INVITED REVIEW

Sex steroids and connectivity in the human brain:A review of neuroimaging studies

Jiska S. Peper a,*, Martijn P. van den Heuvel b, Rene C.W. Mandl b,Hilleke E. Hulshoff Pol b, Jack van Honk c,d

a Institute of Psychology, Brain and Development Lab, Leiden University, The NetherlandsbRudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, The Netherlandsc Experimental Psychology, Utrecht University, The NetherlandsdDepartment of Psychiatry and Mental Health, University of Cape Town, South Africa

Received 9 March 2011; received in revised form 6 May 2011; accepted 6 May 2011

Psychoneuroendocrinology (2011) 36, 1101—1113

KEYWORDSDevelopment;Estradiol;Functional connectivity;Testosterone;White matter

Summary Our brain operates by the way of interconnected networks. Connections betweenbrain regions have been extensively studied at a functional and structural level, and impairedconnectivity has been postulated as an important pathophysiological mechanism underlyingseveral neuropsychiatric disorders. Yet the neurobiological mechanisms contributing to thedevelopment of functional and structural brain connections remain to be poorly understood.Interestingly, animal research has convincingly shown that sex steroid hormones (estrogens,progesterone and testosterone) are critically involved in myelination, forming the basis of whitematter connectivity in the central nervous system. To get insights, we reviewed studies into therelation between sex steroid hormones, white matter and functional connectivity in the humanbrain, measured with neuroimaging. Results suggest that sex hormones organize structuralconnections, and activate the brain areas they connect. These processes could underlie a betterintegration of structural and functional communication between brain regions with age. Specifi-cally, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical andsubcortico-cortical functional connectivity, whereas androgens (testosterone) may decreasesubcortico-cortical functional connectivity but increase functional connectivity between sub-cortical brain areas. Therefore, when examining healthy brain development and aging or wheninvestigating possible biological mechanisms of ‘brain connectivity’ diseases, the contribution ofsex steroids should not be ignored.# 2011 Elsevier Ltd. All rights reserved.

* Corresponding author at: Leiden Institute for Brain and Cognition, Brain and Development Lab, Leiden University, Wassenaarseweg 52, 2333AK Leiden, The Netherlands. Tel.: +31 71 527 6673; fax: +31 71 527 3619.

E-mail address: j.s.peper@fsw.leidenuniv.nl (J.S. Peper).

a va i l a ble at ww w. sc ie nce di r ect . com

j our na l h omepa g e: www.e l se v ie r.c om/l oca te/ psyne ue n

0306-4530/$ — see front matter # 2011 Elsevier Ltd. All rights reserved.

doi:10.1016/j.psyneuen.2011.05.004

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102

2. Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103

3.1. Structural connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103

3.1.1. Puberty and adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104

3.1.2. Elderly samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105

3.2. Functional connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106

3.2.1. Menstrual cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106

3.2.2. Exogenous sex steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107

5. Possible implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108

6. Methodological considerations and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109

7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109

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1. Introduction

Sex steroid hormones are mostly known for their role indevelopment of sex organs and physical maturation duringpuberty (Grumbach et al., 2003). However, the brain is animportant target for sex steroid hormones (McEwen et al.,1982, 1984), wherein they operate as trophic factors affect-ing brain development and plasticity (Garcia-Segura andMelcangi, 2006). Specifically, from animal studies it hasbecome clear that the sex steroid hormones testosterone,progesterone and estrogen are all able to stimulate neuriteoutgrowth, synapse number, dendritic branching and myeli-nation (Cooke and Woolley, 2005; Romeo et al., 2004; Saet al., 2009). These brain organizational effects of sexsteroids can both be established by endogenous fluctuationsduring so-called ‘sensitive periods’ as well as by (exogenous)manipulations of estrogen, testosterone or progesterone(Hines, 2006; McCarthy, 2009). The role of sex steroid hor-mones in human brain function and organization is beingincreasingly emphasized (Pruessner et al., 2010; van Honkand Pruessner, 2010). In this review, we will explore thecontribution of sex steroids to organizing structural andfunctional connections in the human brain.

Human neuroscience over the past decade has demon-strated that our brain operates by the way of functionallyinterconnected networks (Achard and Bullmore, 2007; Cataniand Ffytche, 2005; Sporns et al., 2004). Functional connec-tivity is defined as the temporal correlation or coherence ofdistant neurophysiological events (Aertsen et al., 1989; Fris-ton et al., 1993), suggesting communication between ana-tomically separated brain regions. Functional connectivitycan be measured during a particular task or during rest. Agrowing number of studies have shown that resting statefunctional connectivity provides important insights in theorganization of the human brain: i.e. how regions are linkedtogether and how efficiently regions communicate with eachother (for reviews see Bullmore and Sporns, 2009; Fox andRaichle, 2007; van den Heuvel and Hulshoff Pol, 2010). Forexample, individual differences in efficiency of functionallylinked networks positively predicted individual variation inintellectual performance within healthy subjects (van den

Heuvel et al., 2009b). Test—retest reliability of functionalbrain connectivity is found to be high during rest (Deukeret al., 2009; Zuo et al., 2010), therefore possibly represent-ing a stable neurobiological trait. Nevertheless, functionalconnections are changing throughout development; childrenand adolescents show diffuse patterns of functional connec-tions and mostly short-range connectivity, whereas adultsseem to exhibit a more focal pattern of functional connec-tivity and long distance connections (Boersma et al., 2010;Dosenbach et al., 2010; Uddin et al., 2010).

Communication between brain regions is establishedthrough white matter bundles consisting of (myelinated)axons. The presence of a myelin membrane around the axonimproves signal transduction (Sherman and Brophy, 2005)and, on the behavioral level, has been associated withimproved cognitive and social functioning (Fornari et al.,2007; Paus, 2005). It is the myelin — an insulating substancecreated by glial cells — that is responsible for the tissue’swhite appearance. Histological studies pointed out thatmyelination of axons continues to occur through adolescence(Huttenlocher, 1990; Yakovlev et al., 1967). These post-mortem studies have been replicated by structural neuroi-maging 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 andmicrostructural properties of white matter (such as myelin)form the basis of anatomical connectivity in the centralnervous system (Kumar and Cook, 2002).

Importantly, sex steroids are able to influence myelinationthrough their direct impact on glial cells (for review see:Garcia-Segura and Melcangi, 2006). For instance, progester-one increases the number of oligodendrocytes, the formationof 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 (Melcangiet al., 2001). In addition, increased estradiol, progesteroneand testosterone enhance Schwann cell proliferation (FexSvenningsen and Kanje, 1999; Jordan and Williams, 2001).The effects of progesterone on Schwann cell proliferation

Sex steroids and connectivity in the human brain 1103

were most pronounced in females and newborn rats ascompared to male and/or older rats (Fex Svenningsen andKanje, 1999).

Moreover, animal and human studies are accumulatingthat estradiol, progesterone and testosterone are capableof 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 demyeli-nating disease, suggests that testosterone and estradioltreatments have neuroprotective effects (Gold and Voskuhl,2009) such as reduced demyelination and preservation ofaxon numbers in white matter (Tiwari-Woodruff et al., 2007).Thus, sex steroid hormones might play a pivotal role inorganizing structural and, subsequently, functional connec-tions in the human brain.

The prenatal period is a critical time for sex steroids toshape the brain (Collaer and Hines, 1995); sex steroids act onthe central nervous system to organize neural circuits, whichremain dormant until hormonal stimulation in adulthoodactivates these pathways to produce the appropriate adultbehavior (Phoenix et al., 1959). This classical dichotomy hasbeen named the organizational—activational hypothesis.Importantly, from animal studies it has become clear thatchanges in sex hormone surges during later phases of life areable to affect brain organization as well (Schulz et al., 2009).Examples of such large hormonal changes are increases dur-ing puberty and hormonal senescence during aging. Thus, theeffects of steroid hormones on brain structure and functionare likely an interaction of age-related changes and previoushormonal state of the individual (organizational effects ofthe hormones).

Taken together, brain connectivity has been increasinglystudied at a functional and structural level. Structural andfunctional brain connections are correlated with cognitiveperformance and change with age. Nevertheless, the neu-robiological processes contributing to (development of)brain connectivity largely remain to be unknown. Giventheir role in (re-)myelination, animal studies provide con-vincing support that sex steroid hormones are criticallyinvolved in the regulation of structural and functionalconnections in the human brain. In this paper, a reviewis presented on studies investigating the associationbetween sex steroid hormones and connectivity in thehealthy human brain measured with neuroimaging. Wetry to shed light on the following issues: in which pathwaysdo sex steroid hormones exert their effects? And do sexhormones enhance or decrease levels of functional com-munication? What can be said about different developmen-tal phases, such as puberty and adolescence, and aging?Evidence will be sought from studies on endogenous hor-mone fluctuations as well as from studies dealing withexogenous (i.e. direct manipulation of) hormonal levels.First, studies concerning white matter (the basis of anato-mical brain connections) are discussed and second, anoverview of studies on sex steroids and functional connec-tivity is provided. The results will be discussed in terms ofthe involvement of sex steroids in brain development andaging, as well as a possible biological mechanism for sug-gested ‘brain connectivity’ diseases such as multiplesclerosis (Rocca et al., 2009), schizophrenia (Mandlet al., 2010; Skudlarski et al., 2010), autism (Minshewand Keller, 2010), depression (Sheline et al., 2010; Shimony

et al., 2009) and attention deficit hyperactivity disorder(ADHD) (Konrad and Eickhoff, 2010).

2. Method

A PubMed indexed search was carried out with a limitation ofhuman studies using the following keywords (sex steroids) OR(gonadal hormones) OR (testosterone) OR (estradiol) OR(progresterone) AND (white matter) OR (structural connec-tivity) OR (functional connectivity) OR (synchronization) OR(resting state). Only studies using direct measures of sexhormonal levels (e.g. no sex differences) were included. Casestudies or qualitative studies, as well as reports in languagesother than English were excluded.

Measures of white matter consisted of volume, density,hyperintensities, white matter organization or microstruc-ture, quantified by volumetric magnetic resonance imaging(MRI), voxel-based morphometry (VBM), Diffusion TensorImaging (DTI) or Magnetization Transfer Imaging (MTI).

Measures of functional connectivity consisted of restingstate activity, coherence and coupling quantified by func-tional MRI (fMRI/rsMRI), positron emission tomography (PET),electroencephalography (EEG) or magneto-encephalography(MEG). The search terms and inclusion criteria resulted in atotal number of 17 (white matter) and 13 (functional con-nectivity) data-papers on healthy subjects to be included inthis review.

3. Results

3.1. Structural connectivity

Structural brain connectivity can be described as distinctanatomical regions connected by white matter pathways: the‘information highways’ of the brain. Using standard T1-weighted MRI images, cerebral white matter appears brightand can be distinguished from gray matter and cerebrospinalfluid. White matter volumes can be quantified by applyingintensity thresholds to the image. Focal estimates of whitematter concentration (i.e. white matter density) can beobtained using voxel-based morphometry (VBM). WithVBM, regional differences in white matter are estimatedwithout being confounded by global brain size and shape(Ashburner and Friston, 2000). Using T1-weighted scans,global white matter volume can be quantified, representingtotal connectivity within the brain. When measuring totalwhite matter volume, a correction for total brain volume isusually applied, to measure the relative proportion of whitematter not confounded by differences in brain size. Othermeasures of white matter quantified by MRI are white matterhyperintensities, resulting from atrophy of axons and demye-lination that can be caused by (chronic) reduced local bloodflow (Pantoni and Garcia, 1997; Thomas et al., 2002).

A more direct way of quantifying white matter connec-tivity is Diffusion Tensor Imaging (DTI). DTI measures thediffusion profile of water molecules in vivo allowing us to(indirectly) study microstructural properties of the connect-ing white matter fiber bundles (Jones, 2008). Because inwhite matter fiber bundles the axons run in parallel, thediffusion profile is elongated, pointing in the direction of thefiber bundles. To the best of our knowledge, no human studies

Figure 1 The Hypothalamic-Pituitary-Gonadal (HPG)-axis.Interactions between the hypothalamus, pituitary gland andgonads (females: ovaries; males: testes) are shown. Interrela-tionships between hormones are depicted as stimulatory (+) orinhibitory (�).Adapted, with permission, from Cameron (2004).

1104 J.S. Peper et al.

have been performed that employed DTI and measured sexhormonal levels. Therefore, most studies measuring whitematter and sex steroid levels examined white matter volume,density or white matter hyperintensities. These studies havebeen carried out in pubertal and adolescent samples (partlydescribed elsewhere Peper et al., 2011), or in elderly sub-jects, such as postmenopausal women receiving estrogenreplacement therapy.

3.1.1. Puberty and adolescenceBrains of children in puberty and adolescence are subject toextensive changes. For instance, white matter fibers con-necting the striatum and thalamus to the prefrontal regions,as well as association fiber tracts between the prefrontalcortex and amygdala, and portions of the corpus callosum arestill not fully matured during adolescence (Asato et al., 2010;Bava et al., 2010) (for review, see: Schmithorst and Yuan,2010).

The massive increase in sex hormone levels during thisphase of life raises the possibility to examine to what extentpubertal hormones play a role in mediating brain structure(Blakemore et al., 2010; Peper et al., 2011). Puberty istypified by the reactivation of the hypothalamus—pitui-tary—gonadal (HPG)-axis (the HPG-axis has been relativelyquiet since activity during the perinatal period). In short,gonado-releasing hormone (GnRH) is released from hypotha-lamic neurons (Fig. 1). GnRH subsequently signals the pitui-tary gland to produce both luteinizing hormone (LH) andfollicle stimulating hormone (FSH). In males, LH increasesthe production of testosterone by Leydig cells in the testeswhereas in females, the ovaries produce the estrogen estra-diol. LH is predominantly responsible for ovulation (Grum-bach et al., 2003). Sex steroids in turn, suppress GnRHactivity via a negative feedback mechanism.

It has been proposed that large endogenous sex hormonefluctuations during puberty are capable of organizing braindevelopment (Romeo, 2003; Schulz et al., 2009; Sisk andZehr, 2005). As a consequence, neuronal connections createdduring pre/neonatal life could be modified under the influ-ence of large sex hormone surges taking place in this period.

The first studies directly relating sex hormone levels towhite matter development during puberty and adolescencedate from 2008 (Perrin et al., 2008) and correlated testos-terone levels in both boys and girls with whole brain whitematter volume. In a large sample of adolescents, Perrin et al.(2008) found that increased levels of testosterone predictedwhole brain white matter volume increase in boys, but not ingirls. Testosterone levels vary with the type of androgenreceptor (AR) polymorphism: a smaller number of CAGrepeats within the AR-gene has been associated with higherbasal levels of testosterone (Brum et al., 2005; Manuck et al.,2010). Indeed, the strength of the association between whitematter volume and testosterone depended on the type ofandrogen receptor (AR) polymorphism: boys with relativelyshort variants exhibited a stronger association between tes-tosterone level and white matter volume (Perrin et al.,2008). Moreover, the functional polymorphism in AR alsomodulates age-related increase in relative white mattervolume in boys (Paus et al., 2010), with the short variantsof the AR-gene explaining more age-related white matterincrease than relatively longer variants. In addition to T1-weighted images to measure white matter volume, Perrin

and colleagues applied Magnetization Transfer Imaging (MTI).MTI is an MRI technique assumed to measure the amount ofmacromolecules in tissue (Wolff and Balaban, 1994) and iscorrelated with myelination (Schmierer et al., 2004).Increased levels of testosterone were related to a relativedecrease in MTI signal (Perrin et al., 2008). The authorssuggested that possibly not only myelin increases duringadolescence but also axonal diameter, leading to relativedecreased MTI-signal (Paus, 2010). Indeed, the finding thatandrogens are capable of modulating axonal growth (Fargoet al., 2008) supports this hypothesis.

In less advanced pubertal children (than the samples ofPaus et al., 2010; Perrin et al., 2008), no association wasfound between regional white matter density and testoster-one or estradiol levels in either sex (Peper et al., 2009). Theage difference between the samples (i.e. a mean differenceof approximately 4 years) might account for this discrepancy.Interestingly, luteinizing hormone (LH) secretion precedesthe production of sex steroids by 1—2 years, before externalsigns of puberty are visible (Demir et al., 1996), and LHreceptors are found throughout the brain (Lei and Rao,2001). We therefore focussed on this early endocrinologicalmarker of puberty and white matter growth in 9-year oldchildren. It was found that higher levels of LH are related toincreased overall white matter volume as well as withincreased regional white matter density in prefrontal and

Sex steroids and connectivity in the human brain 1105

temporal brain areas (Peper et al., 2008) (Fig. 2). During thisearly pubertal phase, sex steroids testosterone and estradiolcould not be related to white matter growth. The authorsargued that during different stages of pubertal maturation,distinct pubertal hormones are involved in regulating whitematter growth (Peper et al., 2009).

Although no direct hormonal levels were quantified, Asatoet al. (2010) associated stages of puberty (a proxy of puberty-related increases of estradiol and testosterone) with whitematter structure measured with DTI. They demonstrated thatby mid-puberty, projection fibers connecting the striatumand thalamus to the prefrontal regions, as well as associationfiber tracts, such as the uncinate fasciculus, and more poster-ior mid portions of the corpus callosum are still immature(Asato et al., 2010). Higher integrity of fiber tracts has beenassociated with higher order cognitive functioning (Cataniand Mesulam, 2008). Tracts showing significant maturation byadolescence included the upper brain stem regions of thecorticospinal tract, frontal portions of the corona radiata andthe occipital portion of the inferior fronto-occipital fascicu-lus, i.e. tracts involved in motor and sensory skills (Kandelet al., 2000).

Figure 2 Luteinizing hormone concentration and white matterdensity in early pubertal children. The figure depicts increasedwhite matter density with higher LH levels in 9-year old children(N = 104), corrected for sex. (A) Left cingulum, (B) bilateralmiddle temporal gyri, (C) splenium of the corpus callosum.Displayed are z-values, with the critical z-value of 3.39(a = .05; FDR-corrected)(Peper et al., 2008, reprinted with permission).

3.1.2. Elderly samplesWith respect to normal aging, compromised connectivity hasbeen reported between the hippocampus and posterior brainareas (Dennis et al., 2008) and within the so-called ‘DefaultMode Network’ (DMN), including the superior and middlefrontal gyri, posterior cingulate, middle temporal gyrus,and the superior parietal cortex (Damoiseaux et al., 2008)(for review see Goh, 2011).

White matter volumes have been quantified in healthyelderly subjects after using sex hormone treatments.These treatments, hereafter referred to as hormone repla-cement therapy (HRT), often consist of estrogens, some-times combined with progestin (i.e. progesterone receptoragonists, Ellmann et al., 2009). HRT can be prescribed totreat menopause-related symptoms such as osteoporosisand hot flashes (Grady et al., 1992). Thus, other thanadolescent studies that investigated endogenous sex ster-oid fluctuations, studies in elderly samples mostly scruti-nize the (exogenous) manipulation of sex steroid levels andits role in brain organization (and functional connections,see later on).

There is abundant support for the ‘neuroprotective’effect of estrogens: symptoms of brain aging such as degen-eration of neuronal circuits (Morrison and Hof, 1997) can besuppressed by estrogen (e.g. see reviews by Norbury et al.,2003; Sherwin and Henry, 2008; Smith and Zubieta, 2001; vanAmelsvoort et al., 2001; Wise et al., 2005). For example,estradiol suppresses apoptotic cell death and enhancesexpression of genes that optimize cell survival (Wise,2006). The impact of estrogens on gray matter seems tobe dependent on the specific estrogenic compound used,its route of administration and the time of therapy initiation(Sherwin, 2009).

The role of exogenous estrogens and other sex steroids onwhite matter is less clear. A number of studies carried out inhealthy postmenopausal women have focussed on whitematter hyperintensities. It has been reported that HRTreduces the number and size of white matter hyperintensities(Cook et al., 2002; Liu et al., 2009; Schmidt et al., 1996). Theinverse association between HRT and white matter hyper-intensities was only present in women over 70 years of age(Liu et al., 2009), possibly caused by longer duration ofestrogen therapy in older subjects as reported earlier(Schmidt et al., 1996), Or, alternatively, the 70+ womenmight have had an extended period without hormone expo-sure prior to treatment, making the system more sensitive tohormone treatment later.

Although HRT can consist of a combination of estrogensand progesterone or of estrogens only, diminished whitematter hyperintensities are found to be due to estrogensonly (Liu et al., 2009). Other studies failed to find an associa-tion between HRT and white matter hyperintensities (Lowet al., 2006; Luoto et al., 2000).

With respect to white matter volumes, long-term use ofHRT was associated with an increase of white matter of thewhole brain (Greenberg et al., 2006; Ha et al., 2007, but seeLow et al., 2006) and in the medial temporal lobes (Ericksonet al., 2005) compared to non-HRT users.

In elderly men, no association between endogenous tes-tosterone levels and white matter volumes or white matterhyperintensities was found (Irie et al., 2006; Lessov-Schlag-gar et al., 2005).

1106 J.S. Peper et al.

In sum, studies on white matter volume, density andhyperintensities suggest that sex steroids are implicated instructural connectivity in the human brain: increasing endo-genous levels of testosterone (and LH) during adolescenceand estrogen and progesterone administration during post-menopause are associated with an increase of white mattervolume and a decrease of white matter lesions. The positiveassociation between increased sex steroids and white matterwas found within the cortex as well as in subcortical areas,but was not demonstrated (or investigated) in adolescentgirls or in elderly men. White matter bundles form theneuroanatomical basis of functional connections betweenbrain regions: they allow for communication between widelydistributed and specialized brain areas. In the second part ofthis review, it will be investigated whether sex steroidhormones play a role in functional connections in the brain,and if so: do they enhance or decrease communication and inwhich pathways?

3.2. Functional connectivity

Besides structural white matter connections between brainregions, functional connections, believed to reflect synchro-nization of neuronal activity patterns of anatomically sepa-rated brain regions (Aertsen and Arndt, 1993; Friston et al.,1993; Lowe et al., 2002) have also been examined in thecontext of sex hormones. This synchronization of neuralactivity can be estimated by measuring statistical interde-pendencies between physiological signals such as (resting-state) fMRI BOLD, EEG, MEG and PET (Biswal et al., 1995;Friston et al., 1993; Mazoyer et al., 2001; Stam, 2005).Commonly used measures of functional connectivity arecoherence and coupling (linear measures based on correla-tions) or synchronisation likelihood (non-linear measure)(Stam et al., 2006). Physiological signals can be acquiredat rest or when involved in a specific task. Moreover, func-tional connectivity can be analysed using a region-of-interest(ROI) approach, or — more exploratory — based on a model-free approach, examining functional connectivity betweenall brain regions.

In line with the initial organizational/activational hypoth-esis of sex steroids (Phoenix et al., 1959), it might be arguedthat functional connections are activated during rapidlychanging hormonal milieus such as over the menstrual cycleor after a single administration of sex steroids, whereasstructural connections in the brain network are organizedby more gradually changing levels of sex steroids, such asduring puberty or aging.

3.2.1. Menstrual cycleThe relation between endogenous sex steroid levels andfunctional brain connections can be examined during differ-ent stages of the menstrual cycle. During the menstrual cycleendogenous levels of estradiol and progesterone show con-siderable fluctuations. While during menses both estradioland progesterone levels are low, estradiol levels are highestduring the follicular phase of the cycle (i.e. just beforeovulation around day 10) and progesterone reaches its peakin the midluteal phase around day 22 (Vollman, 1977). In arecent review, the association between functional connec-tivity and endogenous sex hormone fluctuations across themenstrual cycle was described (Weis and Hausmann, 2010).

For example, enhanced levels of estradiol and progesteroneduring the luteal phase of the menstrual cycle are correlatedwith less interhemispheric inhibition (i.e. the suppression ofone hemisphere by the other across the corpus callosum)during a verbal task (Weis et al., 2008) and during a spatialcognitive task (Weis et al., 2010). Moreover, functional con-nectivity between the right temporal lobe and left inferiorparietal lobe is higher within the luteal phase compared tothe menstrual phase (Weis et al., 2010). These data indicatethat when endogenous estradiol and progesterone levels arehigh, functional communication between both hemispheresis enhanced.

3.2.2. Exogenous sex steroidsThe first studies investigating the influence of exogenous sexsteroids and functional connectivity in healthy subjects,found that testosterone is able to modulate functional con-nectivity, measured with EEG (Schutter et al., 2005; Schutterand van Honk, 2004). Specifically, it was reported that duringrest, after a single administration of testosterone in healthywomen, the correlation between low and high frequency EEGpower disappeared, in comparison to placebo (Schutter andvan Honk, 2004). Moreover, the same pattern of diminishedhigh—low frequency coupling in frontal brain areas could beobserved in men with high endogenous testosterone levelscompared to men with low endogenous testosterone (Mis-kovic and Schmidt, 2009). It has been suggested that lowfrequency oscillations reflect subcortical processes, whereashigh frequency neuronal patterns are associated with corticalprocesses (Knyazev, 2007; Robinson, 1999). It was thereforetheorized that testosterone reduces functional communica-tion between subcortical and cortical brain areas (Schutterand van Honk, 2004). Using fMRI, the above hypothesis ofreduced cortico-subcortical connectivity after testosteroneincreases was further strengthened by van Wingen et al.(2010). These authors reported reduced coupling betweenthe amygdala and orbitofrontal cortex (OFC) after a singledose of testosterone administration to healthy women, dur-ing an emotional face-matching task (Fig. 3). Moreover,subcortical connectivity between the amygdala and thalamuswas increased (van Wingen et al., 2010). It was suggestedthat testosterone induced a shift in the amygdalar output:away from the OFC and towards the thalamus (for review see:Bos et al., 2011). This might have implications for lessimpulse control as higher endogenous levels of testosteronewere related to less engagement of impulse control regionssuch as the medial OFC (Mehta and Beer, 2010) and PFC(Stanton et al., 2009). Moreover, it was recently reportedthat high basal levels of testosterone predict less connectiv-ity between the prefrontal cortex and the amygdala in ansocio-emotional processing task (Volman et al., 2011). Thisrecent study by Volman and colleagues supports the assump-tion that testosterone reduces (long-distance) cortico-sub-cortico functional connectivity.

Similar to studies tapping into white matter, effects ofexogenous estrogens on functional connectivity have beenexamined in postmenopausal women. These studies oftenmake use of a ROI-based approach. Ottowitz and colleaguesused resting state PET 24 h after a graded estrogen infusion,to measure covariance of cerebral glucose consumptionbetween the hippocampus (Ottowitz et al., 2008a) or amyg-dala (Ottowitz et al., 2008b) and all other parts of the brain.

Figure 3 Functional decoupling between the amygdala and orbitofrontal cortex after testosterone administration. Testosteronereduces functional coupling of the left amygdala with the left orbitofrontal cortex. Whereas the orbitofrontal cortex was positivelycoupled to the amygdala in the placebo condition, no significant coupling was observed in the testosterone condition. The left panelshows a transverse slice (z = �14) at the peak voxel ( p < 0.001, uncorrected), and the right panel shows the mean regressioncoefficient (�SEM) within the significant cluster (at p < 0.001, uncorrected) in arbitrary units.(From van Wingen et al., 2010, reprinted with permission).

Sex steroids and connectivity in the human brain 1107

Both the amygdala and hippocampus play important roles incortical—subcortical communication (Amaral and Price,1984; Lavenex and Amaral, 2000). Estrogen infusion resultedin premenopausal estrogen levels comparable to the follicu-lar phase of the menstrual cycle, whereas baseline measure-ments represented postmenopausal estrogen levels. It wasfound that estrogen infusion resulted in increased functionalconnectivity between the hippocampus and superior andmiddle frontal gyri (Ottowitz et al., 2008a). Furthermore,functional connectivity also increased between the amygdalaand superior and middle temporal cortices and between theamygdala and superior, ventrolateral and medial prefrontalcortices (Ottowitz et al., 2008b). Among the reported beha-vioral results of increased estrogen-induced functional con-nectivity between the hippocampus, amygdala andprefrontal cortex are enhanced verbal memory (Maki,2005) and less depressive symptomatology (Gillies andMcArthur, 2010). Thus, in contrast with testosterone admin-istration, exogenous estrogen increases functional connec-tivity between cortical and subcortical brain areas.

Functional (subcortical) connectivity between the thala-mus and basal ganglia has also been examined in estrogen-using postmenopausal women (Kenna et al., 2009). Thethalamus and basal ganglia play an important role in mod-ulating cholinergic and dopaminergic systems (Kimura et al.,2004) and estrogen positively impacts activity of both sys-tems (Dluzen and Horstink, 2003; Dumas et al., 2008). UsingPET, functional connectivity between the thalamus and basalganglia was only present in postmenopausal women usingestrogens and not control postmenopausal women (Kennaet al., 2009). Taken together, these PET-studies suggest thatincreased levels of exogenous estrogen are involved in bothenhanced cortical—subcortical cross-talk and increased com-munication within subcortical regions.

Besides exogenous estrogen, functional brain connectivityafter (a single) progesterone administration has been exam-ined (van Wingen et al., 2008). Using fMRI in healthy youngwomen, decreased connectivity between the amygdala andfusiform gyrus was demonstrated after a single administra-tion of progesterone, versus (less pronounced) increasedconnectivity between the amygdala and dorsal anterior cin-

gulate cortex (ACC), compared to placebo (van Wingen et al.,2008). The authors argued that progesterone, or its neuroac-tive steroid allopregnanolone acts on GABA receptors, animportant inhibitory neurotransmitter, thereby possiblyreducing output from the amygdala.

In sum, studies on functional connectivity suggest that sexsteroids are able to influence subcortico-cortical communi-cation, as well as cortico-cortical communication. Exogenousand endogenous testosterone levels seem to decrease sub-cortical—cortical connectivity, whereas testosteroneincreases connectivity between subcortical areas. In addi-tion, administration of estradiol and progesterone as well ashigher endogenous levels relate to increased functional con-nectivity within the cortex as well as increased functionalcortico-subcortical connectivity.

4. Discussion

In this review, we tried to find evidence for a role of sexsteroids in structural and functional human brain connec-tions. Although animal research provides abundant data thattestosterone, estrogens and progesterone are able toincrease white matter microstructural properties such asmyelination, human studies in this field of research stillremain scarce. In general, it could be observed that increas-ing endogenous levels of testosterone during adolescence(mainly in boys) as well as estrogen and progesterone admin-istration in post-menopausal women are associated with anincrease of white matter and with a decrease of white matterhyperintensities. This sex steroid-related increase of whitematter is reported to be a global effect, whereas no informa-tion on specific white matter pathways was available. Inadolescent girls and elderly men, sex steroids could not beassociated with neither white matter volume nor with (less)white matter hyperintensities.

Studies on functional connectivity provided a more spe-cific pattern of associations with sex steroids. Overall, exo-genous and endogenous levels of testosterone seem todecrease subcortical—cortical connectivity, whereas theyincrease connectivity between subcortical brain areas. In

1108 J.S. Peper et al.

addition, administration of estradiol and progesterone aswell as higher endogenous levels relate to increased func-tional connectivity within the cortex and between the cor-tex and subcortex. The brain areas mainly reported to beinvolved included: amygdala, hippocampus, thalamus, basalganglia, prefrontal cortex (orbitofrontal, anterior cingulateand superior frontal gyrus), known for their high density ofsex steroid receptors (Simerly et al., 1990). The pattern ofaltered functional connectivity after sex steroid adminis-tration or internal hormone fluctuations was reported notonly during rest, but also during emotional or languageprocessing.

In general, it seems that endogenous and exogenous sexsteroids are associated with a larger white matter volumeand with less white matter hyperintensities, providing thebasis for anatomical connectivity in the brain. It might beargued that the effects of a single administration are tran-sient and cannot exert long-lasting (organizational) effectson structural brain connections. Functional connections how-ever, might be more susceptible to (or activated by) singleadministrations of sex steroids (at least pertaining to task-related brain connectivity, as demonstrated by Ottowitzet al., 2008a,b; Schutter et al., 2005; van Wingen et al.,2010). Anatomical connectivity on the other hand, might bealtered by a more gradual increase of endogenous steroidlevels, such as during puberty (Schulz et al., 2009). Indeedduring this period white matter volume is increasing withrising levels of testosterone (Paus et al., 2010; Perrin et al.,2008).

However, in this context it might be reasoned that anato-mical and functional connectivity cannot be regarded as twoloosely coupled entities. Therefore, an alternative hypoth-esis could be postulated. Recently, a positive relationshipbetween functional and structural connectivity of the brainnetwork was found (Hagmann et al., 2008; van den Heuvelet al., 2009a) and this relationship strengthened with age(Hagmann et al., 2010). Conform the earlier mentioneddichotomy between organizational and activational effectsof sex steroids (Phoenix et al., 1959), it might be argued thatsex hormones organize structural connections, and activatethe brain areas they connect, leading towards a betterintegration of structural and functional communicationbetween brain regions with age. To further speculate onthat, in the elderly the integration between structural andfunctional communication might decline again (at least per-taining to cognitive processing Andrews-Hanna et al., 2007),possibly through naturally diminishing levels of estrogens andandrogens. Thus, the effects of steroid hormones on brainstructure and function are likely an interaction of age-related changes and previous hormonal state of the indivi-dual (organizational effects of the hormones). This is ahypothesis however, that should optimally be tested withinlongitudinal designs, or within samples covering a large age-range.

5. Possible implications

The results of this review indicate that ovarian hormones(estrogens and progesterone) enhance both cortico-corticaland subcortico-cortical functional connectivity, whereasandrogens (testosterone) decrease subcortico-cortical func-

tional connectivity but increase functional connectivitybetween subcortical brain areas. These findings might pro-vide insights in the pathophysiology of neuropsychiatric ill-nesses with suggested aberrant brain connections and atypical sex difference in prevalence, such as autism, schizo-phrenia and ADHD (males > females) and depression (fema-les > males) (Cahill, 2006). It might be hypothesized that sexsteroids play a role in modulating aberrant connections inthese illnesses.

For instance, in autism spectrum disorder, abnormalitiesin white matter microstructure (Shukla et al., 2010) andvolume (Hardan et al., 2009) have been reported in thecorpus callosum, suggesting suboptimal long-range interhe-mispheric communication. Moreover, a recent study demon-strated an excess of short-range connections and a lack oflong-range connections in autism spectrum disorder (Bartt-feld et al., 2011). Interestingly, autistic traits were found tobe associated with high levels of (prenatal) testosterone(Auyeung et al., 2010; Chura et al., 2010).

Sex steroid production has also been proposed as apotential mechanism contributing to the development ofADHD and major depressive disorder (MDD) (Martel et al.,2009). In their review, Martel et al. put forward thatprenatal testosterone may modulate striatally based dopa-minergic circuits (leading to a greater risk for boys todevelop attentional and hyperactivity symptoms). In addi-tion, they hypothesized that estradiol may impair (short-range) communication within serotonergic pathways (lead-ing to a risk of developing mood disorders) (Martel et al.,2009). Schizophrenia is another suggested ‘disconnectivity’syndrome with a dominant male prevalence (Aleman et al.,2003). It was recently found that schizophrenia patientshave suboptimal globally integrated structural brain net-works, resulting in a restricted structural capacity toincorporate information across distant brain areas (Lynallet al., 2010; van den Heuvel et al., 2010; Zalesky et al.,2011). Interestingly, high endogenous testosterone levelshave been marked as a possible mediator of the vulner-ability to develop psychotic symptoms (van Rijn et al.,2011).

Taken together, these studies provide evidence that tes-tosterone might be implicated in the development of aber-rant long-range connections observed in ADHD, schizophreniaand autism. Moreover, autism and ADHD are diagnosed earlyin development, in addition to being correlated with testos-terone exposure. In contrast, schizophrenia and depressionare more likely to be diagnosed or present after the onset ofpuberty, later in life. Thus, the concept of developmentshould be considered an important component of sex hor-mones and brain function.

Although the effects of exogenous testosterone on whitematter in healthy subjects have not been investigated, stu-dies in certain patient populations receiving testosteronetreatment report changes in white matter. For example,studies in multiple sclerosis, a demyelinating disease, sug-gest that testosterone (and estradiol) treatments have neu-roprotective effects (Gold and Voskuhl, 2009) such asreduced demyelination and preservation of axon numbersin white matter (Tiwari-Woodruff et al., 2007). White mattervolumes were not altered in transsexual patients receivingcross-sex hormone administrations (Hulshoff Pol et al.,2006).

Sex steroids and connectivity in the human brain 1109

Conditions in which patients suffer from gonadal abnorm-alities such as — but not limited to — hypogonadal gonadism,Klinefelter syndrome (low levels of testosterone, Steinmanet al., 2009) or polycystic ovary syndrome (high levels oftestosterone) and receive hormonal replacement therapiescould also shed light on the effects of sex steroid adminis-tration on brain circuitries. However, to the best of ourknowledge, studies directly focussing on sex steroid treat-ment on white matter (lesions) or functional connectivity inthese conditions are currently lacking.

6. Methodological considerations and futuredirections

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 hormonallevels as well as exogenous manipulations. Although bothways offer unique insight into the relation between sexsteroids and brain connections, they differ obviously in inter-pretation of results and both approaches have their ownadvantages and disadvantage. For instance, exogenousmanipulations have shown to be able to directly affect brainnetworks, whereas studying endogenous levels of sex steroidsonly provides an indirect measure (correlational research)and no causal inferences can be drawn. When applying anelegant within subject-placebo controlled design, partici-pants form their own controls and the effects of sex hor-mones can be directly compared within the same individual.On the other hand, (long-term) administration of gonadalhormones to healthy developing individuals might pose ethi-cal constraints.

Pertaining to the direction of causation, it should be notedthat the relation between sex steroids and white matter is bi-directional. Sex hormones are able to increase white matterparameters (e.g. axons, myelination, or supporting glialcells), and, conversely, sex steroids can also be producedfrom white matter (glial steroidogenesis) as shown by animalstudies (Garcia-Segura and Melcangi, 2006) and by humanpost-mortem work (Steckelbroeck et al., 1999).

With respect to processing of MRI data, different types ofbrain analyses could introduce dissimilar findings across stu-dies. For example, by employing a region-of-interest (ROI)approach, functional connections between possibly relevantbrain areas might stay undetected, whereas these areasmight have been observed using a (model-free) whole braintype of analysis. Studies employing ROIs have carefully cho-sen their targets based on for example a high density of sexsteroid receptors, or on earlier reported associations with sexsteroids. This could have introduced a bias towards certainbrain regions to be reported more often (e.g. the amygdalaand hippocampus) than others, such as the cerebellum.Indeed the cerebellum is a brain structure known for its highdensity of sex steroids (Dean and McCarthy, 2008) and theinvolvement in motor, cognitive and affective processes(Schutter and van Honk, 2005).

Thus, ovarian hormones (estradiol and progesterone)seem to enhance both cortico-cortical and subcortico-corti-cal functional connectivity, whereas androgens (testoster-one) may increase functional connectivity betweensubcortical brain areas but decrease subcortico-cortical

functional connectivity. Further research is needed to estab-lish the anatomical basis of these functional connections inthe human brain. Diffusion tensor imaging could be a methodof choice, since this technique enables the examinationcomplete white matter tracts (and microstructural proper-ties of these tracts) of connecting brain areas (Jones, 2008).However, to date no human studies have been carried outthat employed DTI and measured sex hormonal levels, leav-ing the specific white matter tracts on which sex steroidsexert their effects unexplored.

7. Concluding remarks

Studying the role of sex steroid hormones in human brainfunction and organization is an exciting and important newfield of research. Despite a wide variety of methods beingapplied to approximate their effects, evidence is accumulat-ing that androgens, estrogens and progestins are criticallyinvolved in establishing proper communication in the humanbrain network. Therefore, when examining healthy braindevelopment and aging or when investigating possible bio-logical mechanisms of ‘brain connectivity’ diseases, such asdepression, ADHD, autism and schizophrenia, the contribu-tion of sex steroids should not be ignored.

Conflict of interest

The authors declare no competing financial interests.

Role of funding source

This work was supported by a grant from the Dutch Organiza-tion for Scientific Research (NWO) to JSP (VENI 451-10-007)and to JvH (Brain & Cognition 056-24-010). JvH was alsosupported 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 com-ments on earlier versions of the manuscript.

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