this, which Jon Brock has elegantly demonstrated on his blog, is that two people can both meet diagnostic criteria for autism without having even a single trait in common. So Hu and Steinberg's method is supposed to sort autistic people into groups with the people whose clinical profiles most match their own.

They came up with four categories: people with severe language impairment, people with savant skills, people with relatively mild symptoms distributed across all the ADI-R domains (i.e., language, nonverbal communication, social interaction, play skills, interests and behaviors, physical sensitivities and mannerisms, aggression, and savant skills), and people with intermediate (i.e., neither mild nor severe) symptoms who were also less likely than the other groups to have savant skills. Three of these groups were chosen for inclusion in later gene-expression studies: the language-impaired group, the savant group, and the mild-autism group. Other people weeded out of the gene-expression study population were people whose autism was part of a genetic syndrome, like Rett syndrome or Fragile X, people with other psychiatric diagnoses, people who were born prematurely, people with significant cognitive impairment, and female people (!).

(I suspect the last group --- women and girls with autism --- were left out just because there were so few of them. Of the 1,954 people who were sorted into groups, only 428 were female.)

Once all the potential confounders were weeded out, the researchers had cell lines derived from 86 autistic individuals --- 31 in the language-impairment group, 26 in the mild-autism group, 16 in the savant group, and 13 who apparently met inclusion criteria for both the savant and language-impairment groups --- which made up the autistic sample in this study, contrasted with 30 non-autistic controls. The other study Sarachana and colleagues cite as providing evidence of RORA underexpression in autistic people is this one, which predates Hu and Steinberg's method for dividing autistic people into subgroups; its population, since it is composed of identical twins, is a lot smaller: just six sets of twins (five with at least one twin diagnosed with autism) and non-autistic siblings of two of the sets of twins --- fourteen people overall.

So, while the model Sarachana and colleagues propose --- a predisposition for autistic people to suppress expression of RORA, which both creates and is reinforced by a high-androgen environment --- is really interesting, and could shed light on 1) how male and female autistics differ and 2) what the male:female ratio within autism might be in a perfect world where diagnostic criteria weren't geared more toward men and boys, I'd like to see the underexpression-of-RORA finding replicated in a bigger study.

Sources:
Hu, V., Frank, B., Heine, S., Lee, N., & Quackenbush, J. (2006). Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes BMC Genomics, 7 (1) DOI: 10.1186/1471-2164-7-118

Hu, V., Sarachana, T., Kim, K., Nguyen, A., Kulkarni, S., Steinberg, M., Luu, T., Lai, Y., & Lee, N. (2009). Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism Autism Research, 2 (2), 78-97 DOI: 10.1002/aur.73

Hu, V., & Steinberg, M. (2009). Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders Autism Research, 2 (2), 67-77 DOI: 10.1002/aur.72

Sarachana, T., Xu, M., Wu, R., & Hu, V. (2011). Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism PLoS ONE, 6 (2) DOI: 10.1371/journal.pone.0017116

Gender on the Brain: Cordelia Fine Exposes "Neurosexism"

I was given Cordelia Fine's new book, Delusions of Gender, as a Christmas present, and I just finished reading it a couple days ago*.

It's very easy and fun to read, despite going into a lot of technical detail about the design of various studies (although she manages to write about those details in wonderfully clear, simple prose --- I *try* to do that on this blog, but I think her book is better-written, and easier to understand, than many of my researchy posts) and trying to tease out the separate strands of a very complicated knot of biology, psychology, culture that lies underneath the surface of what we understand gender to be.

She spends a lot of time discussing a topic that's also been on my mind a lot recently: fetal testosterone. She takes a much broader view of this literature than I do, because I am focusing exclusively on those studies that I consider relevant to the "extreme male brain" theory of autism, while she's addressing the whole idea that a "male brain" and a "female brain" even exist, much less that they differ as radically as most people writing popular (and academic) books on brain sex seem to think.

She peppers her book with quotations from such works as Louann Brizendine's The Female Brain (if you have time, read Mark Liberman's series of posts on Language Log debunking this book; they're hilarious and eye-opening), Leonard Sax's Why Gender Matters, John Gray's however-many-there-are-now Mars and Venus books, Allan and Barbara Pease's** Why Men Don't Listen and Women Can't Read Maps, and various books authored or co-authored by Michael Gurian of the Gurian Institute: Leadership and the Sexes, It's a Baby Girl!, and What Could He Be Thinking?

As an additional bit of context, she also quotes liberally from sources a hundred years old or more, laying out their nearly-identical visions of the masculine and feminine mind; the only difference is in what kind of pseudoscientific technobabble is used to justify the idea of separate spheres for men and women: in the old books, it is woman's physical frailty, nervous sensitivity and smaller brain that fit her for a purely domestic life, while in the new books, it is her relatively larger corpus callosum, her greater verbal fluency and emotional sensitivity, that fit her for the caring professions or for full-time wife-and-motherhood.

The book is divided into three parts, the first and last of which (called "'Half-Changed World', Half-Changed Minds" and "Recycling Gender") deal with psychological research on the effects of sexism and gender stereotyping on women's choices, behavior and performance on various tests, and with how children learn to sort themselves into gender categories, starting at very young ages.

Those parts of the book fill in the background for the middle part, "Neurosexism," which discusses research into hormonally-driven "hard-wiring" of gendered interests, behaviors and aptitudes. (It's in this part of the book that she tackles the prenatal-testosterone literature). While she does offer some critique on methodological grounds, her biggest beef is with popularizers who extrapolate universal truths from ambiguous results derived from very small, restricted samples of people.

An example:

[W]hen I decided to follow up [Louann] Brizendine's claim that the female brain is wired to empathize, it nonetheless proved to be an exercise that turned up surprise after surprise. I tracked down every neuroscience study cited by Brizendine as evidence for feminine superiority in mind reading. (No, really, no need to thank me. I do this sort of thing for pleasure). There were many such references, over just a few pages of text, creating the impression that it is no mere opinion, but scientifically established fact, that the female brain is wired for empathy in a way that the male brain is not. Yet fact-checking revealed the deployment of some rather misleading practices. For example, let's work our way through the middle of page 162 to the top of page 164 in her book. We kick off with a study of psychotherapists, which found that therapists develop a good rapport with their clients by mirroring their actions. Casually, Brizendine notes, "All of the therapists who showed these responses happened to be women." For some reason, she fails to mention that this is because only female therapists, selected from phone directories, happened to be recruited for the study.
...
A little later, readers are told that "brain-imaging studies show that the mere act of observing or imagining another person in a particular emotional state can automatically activate similar brain patterns in the observer --- and females are especially good at this sort of mirroring." Cited as support for this feminine superiority in emotional mirroring is a 2004 neuroimaging study by cognitive neuroscientist Tania Singer and colleagues, who compared brain activation when someone was either receiving a painful electric shock to the hand or was aware that a loved one was receiving the same painful electric shock to the hand. Singer and colleagues found that some brain regions were activated both by being shocked and watching someone else be shocked. If you think I'm going to be nitpicky about what any sex differences in activation in this study mean, you're wrong. Actually, the problem of interpretation is rather more basic. Only women were scanned.

Even when there aren't gross factual errors in the reporting of the research, Fine's inclusion of social- and developmental-psychology perspectives on gender --- how children learn it, how children and adults learn to change their behaviors, and their understanding of themselves, to fit into it --- makes it clear that whatever gendered differences do turn up on brain scans, they are as likely to be the effects of gender socialization as they are to be the underlying physiological cause of gender.

So, if we're not "hard-wired" by means of prenatal and pubertal hormone surges into immutable, characteristic and complementary "male" and "female" selves, what are we? Are we just blank slates, onto which society can write whatever it likes? Is there no such thing as human nature at all?

That's the alternative vision most commonly invoked in these debates: if you don't accept the idea that gender is hard-wired, you must be an environmental determinist who doesn't believe people are born with anything at all in their heads.

Luckily for us, this isn't a binary, and we don't have to choose between nature and nurture.

Here's Fine again, this time from the Epilogue of her book:

The fluidity of the self and the mind is impressive and is in continual cahoots with the environment. When social psychologists discover, for example, that mere words (like competition), everyday objects (like briefcases and boardroom tables), people, or even scenery can trigger particular motives in us, or that similar role models can seep into our most private ambitions, it makes sense to start questioning the direction of causality between gender difference and gender inequality. We are justified in wondering whether, as gender scholar Michael Kimmel suggests, "gender difference is a product of gender inequality, and not the other way around."

Nor is gender inequality just a part of our minds --- it is also an inextricable part of our biology. We tend to think of the chain of command passing from genes, to hormones, to brains, to environment. (As biologist Robert Sapolsky describes this common misconception, "DNA is the commander, the epicenter from which biology emanates. Nobody tells a gene what to do; it's always the other way around.") Yet most developmental scientists will tell you that one-way arrows of causality are just so last century. The circuits of the brain are quite literally a product of your physical, social, and cultural environment, as well as your behavior and thoughts. What we experience and do creates neural activity that can alter the brain, either directly or through changes in gene expression. This neuroplasticity means that, as [neuropsychologist Anelis] Kaiser puts it, the social phenomenon of gender "comes into the brain" and "becomes part of our cerebral biology."

As for hormones that act on the brain, if you cuddle a baby, get a promotion, see billboard after billboard of near-naked women, or hear a gender stereotype that places one sex at a higher status than the other, don't expect your hormonal state to remain impervious. It won't. "Even how we behave or what we think about can affect the levels of our sex hormones," point out Gene Worship authors Gisela Kaplan and Lesley Rogers. This continuous interplay between the biological and the social means that, as Anne Fausto-Sterling has put it, "components of our political, social, and moral struggles become, quite literally, embodied, incorporated into our very physiological being."

And so, when researchers look for sex differences in the brain or the mind, they are hunting a moving target. Both are in continuous interaction with the social context. Some researchers have even started to investigate how the brain, or hormones, respond differently while doing stereotyped tasks, depending on whether gender stereotypes are made salient. And gender differences in the mind can shift from moment to moment: for example, as stereotype threat is created or dispersed, or self-identity changes. But also, our actions and attitudes change the very cultural patterns that interact with the minds of others to coproduce their actions and attitudes that, in turn, become part of the cultural milieu: in short, "culture and psyche make each other up." When a woman persists with a high-level math course or runs as a presidential candidate, or a father leaves work early to pick up the children from school, they are altering, little by little, the implicit patterns of the minds around them. As society slowly changes, so too do the differences between male and female selves, abilities, emotions, values, interests, hormones, and brains --- because each is inextricably intimate with the social context in which it develops and functions.
...
Our minds, society, and neurosexism create difference. Together, they wire gender. But the wiring is soft, not hard. It is flexible, malleable, and changeable. And, if we only believe this, it will continue to unravel.

This closing statement encapsulates what I like so much about this book; it brings feminism, sociology, and a more accurate, more nuanced understanding of human biology together to give us a broader view of what gender is --- or at least how many different things, over a person's whole lifetime, go into creating gender.

For some other reviews of this book, see Neuroskeptic*** and Echidne of the Snakes (Part 1, Part 2, Part 3).

*I was also given Rebecca M. Jordan-Young's Brain Storm: The Flaws in the Science of Sex Differences, which covers similar ground --- both books poke and prod at the conventional wisdom that sex hormones shape "male" and "female" brains before birth, and that masculine and feminine behaviors, interests and life paths are the inevitable outcomes of these two different types of brain. I haven't finished reading Brain Storm yet, but I will probably also review it here when I do.

**Another of their books, not cited in Fine's book, refers in its title to a particularly stubborn gender stereotype that drives many feminists --- particularly sex-positive feminists --- absolutely batty: Why Men Want Sex and Women Need Love. As if no woman has ever been horny, or no man ever wanted to be loved!

***Who is cited as a source twice, and quoted once, in this book!

Fetal Testosterone and Autistic Traits - Part V(a): More About Visuospatial Abilities

(An addendum to my earlier post on this topic)

Looking back at this article (full text here), I notice something I didn't write about in my earlier (as yet unpublished) post about it --- one of the things its authors were testing for, looking to see if it had any relation to how much testosterone they found in their study participants' mothers' amniotic fluid, was IQ (measured using the Wechsler Abbreviated Scale of Intelligence, or WASI).

More importantly, the researchers also tracked their subjects' scores on one particular subscale of the Wechsler test --- Block Design --- which has been shown over and over again to be something autistic people are very, very good at.

Not only are we better, overall, than non-autistic people are at this task, we also score much higher on it than we do on any other subscale of a Wechsler IQ test.

Our scores, when you plot them across all the different subscales, tend to show this characteristic pattern, of a valley on the (verbal) Comprehension subscale and a very high peak on the Block Design subscale:

(Image adapted from Figure 1 in Dawson et al., 2007; each square along the line represents a different subscale of the Wechsler Intelligence Scale for Children - Third Edition)

Here is another image, from a much older study, showing the difference between the distribution across the different subscales of a Wechsler test of autistic and non-autistic test-takers' scores.

(Figure 5, in Shah and Frith, 1993; both solid lines represent groups of autistic children --- the line connecting unfilled circles represents autistic children with high overall IQs, while the line connecting darkened circles represents autistic children with low overall IQs. Dotted lines represent various non-autistic groups: children with intellectual disability but not autism, children without disabilities, and teenagers without disabilities)

The peaked shape is present in both the low-overall-IQ and high-overall-IQ autistic groups, while both the low- and high-IQ controls' scores are more or less the same across all the subscales.

So, if more testosterone in the womb ---> autistic-like brains, you would expect 1) boys to score higher than girls on this task, 2) boys to show greater disparity between Block Design scores and other scores, 3) both absolute and relative Block Design scores to correlate with fetal testosterone within each sex.

As raw scores for each subscale of the WASI were not given in Auyeung et al., 2009, I can't tell anything about whether their subjects' Block Design scores were particularly high relative to the other subscales.

However, I can tell you that there were no sex differences on Block Design --- boys' average score was 19.14 to girls' 16.26, but the standard deviation for both sexes is probably somewhere between 9.5 and 10*, making the difference between the sexes a little less than one-third of a standard deviation, and thus not statistically significant.

Also, within each sex, amniotic testosterone had no relationship to any of the IQ measures the researchers reported --- not full-scale IQ, not verbal IQ, not performance IQ and not the Block Design subscale of performance IQ.

So, this cognitive ability characteristic of autism doesn't seem to vary with sex or with androgenicity.

*Standard deviations are only given for boys and girls separately; for boys, it is 9.41; for girls, 10.08. There are 43 boys and 31 girls in this study population.

Auyeung, B., Baron-Cohen, S., Ashwin, E., Knickmeyer, R., Taylor, K., & Hackett, G. (2009). Fetal testosterone and autistic traits British Journal of Psychology, 100 (1), 1-22 DOI: 10.1348/000712608X311731

Dawson, M., Soulieres, I., Ann Gernsbacher, M., & Mottron, L. (2007). The Level and Nature of Autistic Intelligence Psychological Science, 18 (8), 657-662 DOI: 10.1111/j.1467-9280.2007.01954.x

Shah, A., & Frith, U. (1993). Why Do Autistic Individuals Show Superior Performance on the Block Design Task? Journal of Child Psychology and Psychiatry, 34 (8), 1351-1364 DOI: 10.1111/j.1469-7610.1993.tb02095.x

Fetal Testosterone and Autistic Traits - Part V: Visuospatial Abilities

EXECUTIVE SUMMARY: Researchers looking into the separate questions, "How do male and female minds differ?" and "How do autistic people differ from non-autistic people?" have discovered --- independently of each other --- an assortment of cognitive strengths peculiar to each of the groups being studied. Now that Simon Baron-Cohen has floated the idea that autism is just an extreme version of the normal male brain, it would make sense to check if the cognitive strengths of autistic people, and of all men, really do overlap, and whether prenatal testosterone exposure seems to play any role in the development of any of those aptitudes.

One recent study (Falter et al., 2008) compared groups of autistic and typically developing schoolchildren on three visual/spatial tasks that normally show a male advantage: mentally rotating three-dimensional objects, positioning a cursor over a moving image, and spotting a shape hidden somewhere in a larger pattern or line drawing, or "figure disembedding". They also measured the children's second-to-fourth digit ratios, as an indicator of prenatal testosterone exposure.

Their results were not consistent with what they predicted based on the extreme-male-brain theory of autism: the autistic children did better at figure disembedding, worse at targeting the moving image, and were slightly faster (but not more accurate) at mental rotation. On further analysis, though, they seemed to be faster at different parts of the (complex, multi-step) mental-rotation process than non-autistic men seem to be. The researchers were able to break down the results of the mental-rotation task into "rotational" and "non-rotational" components --- that is, to separate the actual visualization of the object rotating from the other factors, like comparing the rotated object in your head to the one shown on the screen and deciding whether they are the same. Autistic people seem to be faster at the non-rotational parts of this process, while non-autistic, male people seem to be faster at the rotational part. So, different cognitive skills underlie the two groups' respective advantages at the same complex task.

Finally, testosterone seemed to play no role whatsoever in predicting a child's success at either mental rotation or figure disembedding; the only task that showed a relationship between digit ratios and performance on that task was targeting, which 1) was harder for the supposedly "hyper-masculine" autistic boys, and 2) was easiest for the boys with middling digit ratios --- the ones with very low, "masculinized" digit ratios performed worse, as did the ones with high, "feminized" digit ratios. There were also no group differences in digit ratio between autistic and non-autistic boys.

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The term "visuospatial abilities" covers a lot of ground, and might include different skill sets depending on where and how it's being used.

For example, one of the most-studied (and most reliably replicated) cognitive differences between the sexes is a male advantage in the ability to rotate three-dimensional images on one's head; other spatial skills that tend to show a male advantage are aiming, predicting a projectile's trajectory . If autism is the same thing as having an "extreme male brain," you would expect autistic people to do better at these tasks than non-autistic people of their same gender.

There is also a well-established constellation of visual and spatial skills that autistic people tend to be better at than non-autistic people: the Block Design subscale of the Weschler intelligence tests, spotting a shape hidden inside a larger pattern (i.e., disembedding a figure), distinguishing a target figure from a crowd of "distractor figures" that are similar but not identical to the target, and reproducing a distorted or impossible image. It would be equally instructive, as far as investigating the extreme-male-brain hypothesis is concerned, to look for sex differences in how non-autistic people do on these tasks; you would also want to look for a relationship between those abilities and prenatal testosterone exposure. If the autistic cognitive style is essentially the same as the masculine one, you would predict exposure to higher levels of testosterone in utero would correlate with higher scores on the Block Design, faster and more accurate performance on visual-search tasks (like the Embedded Figures test or the tasks described in this study), and greater accuracy on drawing tasks, like the perspective-drawing task described here or the shape-drawing task described here (PDF).

One relatively recent study, carried out by Christine Falter, Kate Plaisted and Greg Davis and published in the Journal of Autism and Developmental Disorders, directly addresses the prediction I made in the second paragraph. Those researchers identified three visuo-spatial tasks that usually show a male advantage (or correlate with prenatal testosterone exposure, or both) --- mental rotation, targeting and figure-disembedding --- and tested a group of 28 autistic schoolchildren (27 of whom were boys) and a group of 31 typically-developing children matched for age, sex and nonverbal IQ on those tasks. They also measured the children's second-to-fourth digit ratio, as an indirect measure of prenatal testosterone exposure.

(Sample image from the Embedded Figures Test)

They found no significant differences between the autistic children and the typically-developing children in terms of digit ratio; depending on how the study participants were grouped (because each skill was tested in a differently-sized subset of the total study population), either the autistic half or the neurotypical half of a given subgroup might have slightly higher 2D:4D. These differences were so slight as to be statistically insignificant, regardless.

Overall, the autistic children did better at both mental rotation of 3-D objects (measured by having the children turn a computer-generated image of a solid to match the view of that solid the computer showed them) and figure disembedding than the typically-developing children; they were both faster and more accurate at these tasks. (Although, for the mental-rotation task, the difference was very slight). However, they performed worse than the typically-developing children at the targeting task, in which they had to position a cursor over an image that would appear at random points within certain regions of the computer screen*. Also, the mental-rotation results are a bit more complicated than just looking at the mean reaction times and accuracies of both groups would lead you to believe. The study authors did a linear regression of each of those two outcome variables with the degree of rotation (i.e., how far from its original position did the participants have to rotate the object?), which apparently allowed them to separate out the different cognitive processes used in mental rotation:

Across participants, the degree of rotation showed a strong linear relationship with reaction time, RT (R = .99, F(1,3) = 227.88, p = .001), and accuracy scores, ACC
(R = .98, F(1,3) = 59.84, p = .004). Accordingly, consistent with previous studies of mental rotation, RT and ACC were each regressed linearly against angle of rotation for each participant, to yield a rotation slope and an intercept. The slope for each participant indexed the speed with which they mentally "rotated" objects in degrees per second. The intercept yielded by these regressions indexed non-rotational aspects of performance, presumably related to the speed with which participants mentally compare three-dimensional objects as well as decision making and response variables.

Only the linear regression for reaction time showed any difference between the autistic and typically-developing groups, and there the difference was only in the intercept; the slopes of the two groups' lines were more or less the same.

(Figure 1, in Falter et al., 2008 --- graph showing the linear relationship of degree of rotation with reaction time)

Since two of the three authors of this paper (Falter and Davis) had also been involved in a similar study comparing men and women, using the same linear-regression method in their analysis of their results, they were in a position to notice differences between the men's results in the 2006 study and the autistic children's results from the 2008 study.

While both of the studies found overall differences that seem to lend support to Baron-Cohen's hypothesis --- men outperformed women, and autistic boys** outperformed typically-developing boys --- the linear regressions of both sets of data revealed different factors contributing to each better-performing group's advantage: while the autistic group in Falter et al. (2008) seemed to be better at the non-rotational aspects of this task, the male group in Falter et al. (2006) was faster at performing the rotations themselves. (In other words, if you were to compare the graphs made of the linear regressions of their results, the graphs in the 2006 study would have different slopes, while the graphs in the 2008 study have about the same slope, but different intercepts).

(Figure 2, in Falter et al., 2008 --- graph showing relationship of second-to-fourth digit ratio to reaction time on Targeting task)

Neither the mental-rotation task nor the figure-disembedding task showed any relationship to digit ratio; however, there was a quadratic relationship between 2D:4D and reaction time on the targeting task, with children having both very high (above 1.0) and very low (below 0.90) digit ratios taking longer to position the cursor correctly than their peers with mid-range digit ratios.

An older study, carried out in 1992 by Jo-Anne Finegan, G. Alison Niccols, and Gabriel Sitarenios, compared testosterone levels in the amniotic fluid of women who had undergone amniocentesis at Toronto General Hospital during the mid-1980s with those women's children's later results (at age four, in this study) on a wide range of cognitive tests.

The visuospatial tasks included in this study were fairly similar to the ones Falter, Plaisted and Davis used: there was a figure-disembedding task (the Preschool Embedded Figures Test, in which a triangle is hidden somewhere in various line drawings of familiar objects), a block-building task, in which the person giving the test builds structures of varying complexity out of 1-inch cubes, and the child is supposed to build the same thing. It's not the same as the Block Design test, but it seems pretty close to it to me. The one thing Falter et al. test that Finegan et al. do not is targeting, and Finegan et al. test a few things Falter et al. don't: picture-puzzle solving (which I guess is also analogous to Block Design) and geometric-form copying (analogous to the drawing tasks I mentioned above, in the paragraph about autistic people's visuospatial strengths).

(Sample image from the Preschool Embedded Figures Test)

That study found no significant sex differences in any of the skills being investigated; it also found no relationship between prenatal testosterone and performance of three of the four tasks I describe above --- figure disembedding, puzzle solving and shape drawing were all independent of prenatal testosterone exposure in both sexes. For girls, there was a significant negative relationship between prenatal testosterone and scores on the block-building task --- the higher female scorers on this test tended to have lower levels of prenatal testosterone exposure than their lower-scoring peers; for boys, there was a small trend in the opposite direction --- with high scorers tending to have higher prenatal testosterone levels --- but that relationship wasn't statistically significant.

Falter et al.'s results tell me that the area of overlap between 1) the things men are usually found to better at than women, and 2) the things that autistic people are usually found to be better at than non-autistic people, within the larger domain of visuo-spatial skills, is fairly small. Also, the two "masculine" skills that autistic people tend to do better at --- figure disembedding and mental rotation --- are not at all correlated with an indirect measure of prenatal androgen exposure.

Because there is some uncertainty around the use of digit ratios as a marker for prenatal testosterone exposure, I wanted to find a study of similar cognitive abilities that measured that variable directly. Finegan et al.'s study was the only one I could find that did this, even though it was old and didn't have any autistic participants. Their results showed that prenatal testosterone has no effect on young children's performance at most visuospatial tasks, and, on the tasks it does influence, it seems to affect boys and girls differently, with higher levels of testosterone exposure boosting boys' scores but lowering girls'.

*It doesn't surprise me at all that autistic people would be slower at that, given our difficulties with motor planning. Even apart from that, some studies have found that we are not as good as neurotypical people in tracking moving visual stimuli --- see this review (full text here) for more detail.

**I use "boys" here because there were a total of two girls --- one in the autistic group, and the other in the control group --- in this study population of fifty-nine children.

Sources:
Falter CM, Plaisted KC, & Davis G (2008). Visuo-spatial processing in autism--testing the predictions of extreme male brain theory. Journal of autism and developmental disorders, 38 (3), 507-515 PMID: 17674175

Finegan, J., Niccols, G., & Sitarenios, G. (1992). Relations between prenatal testosterone levels and cognitive abilities at 4 years. Developmental Psychology, 28 (6), 1075-1089 DOI: 10.1037/0012-1649.28.6.1075

Voyer D, Voyer S, & Bryden MP (1995). Magnitude of sex differences in spatial abilities: a meta-analysis and consideration of critical variables. Psychological bulletin, 117 (2), 250-270 PMID: 7724690

Fetal Testosterone and Autistic Traits - Part IV: Verbal Abilities

Apart from eye contact and looking behavior, one of the earliest signs that a child might be autistic is a delay in the acquisition of speech*. Many of us continue to have difficulties with language as older children, adolescents and adults --- difficulties both with producing speech, and with understanding other people's speech.

Thus, if autism really results from hypermasculinization of the developing brain in utero by testosterone, you would expect children exposed to higher levels of testosterone during gestation to 1) develop speech somewhat later than children exposed to less testosterone, 2) have somewhat poorer verbal skills in general, perhaps reflected by an imbalance between verbal and performance IQ, and 3) do relatively poorly at comprehending spoken language, compared to their less-androgenic peers.

To help answer those questions, Svetlana Lutchmaya, Simon Baron-Cohen and Peter Raggatt (full text here) measured testosterone levels in the amniotic fluid of 87 women and then tested their children twice, at the ages of eighteen and twenty-four months, on the size of their vocabularies using the Communicative Development Inventory (CDI).

They found a significant sex difference in vocabulary size --- on average, the 40 girls in this study knew about 87 words at eighteen months old, while the 47 boys had an average vocabulary size of around 42 words. There was a huge amount of variation within each group, though: the boys' scores ranged from zero (which I'm assuming to mean they didn't speak at all --- three boys had this result) to 222 words; while the girls' scores ranged from 2 to 318. So, the least verbal girl(s) could all say at least a few words, while three boys couldn't say any words at all; while the most verbal girl(s) knew almost a hundred (or ~50%) more words than the most verbal boy(s).

This pattern persisted when the children (most of them, at least --- at this stage, the sample consisted of 43 boys and 38 girls) were followed up at twenty-four months old: then, the boys' average vocabulary consisted of 197 words (ranging from a low score of zero to a high score of 414); the girls knew about 275 words on average (ranging from 15 to 415). So, while the most talkative boys had caught up with the most talkative girls by this time, the sexes' average and low-end scores still diverged.

In their statistical analysis of these data, and on the seven other variables they tracked, the researchers found the strongest relationship between sex and vocabulary size, followed by level of parental education. Fetal testosterone came in third for both sexes together, and was not a significant predictor of vocabulary size at all within either sex. So I think it's probably fair to conclude that the reason testosterone showed up as a significant factor at all in the analysis of the pooled data is because it's strongly correlated to sex.

A much older study (Finegan, Niccols, and Sitarenios, 1992) also looked for a potential relationship between prenatal testosterone (measured in amniotic fluid) and young children's performance on a broad assortment of cognitive tests. Some of these tests measured verbal abilities; the Comprehension scale of the Reynell Developmental Language Scales tested a child's understanding of individual words, concepts, and different meanings conveyed by different sentence structures; and several subdomains within the McCarthy Scales of Children's Abilities --- Oral Vocabulary, Verbal Fluency and Opposite Analogies --- tested the children's expressive language abilities. Of those latter three, the first is a rough measure of vocabulary size (though, unlike the measure used by Lutchmaya and her colleagues, it doesn't ask the parents how many words their child knows; instead, it asks children to define a series of 10 words, increasing in difficulty from familiar objects and animals to more abstract concepts, like "loyal"), while the second two measure how quickly a child can come up with words of a specific type.

Of all those measures, only one --- Language Comprehension --- was found to correlate with prenatal testosterone, and that relationship was only seen in girls.


(Figure 1, in Finegan et al., 1992 --- graphs showing the relation of prenatal testosterone levels, plotted on the x-axes, with scores on the Reynell Language Comprehension subscale. The graph on the left, with the black dots, shows the results for girls; the graph on the right shows boys' results. You can see that there's only a correlation of any kind for the girls).



In girls, there was a negative quadratic relationship between prenatal testosterone and scores on the Language Comprehension test, meaning that girls with middling levels of prenatal testosterone exposure --- not the highest or the lowest --- tended to get the highest scores on this task. No relationship whatsoever was found between prenatal testosterone and either comprehension or expression of language for boys.

That study tracked other variables as well as prenatal testosterone, and while none of those variables (including testosterone) predicted how well the children did on any of the expressive-language tasks, family background (a measure including parental socioeconomic status, and the mother's IQ and education) was also a significant predictor of language comprehension. This is somewhat in line with Lutchmaya et al.'s results, which found parental education to be an important predictor of a child's vocabulary size, but also a little different, since Lutchmaya and colleagues were measuring how much the children in their sample spoke, not how much they understood --- expressive language, not receptive language, which Finegan and colleagues did not find any predictors for. Finegan et al.'s children were older than Lutchmaya et al.'s, though, and the measures the two groups of researchers used were very different. The one thing they seem clearly to agree on is that there probably isn't any correlation between prenatal testosterone exposure and language abilities as manifested in early childhood, or if there is it's a very weak one.

*This impairment in verbal communication is actually one of the diagnostic criteria for various ASDs --- with (classical autism) or without (Asperger syndrome) delayed acquisition of speech.

Sources:
Lutchmaya, S., Baron-Cohen, S., & Raggatt, P. (2001). Foetal testosterone and vocabulary size in 18- and 24-month-old infants Infant Behavior and Development, 24 (4), 418-424 DOI: 10.1016/S0163-6383(02)00087-5

Lutchmaya, S., Baron-Cohen, S., & Raggatt, P. (2001). Foetal testosterone and vocabulary size in 18- and 24-month-old infants Infant Behavior and Development, 24 (4), 418-424 DOI: 10.1016/S0163-6383(02)00087-5