Sex steroids and the organization of the human brain.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Lombardo et al. Studying the biological mechanisms underlying sexual differentiation in the human brain provides important insights into the etiology and trajectory of neuro-developmental disorders in males and females (Baron-Cohen et al., 2011). Sex steroid hormones, the end products of the hypothalamus-pituitary-gonadal axis, exert powerful effects on the organization and sexual differentiation of brain structures. From animal studies, it has become clear that during early development, exposure of the brain to testosterone and es-tradiol leads to irreversible changes in the nervous system (McCarthy et al., 2012). Moreover, fetal exposure to sex steroids has a major impact on the sexual differentiation of the brain (McCarthy et al., 2012). For example, high levels of fetal tes-tosterone (FT) result in brain masculin-ization in experimental animals, such as enlargements of the volume and soma size of the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and ventro-medial hypothalamus (Zuloaga et al., 2008). In humans, studies of the effects of FT often rely on indirect measures such as the ratio between the index finger (2D) and ring finger (4D) or on opposite-sex twin studies. Specifically, a smaller 2D:4D ratio correlates with higher FT exposure, and through the intrauterine presence of a male fetus, opposite-sex twin girls are exposed to higher FT levels than same-sex twin girls. Using the latter indirect measure of FT, earlier reports showed that total brain volume and cerebellum volume, typically found to be larger in males, were positively correlated with higher FT exposure (Peper et al., 2009). A recent paper by Lombardo et al. (2012) provided direct evidence for an association between FT levels and sexual differentiation of brain gray matter in humans. In this pioneering study of 28 developing boys, FT levels were determined from amniotic fluid. Amniocentesis was performed between 13 and 20 weeks of gestation , which is a critical period of brain masculinization. When these boys were 8 –11 years old, a structural MRI was made. Using voxel-based morphometry, gray matter regions within the whole brain of these 28 boys were identified showing significant correlations with FT levels. The amygdala and hypothalamus were included as …