Sunday, November 30, 2008

Intersex (for lack of a better word)... the title of a book by Thea Hillman, in which (according to a review by David S. Hall),
She speaks of her experiences as a young child, being diagnosed with Congenital Adrenal Hyperplasia, and what that experience meant to a four year old girl who was growing pubic hairs, a child who was poked and examined by many doctors, and had a total lack of personal privacy of her body. She comes back to this experience many times in the stories she tells of her life as a person who does not really know what gender she is.
Congential Adrenal Hyperplasia (CAH) is an autosomal recessive genetic disorder that...
is characterized by severe androgen excess beginning in the fetus. In about 95% of patients CAH is caused by a defect in the 21-hydroxylase gene (CYP21), leading to an impaired synthesis of cortisol ["stress hormone" produced by the adrenal gland] and aldosterone [hormone that causes the kidneys to retain sodium and water]. The low cortisol level triggers an increased production of adrenocorticotropic hormone, resulting in hyperplasia of the adrenal glands with increased synthesis of steroid precursors and elevation of androgen levels. The androgen excess is present from early embryogenesis, and causes in girls varying degrees of virilization of the external genitalia, depending on the degree of enzyme deficiency. summarized in a new paper by Ciumas and colleagues (2008).

In Intersex (for lack of a better word),
[Hillman] speaks about her "outwardly simple though visually misleading, internally complicated gender."
Ciumas et al. wanted to investigate whether fetal testosterone exposure is the major underlying mechanism for sexual dimorphism in the human brain. In particular, sex differences in the anatomy and physiology of the hypothalamus and the amygdala were of interest. Thus, they turned to adult women with CAH, since
Certain rare conditions, so called experiments of nature, may here potentially offer unique information.
A review of the literature suggested that some "sex-atypical" traits and behaviors may occur with CAH, but not all studies have agreed.

Normal is a weapon of mass destruction.

What is “normal”? Hall's review of Intersex continues:
She speaks of her mother's prayers that she would be normal. She speaks of normal this way:

"I take the war on terror personally because the war on terror is really a war on difference, because my body strikes terror in the hearts of other Americans.

"My body and the bodies of the people I love are the most intimate sites of American imperialism. Because our sex anatomy isn't normal, they operate on us without our consent. Because who we have sex with isn't normal, they won't let us get married. Because our gender isn't normal, they don't give us jobs, health care, or housing. We work, we pay rent, we pay taxes, but because we're not normal, we don't get the same freedoms other Americans enjoy, the same freedoms American soldiers are murdering to protect."

The study, which was not conducted in America but in Sweden by Dr. Ivanka Savic Berglund's group1 at the prestigious Karolinska Institute, was a continuation of their work on sex hormones and olfaction. Previously (Savic et al., 2001), they demonstrated that heterosexual men (HeM) and heterosexual women (HeW) showed different hypothalamic responses to smelling the putative pheromones, androstadienone (AND) and estratetraenol (EST). Specifically they used PET (positron emission tomography) to measure changes in cerebral blood flow responses to inhaling various odorants, which included sex steroids, butanol, cedar oil, lavender oil, and eugenol (clove). EST induced activity in the hypothalamus of HeM but in olfactory regions of HeW. Conversely, AND induced activity in the hypothalamus of HeW but in olfactory regions of HeM, which is not too surprising if these substances are, in fact, pheromones. The opposite sex pheromone is not processed like a regular scent, whereas the same sex pheromone is.

Furthermore, they also examined hypothalamic responses to these putative pheromones in gay men (Savic et al., 2005) and lesbians (Berglund et al., 2006). In the first experiment, the comparison of gay men, straight men, and straight women was pretty straightforward (so to speak). HeM and HeW scored as 0 on the Kinsey scale (exclusively heterosexual), and the gay male subjects scored as 6 (exclusively homosexual). The results were as expected: the hypothalami of gay men were activated by AND, not EST (which was treated like any other odor). The results from the second experiment were less than straightforward. The lesbian group (between 5 and 6) did not look "just like straight men." Instead,
...the lesbian subjects did not show a differentiated pattern of activation with AND and EST; they engaged the amygdala and the piriform and the insular cortices (the classical odor-processing circuits) when smelling both of these compounds.
As a consolation prize, however, the lesbians were unlike HeW (since AND didn't turn on their hypothalami) and somewhat like HeM (since EST activated one overlapping region of the hypothalamus at a lower statistical threshold). [For more info on this study, see Sweat, Urine, and Sexual Orientation and The PNAS Word.]

Note that I did not say anything about activity in specific hypothalamic nuclei [such as the so-called sexually dimorphic nucleus], because the PET method doesn't have the spatial resolution required to distinguish between them.

That brings us to the present experiment. As you might guess, the question was whether CAH women looked more like HeM than HeW when sniffing the steroids.

Is that what they found?
Despite the genetically verified diagnosis and parental reports about boy-typical play behavior during childhood, the pattern of activation in the presently investigated CAH women was remarkably similar to that of female controls, and different from the pattern of male controls. CAH women and HeW activated the anterior hypothalamus with AND, whereas HeM activated this region with EST. Furthermore, whilst the amygdala connectivity differed between the male and female controls, no difference was observed between control females and CAH females. Thus, both with respect to aspects of functional organization and functional activation of the limbic circuits CAH women showed a pattern congruent with their biological sex, and different from the opposite sex. Our hypothesis that these specific aspects of cerebral dimorphism would have masculine features in CAH women was thereby rejected.
So no, it was not what they found.

Figure 1 (Ciumas et al., 2008). Illustration of group-specific activations with putative pheromones and odors. The Sokoloff's color scale illustrates Z values reflecting the degree of activation. As the same brain section is chosen, the figures do not always illustrate maximal activation for each condition. Clusters of activated regions are superimposed on the standard brain MRI, midsagittal plane.

This failure to show a difference between CAH women and control women was obtained even though the two groups were not particularly well-matched for sexual orientation! [a glaring weakness that could have been rectified by recruiting a few bisexual control women]. Eight of the CAH women rated as Kinsey 0, but three others rated as 2, 4, and 5.2

At any rate, these results provide no support for the notion that exposure to high levels of fetal testosterone will result in the "masculinization" of sexually dimorphic limbic circuits. Why? What does this have to say about fetal testosterone and the "male brain" view of development (e.g., Christine Knickmeyer & Baron-Cohen, 2006)? Ciumus et al. were puzzled, but offered the following speculations:
Explanations to these discrepancies are not evident from the present data. We can only conclude that intrauterine virilization of genitalia is not necessarily paralleled by a masculinization of the limbic brain, at least not with respect to signal response to AND and EST, and the baseline amygdala connectivity, which are 2 indices of sex-dimorphism. It is theoretically possible that various sex dimorphic features are affected by fetal testosterone in a dose dependent manner. Whilst such a scenario could be attributed for the differences between HeM and HeW (with extremely high testosterone levels in male fetuses), it is less likely to explain the "male" like AND and EST activation and functional connectivity in lesbian women described in our previous studies. None of our lesbian participants in these studies had genital masculinization, which is expected already at moderate elevations of fetal testosterone. An alternative possibility is that various sex dimorphic features may have different etiological factors; in this respect recent studies by Arnolds group at UCLA are of particular interest as they indicate existence of early, and testosterone-independent chromosomal effects on the brain. Finally, several different etiological factors could contribute to a same sexually dimorphic cerebral feature, for example, psychosexual outcome. The 3 alternatives are not mutually exclusive. Although presently speculative, in the view of present results they all seem relevant to address in the near future.
So there's no neat conclusion, only ambiguity. The calls for future studies are issued. But where does it all fit, in the grand scientific scheme of things? In the less grandiose human scale of things, to be different and yet not-so-different? When talking about her participation in the Intersex and Transgender communities, Thea Hillman says:
"I fear that regardless of the fact that I've been hormonally altered since age six in order to achieve and maintain a mythical gender ideal, I can't safely talk about my concerns about hormones and surgery in our community for fear of being seen as anti-trans and anti-surgery."

1 In the recent past, The Neurocritic (and other neuropundits) have been critical of Savic's work on cerebral asymmetry and sexual orientation, but we'll put that aside for today.

2 Another potential source of variability was the severity of the condition, which ranged from 1 to 5 (least to most severe), with a mean value of 3.18 in the 11 participants. Only four of the CAH women rated a severity of 4 or 5, so this might have obscured potential group differences in the data.


Berglund H, Lindström P, Savic I. (2006). Brain response to putative pheromones in lesbian women. Proc Natl Acad Sci. 103:8269-74.

Christine Knickmeyer R, Baron-Cohen S. (2006). Fetal testosterone and sex differences. Early Hum Dev. 82:755-60.

Savic I, Berglund H, Gulyas B, Roland P. (2001). Smelling of odorous sex hormone-like compounds causes sex-differentiated hypothalamic activations in humans. Neuron 31:661-8.

Savic I, Berglund H, Lindström P. (2005). Brain response to putative pheromones in homosexual men. Proc Natl Acad Sci. 102:7356-61.

C. Ciumas, A. L. Hirschberg, I. Savic (2008). High Fetal Testosterone and Sexually Dimorphic Cerebral Networks in Females. Cerebral Cortex DOI: 10.1093/cercor/bhn160.

Active masculinization by fetal testosterone is believed to be a major factor behind sex differentiation of the brain. We tested this hypothesis in a 15O-H2O positron emission tomography study of 11 women with congenital adrenal hyperplasia (CAH), a condition with high fetal testosterone, and 26 controls. Two indices of cerebral dimorphism were measured—functional connectivity and cerebral activation by 2 putative pheromones (androstadienone [AND] and estratetraenol [EST]), previously reported to activate the hypothalamic networks in a sex-differentiated manner. Smelling of unscented air was the baseline condition, also used for measurements of functional connectivity from the amygdala. In CAH women and control women AND activated the anterior hypothalamus, and EST the amygdala, piriform, and anterior insular cortex. The pattern was reciprocal in the male controls. Also the functional connections were similar in CAH women and control women, but different in control men. Women displayed connections with the contralateral amygdala, cingulate, and the hypothalamus, men with the basal ganglia, the insular and the sensorimotor cortex. Furthermore, the connections were in CAH and control women more widespread from the left amygdala, in men from the right amygdala. Thus, we find no evidence for masculinization of the limbic circuits in women with high fetal testosterone.

"Normal is a weapon of mass destruction.
It's just as deadly, and just like those weapons,
it'll never be found."

-Thea Hillman, writer and intersex activist

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At July 22, 2009 7:24 AM, Anonymous Lilith said...

Great post. I've been trying to get a glimpse at the methodology used in this study, but could not find an open-access copy. I've noticed you used some figures from the original study. If you have the study, would you please send me a copy at ? Thanks.

At July 22, 2009 9:00 AM, Blogger The Neurocritic said...

I just sent you the Ciumas et al. paper.


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