Invited reviewSex steroids and connectivity in the human brain: A review of neuroimaging studies
Introduction
Sex steroid hormones are mostly known for their role in development of sex organs and physical maturation during puberty (Grumbach et al., 2003). However, the brain is an important target for sex steroid hormones (McEwen et al., 1982, McEwen et al., 1984), wherein they operate as trophic factors affecting brain development and plasticity (Garcia-Segura and Melcangi, 2006). Specifically, from animal studies it has become clear that the sex steroid hormones testosterone, progesterone and estrogen are all able to stimulate neurite outgrowth, synapse number, dendritic branching and myelination (Cooke and Woolley, 2005, Romeo et al., 2004, Sa et al., 2009). These brain organizational effects of sex steroids can both be established by endogenous fluctuations during so-called ‘sensitive periods’ as well as by (exogenous) manipulations of estrogen, testosterone or progesterone (Hines, 2006, McCarthy, 2009). The role of sex steroid hormones in human brain function and organization is being increasingly emphasized (Pruessner et al., 2010, van Honk and Pruessner, 2010). In this review, we will explore the contribution of sex steroids to organizing structural and functional connections in the human brain.
Human neuroscience over the past decade has demonstrated that our brain operates by the way of functionally interconnected networks (Achard and Bullmore, 2007, Catani and Ffytche, 2005, Sporns et al., 2004). Functional connectivity is defined as the temporal correlation or coherence of distant neurophysiological events (Aertsen et al., 1989, Friston et al., 1993), suggesting communication between anatomically separated brain regions. Functional connectivity can be measured during a particular task or during rest. A growing number of studies have shown that resting state functional connectivity provides important insights in the organization of the human brain: i.e. how regions are linked together and how efficiently regions communicate with each other (for reviews see Bullmore and Sporns, 2009, Fox and Raichle, 2007, van den Heuvel and Hulshoff Pol, 2010). For example, individual differences in efficiency of functionally linked networks positively predicted individual variation in intellectual performance within healthy subjects (van den Heuvel et al., 2009b). Test–retest reliability of functional brain connectivity is found to be high during rest (Deuker et al., 2009, Zuo et al., 2010), therefore possibly representing a stable neurobiological trait. Nevertheless, functional connections are changing throughout development; children and adolescents show diffuse patterns of functional connections and mostly short-range connectivity, whereas adults seem to exhibit a more focal pattern of functional connectivity and long distance connections (Boersma et al., 2010, Dosenbach et al., 2010, Uddin et al., 2010).
Communication between brain regions is established through white matter bundles consisting of (myelinated) axons. The presence of a myelin membrane around the axon improves signal transduction (Sherman and Brophy, 2005) and, on the behavioral level, has been associated with improved cognitive and social functioning (Fornari et al., 2007, Paus, 2005). It is the myelin – an insulating substance created by glial cells – that is responsible for the tissue's white appearance. Histological studies pointed out that myelination of axons continues to occur through adolescence (Huttenlocher, 1990, Yakovlev et al., 1967). These post-mortem studies have been replicated by structural neuroimaging work, showing an increase of white matter volume (Paus et al., 1999) and white matter integrity (Asato et al., 2010) with development (for reviews see Paus, 2010, Schmithorst and Yuan, 2010). The overall organization and microstructural properties of white matter (such as myelin) form the basis of anatomical connectivity in the central nervous system (Kumar and Cook, 2002).
Importantly, sex steroids are able to influence myelination through their direct impact on glial cells (for review see: Garcia-Segura and Melcangi, 2006). For instance, progesterone increases the number of oligodendrocytes, the formation of myelin sheaths, and the synthesis of myelin proteins (Baulieu and Schumacher, 2000).
Also, sex steroid hormones (and their metabolites) increase gene-expression of myelin proteins (Melcangi et al., 2001). In addition, increased estradiol, progesterone and testosterone enhance Schwann cell proliferation (Fex Svenningsen and Kanje, 1999, Jordan and Williams, 2001). The effects of progesterone on Schwann cell proliferation were most pronounced in females and newborn rats as compared to male and/or older rats (Fex Svenningsen and Kanje, 1999).
Moreover, animal and human studies are accumulating that estradiol, progesterone and testosterone are capable of re-myelination after nerve injuries (Arevalo et al., 2010, De Nicola et al., 2006, Melcangi and Mensah-Nyagan, 2006). For example, evidence from multiple sclerosis, a demyelinating disease, suggests that testosterone and estradiol treatments have neuroprotective effects (Gold and Voskuhl, 2009) such as reduced demyelination and preservation of axon numbers in white matter (Tiwari-Woodruff et al., 2007). Thus, sex steroid hormones might play a pivotal role in organizing structural and, subsequently, functional connections in the human brain.
The prenatal period is a critical time for sex steroids to shape the brain (Collaer and Hines, 1995); sex steroids act on the central nervous system to organize neural circuits, which remain dormant until hormonal stimulation in adulthood activates these pathways to produce the appropriate adult behavior (Phoenix et al., 1959). This classical dichotomy has been named the organizational–activational hypothesis. Importantly, from animal studies it has become clear that changes in sex hormone surges during later phases of life are able to affect brain organization as well (Schulz et al., 2009). Examples of such large hormonal changes are increases during puberty and hormonal senescence during aging. Thus, the effects of steroid hormones on brain structure and function are likely an interaction of age-related changes and previous hormonal state of the individual (organizational effects of the hormones).
Taken together, brain connectivity has been increasingly studied at a functional and structural level. Structural and functional brain connections are correlated with cognitive performance and change with age. Nevertheless, the neurobiological processes contributing to (development of) brain connectivity largely remain to be unknown. Given their role in (re-)myelination, animal studies provide convincing support that sex steroid hormones are critically involved in the regulation of structural and functional connections in the human brain. In this paper, a review is presented on studies investigating the association between sex steroid hormones and connectivity in the healthy human brain measured with neuroimaging. We try to shed light on the following issues: in which pathways do sex steroid hormones exert their effects? And do sex hormones enhance or decrease levels of functional communication? What can be said about different developmental phases, such as puberty and adolescence, and aging? Evidence will be sought from studies on endogenous hormone fluctuations as well as from studies dealing with exogenous (i.e. direct manipulation of) hormonal levels. First, studies concerning white matter (the basis of anatomical brain connections) are discussed and second, an overview of studies on sex steroids and functional connectivity is provided. The results will be discussed in terms of the involvement of sex steroids in brain development and aging, as well as a possible biological mechanism for suggested ‘brain connectivity’ diseases such as multiple sclerosis (Rocca et al., 2009), schizophrenia (Mandl et al., 2010, Skudlarski et al., 2010), autism (Minshew and Keller, 2010), depression (Sheline et al., 2010, Shimony et al., 2009) and attention deficit hyperactivity disorder (ADHD) (Konrad and Eickhoff, 2010).
Section snippets
Method
A PubMed indexed search was carried out with a limitation of human studies using the following keywords (sex steroids) OR (gonadal hormones) OR (testosterone) OR (estradiol) OR (progresterone) AND (white matter) OR (structural connectivity) OR (functional connectivity) OR (synchronization) OR (resting state). Only studies using direct measures of sex hormonal levels (e.g. no sex differences) were included. Case studies or qualitative studies, as well as reports in languages other than English
Structural connectivity
Structural brain connectivity can be described as distinct anatomical regions connected by white matter pathways: the ‘information highways’ of the brain. Using standard T1-weighted MRI images, cerebral white matter appears bright and can be distinguished from gray matter and cerebrospinal fluid. White matter volumes can be quantified by applying intensity thresholds to the image. Focal estimates of white matter concentration (i.e. white matter density) can be obtained using voxel-based
Discussion
In this review, we tried to find evidence for a role of sex steroids in structural and functional human brain connections. Although animal research provides abundant data that testosterone, estrogens and progesterone are able to increase white matter microstructural properties such as myelination, human studies in this field of research still remain scarce. In general, it could be observed that increasing endogenous levels of testosterone during adolescence (mainly in boys) as well as estrogen
Possible implications
The results of this review indicate that ovarian hormones (estrogens and progesterone) enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) decrease subcortico-cortical functional connectivity but increase functional connectivity between subcortical brain areas. These findings might provide insights in the pathophysiology of neuropsychiatric illnesses with suggested aberrant brain connections and a typical sex difference in prevalence,
Methodological considerations and future directions
When interpreting the findings discussed in this review, several methodological issues need to be taken into account. We provided an overview of studies on endogenous hormonal levels as well as exogenous manipulations. Although both ways offer unique insight into the relation between sex steroids and brain connections, they differ obviously in interpretation of results and both approaches have their own advantages and disadvantage. For instance, exogenous manipulations have shown to be able to
Concluding remarks
Studying the role of sex steroid hormones in human brain function and organization is an exciting and important new field of research. Despite a wide variety of methods being applied to approximate their effects, evidence is accumulating that androgens, estrogens and progestins are critically involved in establishing proper communication in the human brain network. Therefore, when examining healthy brain development and aging or when investigating possible biological mechanisms of ‘brain
Conflict of interest
The authors declare no competing financial interests.
Role of funding source
This work was supported by a grant from the Dutch Organization for Scientific Research (NWO) to JSP (VENI 451-10-007) and to JvH (Brain & Cognition 056-24-010). JvH was also supported by grants from the Hope for Depression Foundation (HDRF) and Utrecht University High-Potential programme. These funding sources had no further role in the study design, in data collection, analysis and interpretator of the data.
Acknowledgments
The authors thank Dennis J.L.G. Schutter for valuable comments on earlier versions of the manuscript.
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