Building on the long history of testing the organizing effects of early sex steroids on later sexual dimorphism in non-human
species (Phoenix et al., 1959
), the present study is the first to show in humans
that FT influences specific brain regions that later develop in a sexually dimorphic fashion. Because our sample was restricted to only males, the results cannot be easily explained by systematic differences between males and females in X-linked gene expression. Whether the observed effect of FT extends to females, or whether altogether different mechanisms affect variation in local gray matter volume in these regions is still an open question. However, we can infer that sexual dimorphism in some parts of the human brain can come about through the early organizing influence that FT has on these regions within males. In other words, sexual dimorphism in these regions is expressed later in life because FT acts as a proximate signal in early development that influences early cellular processes (i.e. gene expression) that push later local gray matter throughout development in a direction that makes a difference between males and females more pronounced. Exactly what cellular processes FT influences early on to organize these brain regions for later sexually dimorphic development should be explored more in future research.
It is interesting to note that the regions we have identified here have also been observed to be sensitive to later testosterone and individual differences in androgen sensitivity. Paus and colleagues recently found that GM density in many regions including PT/PO and plOFC were negatively related to current bioavailable testosterone levels and this effect was more pronounced in those with a polymorphism of the androgen receptor gene (AR
) associated with enhanced androgen sensitivity (Paus et al., 2010
). Similarly, Raznahan and colleagues observed longitudinal evidence that RTPJ exhibits a protracted period of increased cortical thickness in individuals with the AR
polymorphism associated with enhanced androgen sensitivity (Raznahan et al., 2010
). These observations suggest that individual differences in sensitivity to androgens and both early organizational and later activational influences of androgen surges may be important for the expression of sexual dimorphism in these regions.
While we have highlighted three particular sexually dimorphic brain regions whose gray matter volume is related to FT levels, it is noteworthy that not all sexually dimorphic brain regions are related to FT or vice versa. For example, the amygdala and hypothalamus are known to be sexually dimorphic (Swaab and Fliers, 1985
; Good et al., 2001
), related to early and current androgen levels (Jacobson et al., 1981
; Cooke et al., 1999
), and at least for the amygdala, related to sex chromosome differences and X-linked gene expression (Good et al., 2003
). In the NIH-dataset, these and other regions were sexually dimorphic in volume. With respect specifically to the amygdala, while we found a subregion of the amygdala that was positively related to FT, it did not overlap with the subregions that showed a Male>Female sexual dimorphism. There are several possible explanations for the lack of a conjunction between sexual dimorphism and FT-effects. First, it is possible that the difference in field strengths of the magnets in the FT-cohort (3T) and NIH-cohort (1.5T) could have led to biases for effects in one cohort but not the other (Tardif et al., 2011
). Second, while the NIH-cohort constitutes a random sample of the general population, the FT-cohort is a selective subsample of the general population. The FT-cohort is different in that they were more likely to be born to older mothers. Although all the participants in the FT-cohort are considered ‘typically developing’ children there is still some possibility that some of the lack of correspondence between the data from these two datasets may reflect differences in maternal age of the two cohorts.
Finally, the lack of a conjunction between FT-effects and sexual dimorphism for some brain regions may be due to a variety of other effects such as genetic differences from the sex chromosomes, interactions with later androgen surges, and other epigenetic influences. Regarding later androgen surges, interactions between FT and activational effects of current testosterone (CT) in puberty is one important area for focus in future work. In the current study, some of the older participants may have already entered puberty and this would create a potential difference in CT between older versus younger children. However, in the current study this potential effect covaries with age and the fact that age is a covariate in all analyses makes it less likely that this is a potential issue obscuring any FT-influences observed in the current study. Nevertheless, in future studies it will be important to test both FT and CT effects and any interactions they may have on local variation in human brain structure.
With regard to other epigenetic influences, one potential candidate is maternal influences on the fetal environment. Given the robust sex differences found in testosterone in amniotic fluid and the lack of any relationship between FT and testosterone in maternal blood, the fetus is generally considered the primary source of testosterone in the amniotic fluid (van de Beek et al., 2004
). However, recent research suggests that the placenta is capable of synthesizing de novo androgens and estrogens (Escobar and Carr, 2011
; Escobar et al., 2011
). These types of placental influences should be investigated in future work to determine whether any such de novo sex steroids diffuse from the placenta into the amniotic fluid and how this may affect the fetus. If such sex steroids can enter into the amniotic fluid, it would constitute a further placental influence in addition to contributions made by the fetus itself. Teasing apart these more complex explanations in humans will be a challenge for future research.
The functions of the brain regions that are influenced by FT are especially interesting because of how they relate to previous literature on sex differences in cognition and behavior as well as behavioural correlations with FT. PT/PO overlaps with key language regions such as Wernicke’s area and extends into parietal language areas known as Geschwind’s Territory (Catani et al., 2005
). We previously showed that increasing FT predicts smaller vocabulary at both 18 and 24 months; a result consistent with girls having larger vocabularies at this age (Lutchmaya et al., 2002a
). Similarly, RTPJ/pSTS function has been associated with a host of social-cognitive and social-perceptual abilities such as mentalizing, social attention, eye gaze processing, and empathy (Saxe and Powell, 2006
; Decety and Lamm, 2007
; Nummenmaa and Calder, 2009
). We previously showed that increasing FT predicts less eye contact at 12 months (Lutchmaya et al., 2002b
), decreased attributions of intentionality at 4 years (Knickmeyer et al., 2006
), and decreased empathy at 8 years of age (Chapman et al., 2006
). More recently, we showed that the extent to which current testosterone in adults impairs mentalizing performance is dependent on how much FT one was exposed to (van Honk et al., 2011
). Thus, the current results suggest that the links between FT and behavior/cognition may be mediated by the influence that FT has in shaping brain structure underlying such functions. Future work should look specifically at whether FT-effects on brain structure indeed mediate the links between FT and sexually dimorphic cognition and behavior.
These results may also have implications for neurodevelopmental conditions with skewed sex ratios (e.g., autism, developmental language, conduct disorder). Exactly how these results bear on such conditions remains to be seen. However, many neurodevelopmental conditions affect males more than females and many are characterized by deficits that are sexually dimorphic in the general population (e.g., language development, social cognition, self-regulation). These deficits have been hypothesized to be related to exposure to FT levels (Geschwind and Galaburda, 1985
; Moffitt et al., 1998
; Baron-Cohen, 2002
; Rutter et al., 2004
; Auyeung et al., 2009
; Auyeung et al., 2010
; Baron-Cohen et al., 2011
). Furthermore, the sexually dimorphic brain regions we have found to be related to FT are all key brain areas for these particular conditions (Shaywitz et al., 1998
; Rojas et al., 2002
; Gervais et al., 2004
; Pelphrey et al., 2005
; Redcay and Courchesne, 2008
; Passamonti et al., 2010
; Lombardo et al., 2011
; Raine et al., 2011
). Thus, it will be important to look at FT and/or sex chromosome effects as potential mechanisms behind these conditions or how such mechanisms may affect one’s risk for developing these types of conditions in early development (Baron-Cohen et al., 2011
In sum, this study provides the first evidence that FT has an organizing effect on some sexually dimorphic areas of the human brain. Along with prior work on how FT influences behavior, this work highlights FT as an important developmental mechanism contributing to sex differences in neuroanatomy. Work on the organizing effects of FT on the developing human brain may be one important route for furthering our understanding of neurodevelopmental conditions that asymmetrically affect males more than females.