Sex steroids and brain structure in pubertal boys and girls

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Summary

Sex steroids exert important organizational effects on brain structure. Early in life, they are involved in brain sexual differentiation. During puberty, sex steroid levels increase considerably. However, to which extent sex steroid production is involved in structural brain development during human puberty remains unknown. The relationship between pubertal rises in testosterone and estradiol levels and brain structure was assessed in 37 boys and 41 girls (10–15 years). Global brain volumes were measured using volumetric-MRI. Regional gray and white matter were quantified with voxel-based morphometry (VBM), a technique which measures relative concentrations (‘density’) of gray and white matter after individual global differences in size and shape of brains have been removed.

Results showed that, corrected for age, global gray matter volume was negatively associated with estradiol levels in girls, and positively with testosterone levels in boys. Regionally, a higher estradiol level in girls was associated with decreases within prefrontal, parietal and middle temporal areas (corrected for age), and with increases in middle frontal-, inferior temporal- and middle occipital gyri. In boys, estradiol and testosterone levels were not related to regional brain structures, nor were testosterone levels in girls. Pubertal sex steroid levels could not explain regional sex differences in regional gray matter density. Boys were significantly younger than girls, which may explain part of the results.

In conclusion, in girls, with the progression of puberty, gray matter development is at least in part directly associated with increased levels of estradiol, whereas in boys, who are in a less advanced pubertal stage, such steroid-related development could not (yet) be found. We suggest that in pubertal girls, estradiol may be implicated in neuronal changes in the cerebral cortex during this important period of brain development.

Introduction

Puberty is an episode in life which is characterized by hormonal fluctuations. During this period, there is a marked increase in sex steroids testosterone and estradiol, the end products of the maturing hypothalamus–pituitary–gonadal (HPG)-axis (Grumbach and Styne, 2003).

During puberty, sex steroids lead to the maturation of secondary sexual characteristics in a sex-specific manner (Grumbach and Styne, 2003). However, sex steroids also exert a wide range of effects on brain morphology, as the brain is an important target tissue for steroid hormone receptors (McEwen et al., 1982, McEwen, 1984). Among the important organizing effects of sex steroids is their influence on neurogenesis, receptor expression and neurite outgrowth (Romeo and McEwen, 2004). Most of these organizational effects take place during the prenatal period; however, these effects are subject to changing hormonal fluctuations throughout life and are not always irreversible (Pilgrim and Hutchison, 1994). Indeed, in adults, pharmacologically induced changes in levels of testosterone and estradiol have been shown to alter total brain and hypothalamus volumes (Hulshoff Pol et al., 2006).

During puberty, global gray (GM) matter volume within the cerebrum decreases (Giedd et al., 1999) and white matter (WM) volume increases (Giedd et al., 1999, Paus et al., 1999). Also, region-specific gray matter decreases have been reported in frontal, parietal and temporal areas (Jernigan et al., 1991, Giedd et al., 1999, Sowell et al., 2002, Sowell et al., 2004, Gogtay et al., 2004, Wilke et al., 2007). It has been suggested that these neuro-anatomical changes during puberty and adolescence reflect the refinement of neuronal connections which could be related to cognitive and emotional development (Paus, 2005, Blakemore, 2008).

In keeping with the notion that puberty is a period of steroid-dependent brain organization (Romeo, 2003), the idea has been put forward that around the onset of puberty hormonal changes trigger selective neuro-anatomical alterations, as indirectly shown by gray matter decreases in frontal and parietal lobes (Giedd et al., 1999). Recently, in the early phase of puberty (at 9 years of age), elevated levels of the precursor of sex hormones, luteinizing hormone (LH) were found to be associated with cerebral white matter increases, whereas LH was not associated with gray matter (Peper et al., 2008). With the emergence of secondary characteristics of puberty (a result of sex steroid production), gray matter density decreases were found in frontal and parietal areas in 9-year-olds (Peper et al., in press). Thus, during early puberty, variation in pubertal mechanisms is accompanied by distinct structural brain changes. Interestingly, it was recently argued that the adolescent brain might respond differentially to changing steroid hormones levels over time (Sisk and Zehr, 2005) as brain development during puberty and adolescence is a dynamic and protracted process characterized by region-specific gray matter decreases and global white matter increases (Giedd et al., 2006). Consequently, it can be suggested that sex steroids testosterone and estradiol play a more prominent role in brain development in an advanced stage of puberty, compared to LH which is a marker of early puberty (Demir et al., 1996). In a first recent study on the interrelations between brain organization and sex steroid hormones in 30 children between 8 and 15 years of age, sex steroid levels were associated with sexual dimorphic gray matter areas (Neufang et al., in press).

The aim of the current study was to explore the interrelations between naturally occurring pubertal rises in testosterone and estradiol and brain structure in 10–15-year-old boys (37 subjects) and girls (41 subjects). As the progression of puberty is associated with global and regional gray matter decreases and white matter increases, it was expected that sex steroids are involved in these processes. The production of sex steroids occurs in a sex-specific manner. Also, the exposure to sex steroids has been implicated in the development and/or maintenance of sex differences in brain structure and these organizational effects of steroids are subject to changing hormonal fluctuations throughout life (Pilgrim and Hutchison, 1994). Therefore, we assessed the influence of sex steroids in boys and girls separately. Moreover, we explored to what extent pubertal rises of testosterone and estradiol levels are associated with sexually dimorphic brain areas.

Section snippets

Participants

The total sample consisted of 78 children between 10.0 and 14.9 years (Table 1), including 37 boys and 41 girls. These children are older siblings of twin-pairs which are described elsewhere (Peper et al., 2008, Peper et al., in press; van Leeuwen et al., 2008). Exclusion criteria consisted of any major medical or psychiatric illness and participation in special education. Parents and the participants themselves gave written informed consent to participate in the study. The study was approved

Pubertal hormones and secondary sexual characteristics

On average, girls were older than boys (F(1,77) = 5.45, p < .02) (Table 1). Moreover, girls were in more advanced stages of puberty (mean Tanner stage) (F(1,77) = 33.83, p < .0001). Indeed, all girls showed development of secondary sexual characteristics, compared to 62% of the boys (N = 23). After correction for age on the total sample of children, testosterone levels were equal in boys and girls (F(1,66) = 1.06, p = .31). Estradiol levels were higher in girls as compared to boys (F(1,71) = 32.20, p < .0001).

Discussion

To our knowledge, this is the first study investigating interrelations between naturally occurring pubertal rises in testosterone and estradiol and brain structure in 10–15-year-old boys (37 subjects) and girls (41 subjects) separately. Gray matter volume decreases with age was observed in girls only. After correcting for age, in girls, a higher level of estradiol was associated with a smaller global gray matter volume, whereas in boys, a higher level of testosterone was associated with larger

Role of the funding source

NWO had no further role in the study design, in data collection, analysis and interpretation of the data.

Conflict of interest

None declared.

Acknowledgments

This work was supported by a grant from the Dutch Organization for Scientific Research (NWO) to HEH (051.02.061) and HEH, DIB and RSK (051.02.060).

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    Current address: Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.

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