Elsevier

NeuroImage

Volume 49, Issue 2, 15 January 2010, Pages 1205-1212
NeuroImage

Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain

https://doi.org/10.1016/j.neuroimage.2009.09.046Get rights and content

Abstract

Previous studies suggest organizing effects of sex hormones on brain structure during early life and puberty, yet little is known about the adult period. The aim of the present study was to elucidate the role of 17β-estradiol, progesterone, and testosterone on cortical sex differences in grey matter volume (GM) of the adult human brain. To assess sexual dimorphism, voxel-based morphometry (VBM) was applied on structural magnetic resonance images of 34 healthy, young adult humans (17 women, 17 men, 26.6 ± 5 years) using analyses of covariance. Subsequently, circulating levels of sex hormones were associated with regional GM using linear regression analyses. After adjustment for sex and total GM, significant associations of regional GM and 17β-estradiol were observed in the left inferior frontal gyrus (β = 0.39, p = 0.02). Regional GM was inversely associated with testosterone in the left inferior frontal gyrus (β = −0.16, p = 0.04), and with progesterone in the right temporal pole (β = −0.39, p = 0.008). Our findings indicate that even in young adulthood, sex hormones exert organizing effects on regional GM. This might help to shed further light on the underlying mechanisms of both functional diversities and congruence between female and male brains.

Introduction

Structural sex differences in the developing and adult brain have been described by a large number of studies, pointing to both functional diversities and compensation mechanisms between women and men (reviewed, for example, in Cahill, 2006, Cosgrove et al., 2007, De Vries, 2004). Using post-mortem techniques and in vivo magnetic resonance imaging (MRI), it has been consistently shown that even to some extent independent from body size, female brains are on average smaller compared to males (Filipek et al., 1994, Gur et al., 1999, Nopoulos et al., 2000, Passe et al., 1997, Peters, 1991, Rabinowicz et al., 1999, Witelson et al., 1995). In addition, relative to cerebrum size, cerebral spinal fluid (CSF) volume (Agartz et al., 1992, Giedd et al., 1997, Grant et al., 1987, Gur et al., 1999, Lemaître et al., 2005) and white matter (WM) volume (Filipek et al., 1994, Gur et al., 1999, Lemaître et al., 2005) are greater in males than in females, whereas females exhibit greater cortical grey matter (GM) volume (Allen et al., 2003, Gur et al., 1999, Lemaître et al., 2005). In addition, distinct cortical and subcortical regions have been identified to be sexually dimorphic. For example, females tend to have larger volumes or cell packing density in language-related fields such as Boca's and Wernicke's areas (Harasty et al., 1997, Jacobs et al., 1993, Schlaepfer et al., 1995, Witelson et al., 1995), but also in the right hemisphere in the parietal and temporal association cortices (Good et al., 2001, Sowell et al., 2007), in the dorsolateral prefrontal (Schlaepfer et al., 1995), orbitofrontal, superior frontal, and lingual gyri (Goldstein et al., 2001), right inferior parietal cortex (Nopoulos et al., 2000), anterior cingulate cortex (Good et al., 2001, Paus et al., 1996), as well as in the hippocampus (Filipek et al., 1994, Giedd et al., 1996, Murphy et al., 1996), whereas males exhibit greater volumes or neuronal densities in the medial frontal cortex (Goldstein et al., 2001, Zhou et al., 1995), amygdala (Giedd et al., 1996), hypothalamus (Allen et al., 1989, Swaab and Fliers, 1985), mesial temporal lobes (Good et al., 2001), paracingulate gyrus (Paus et al., 1996), and cerebellum (Carne et al., 2006, Good et al., 2001). However, results are partially conflicting, e.g., regarding the corpus callosum (Allen et al., 1991, Bishop and Wahlsten, 1997). These divergent findings might be explained by different age range of the respective subjects investigated (Raz et al., 2004, Sowell et al., 2007) and on the different methods used (Chen et al., 2007, Shah et al., 2004, Sowell et al., 2007, Witelson et al., 1995), for example, considering post-mortem evaluation, in vivo region-of-interest (ROI) analysis, or voxel-based morphometry (VBM).

Structural sex differences in the adult brain have been suggested to depend on “activating” (i.e., facilitation of reproductive behaviour) and “organizing” (i.e., irreversible neuronal changes) effects of circulating sex steroid hormones, both during neonatal differentiation, but also later in life (Cooke et al., 1998, Kawata, 1995). The original hypothesis limited organizational effects to the embryonic period, whereas in recent considerations, steroid hormones are thought to organize neuronal circuits also during puberty (Sisk and Foster, 2004). For a long time it is known that exposure to testosterone during gestation induces masculinization of the brain by aromatization to estrogens (Arnold and Gorski, 1984, MacLusky and Naftolin, 1981, McEwen et al., 1977). Recently, Neufang et al. (2009) found that increasing levels of circulating testosterone during puberty in boys may contribute to the emerging sex differences in the amygdala and hippocampus region during adolescence, whereas Peper et al. (2009) found grey matter changes to be associated with increasing levels of 17β-estradiol in pubertal girls.

In addition, animal studies have demonstrated that hippocampal synaptic plasticity and neurogenesis in the adult brain are dependent on testosterone and estrogens (Galea et al., 2006, MacLusky et al., 2006). However, whether circulating steroid hormones exert organizational influence on brain morphology and structure in the adult period of humans is to date rather unknown (e.g., De Vries, 2004, Stein et al., 2008), but first recent studies indicated that pharmacologically induced changes in steroid levels lead to changes in neocortical volume in young adult transsexuals (Pol et al., 2006) and after menopause in women (Boccardi et al., 2006a, Eberling et al., 2003, Lord et al., 2008).

The aim of the present study was to investigate the role of levels of circulating estrogen, progesterone, and testosterone on regional sex differences in GM volume, using VBM on structural magnetic resonance (MR) images of healthy, young adult humans. Considering not only differences between women and men in brain-related domains including specific cognitive abilities (e.g., Kimura, 1996), the prevalence of some psychiatric and neurological diseases (e.g., Kessler et al., 1993), but also exciting congruence within the sexes (De Vries, 2004), our findings might help to shed further light on the functional and structural relevance of sex steroid hormones on the human brain in adulthood.

Section snippets

Subjects

Thirty-four healthy young subjects (17 women and 17 men; aged 26.6 ± 5 years, mean ± SD) in a narrow age range and with similar educational levels (≥ 12 years of education) were recruited via advertisement at the Medical University of Vienna, Austria. All subjects underwent a medical examination at the screening visit including medical history, electrocardiogram, and routine laboratory tests. Exclusion criteria were history of severe disease, any psychiatric or neurological disorder, drug abuse

Global sex differences

Total volumes of GM, WM, and CSF are given in Table 2. In this sample, we observed a trend towards smaller total GM volume in women compared to men (Mann–Whitney U-test due to non-normal distribution of total GM volume in men, U = 93, p = 0.076). In addition according to independent t-tests, women had significantly smaller total volumes of WM (t(32) = 3.71, p < 0.001), CSF (t(32) = 4.73, p < 0.0001), and intracranial volumes (t(32) = 4.58, p < 0.0001), but greater grey-to-white matter ratios (t(32) = −3.67, p < 

Discussion

In the present study, we found first-time evidence that even in young adulthood, regional GM volumes of sexual dimorphic areas as revealed by VBM are associated with circulating levels of sex hormones. Areas in which women had larger relative GM volumes compared to men were located in the left inferior frontal gyrus (triangular part), in the left superior parietal gyrus, in the right precuneus, and in the right inferior temporal gyrus after adjustment for total GM volume. Moreover, cluster GM

Conclusion

This is the first study indicating that circulating sex hormones are related to GM volume in sexually dimorphic brain areas in young adult subjects. Our findings point to an organizing action of steroid hormones on brain morphology, which might continue even after puberty in young adulthood. This might contribute to differences in neuronal processing associated with overt diversity (Kimura, 1996) or congruence (De Vries, 2004) in cognitive abilities between women and men, and might also be of

Acknowledgments

This research was supported by grants from the Austrian National Bank (OENB P11468) and the Medical Science Fund of the City of Vienna (BMF P2515) to R.L. The authors thank Christian Windischberger for technical assistance and Patrycja Stein, Christoph Spindelegger, and Ulrike Moser for medical support.

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