How its Made: Organisational Effects of Hormones on the

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Journal of Neuroendocrinology
From Molecular to Translational Neurobiology
Journal of Neuroendocrinology 22, 736–742
ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd
REVIEW ARTICLE
How it’s Made: Organisational Effects of Hormones on the Developing
Brain
M. M. McCarthy
Departments of Physiology and Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Journal of
Neuroendocrinology
Correspondence to:
Margaret M. McCarthy, Departments
of Physiology and Psychiatry,
University of Maryland School of
Medicine, Baltimore, MD 21201, USA
(e-mail: mmccarth@umaryland.edu).
Gonadal steroid hormones exert permanent organisational effects on the developing brain and
thereby direct adult hormonal responsiveness to dictate sex-specific behaviour and physiology.
Considerable progress has been made in elucidating the cellular mechanism of action of androgens and oestrogens during the perinatal sensitive period during which organisation occurs. This
review highlights the findings obtained with respect to differential cell death and synaptogenesis
with an emphasis on region-specific mechanisms that involve diverse signalling molecules
including tumour necrosis factor-a, BAX, GABA, glutamate, prostaglandin E2, FAK and paxillin.
Key words: oestrogens, androgens, GABA, TNFa, prostaglandins, sexual differentiation.
Elucidating the cellular mechanisms by which steroids permanently
organise the developing brain along a masculine or feminine phenotype has been best advanced by the study of animal models.
These findings are of considerable interest in their own right for
what they teach us about the myriad of ways that hormones can
act to modify the nervous system and behaviour, as well as the
various strategies for filling an ecological niche by diversifying
within one species. However, when it comes to the study of sex
differences in the mammalian brain, the question of how it relates
to humans almost invariably arises, although the answers remain
elusive.
There are two major challenges to the study of the biological
basis of sex differences in human brain and behaviour. One is the
pervasive and unavoidable impact of culture, society, parental
expectations and experience. Research on animals has taught us
that experience can modify the brain in as profound a way as
genetics or hormones, and that the resultant changes are indeed
biological. However, in humans, the combination of these forces is
infinitely variable and we can therefore never isolate them from a
single parameter such as hormones. Thus, it is possible that we will
never be able to achieve the level of understanding of sexual differentiation of the human brain that we can for animals on which we
can conduct controlled experiments. Furthermore, this speaks
directly to the second challenge, which is that we know enough
about the process in rodents, birds, nonhuman primates and
humans to realise that there is a distinction in the primary mediating hormone. The majority of endpoints sexually differentiated in
the rodent or bird brain are the result of oestradiol action during a
perinatal sensitive period. Androgens certainly play a role, and the
doi: 10.1111/j.1365-2826.2010.02021.x
complexity of that role is continuing to emerge (1), although the
need for oestrogens to (at the very least) initiate the process is
clear. By contrast, in primates, including humans, there is no clear
need for oestrogens for psychosexual differentiation. We know this
both from the extensive studies performed in primates (2) and naturally occurring variations in humans such as XY women with
androgen insensitivity syndrome and XX men with null mutations
in the oestrogen receptor or aromatase enzyme. In each case, gender identity follows the lines of androgens, and not oestrogens (3,
4). It has been argued that this makes studies in rodents irrelevant
to understanding primates. However, this conclusion is premature
in the absence of knowledge about the cellular cascades that are
initiated by steroids to organise the brain along a masculine or
feminine phenotype because it is these signalling pathways that
genuinely change the brain, and not the steroids themselves. Oestrogens and androgens may converge on the same cellular cascades
and therefore ultimately have the same effect in the rodent and
primate brain, or they make invoke entirely separate mechanisms
and the two systems may have no bearing on each other. Until we
know the cellular mechanisms beyond steroid binding in at least
one species, we cannot even begin to address this question. The
goal of this review is to summarise the current state-of-the-art
regarding some of those mechanisms in the laboratory rat.
Sex differences in the brain are established during
a developmental sensitive period
At present, we consider it self-evident that sex differences in
behaviour are the direct descent of sex differences in the brain, but
Organisational effects of hormones on the developing brain
it was not always so. The beginning of the modern era is marked
by a single publication in 1959 in the journal Endocrinology titled
‘Organising action of prenatally administered testosterone propionate on the tissues mediating mating behaviour in the female guinea pig,’ by Phoenix, Goy, Gerall and Young (5). There are two
things about this paper that make it remarkable. The first is the
clear articulation and testing of the hypothesis that developmental
hormonal exposure determined adult behaviour. This has since been
codified as the iconic organisational ⁄ activational hypothesis of sexual differentiation of the brain (Fig. 1). The second is the title; note
the use of the word ‘tissue’ instead of brain. The concluding paragraph of the paper included the statement ‘An assumption seldom
made explicit is that modification of behavior follows an alteration
in the structure or function of the neural correlates of that behavior. We are assuming that testosterone or some metabolite acts on
those central nervous tissues in which patterns of sexual behavior
are organised.’ This was the authors planting the flag, their version
of the Watson and Crick ‘It has not escaped our notice that the
specific pairing we have postulated immediately suggests a possible
copying mechanism for the genetic material’ at the end of their
1953 paper describing the structure of DNA. The claim of Phoenix
et al. (5) that hormones permanently organised the developing
brain to determine adult behaviour was equally heretical and transforming.
A third no less remarkable aspect of this paper was that it also
foreshadowed the discovery that, in many instances, it was the
Sensitive period
Male plasma testosterone levels
Conception
Late gestation
E2
Birth
Puberty
T
Organisation
Activation
Fig. 1. Hormonally-mediated sexual differentiation of the brain. The organisational ⁄ activational construct for sexual differentiation is based on the
principle of an early sensitive period that is operationally defined as beginning with the onset of gonadal secretion of steroid hormones in the male,
and as termination being that point at which the female becomes unresponsive to the impact of exogenously administered steroid hormone. The actions
of gonadal steroids during this sensitive period are considered organisational, and generally permanent, and this differentiated neural substrate is then
acted upon (activational) by the appropriate gonadal steroids in adulthood
to produce stereotypic sexual behaviour or physiology. Different physiological and behavioural endpoints vary in the precise timing of the sensitive
period, although most differentiation is complete by the end of the first
postnatal week of life. E2, oestradiol.
737
metabolite of testosterone, oestradiol, and not testosterone itself
that induces organisational effects on the developing brain. In the
intervening 50 years, there have been major advances to support
the dogma of the organisational ⁄ activational hypothesis of sexual
differentiation of the brain, and many challenges as well. The goal
of this review is to highlight some of the mechanistic advances
and to discuss how understanding fundamental cellular processes
can also speak to higher issues of the significance and impact of
sex differences in the brain.
Masculinisation of the preoptic area involves
oestradiol-mediated changes in cell survival, cell death
and synaptogenesis
The preoptic area (POA) contains among the most robust sex differences in the brain and is critical to the normal expression of male
sexual behaviour and pulsatile control of gonadotrophin secretion
from the pituitary. High levels of oestrogen receptor (ER) and aromatase enzyme further implicate this as the key brain sight mediating oestradiol-induced masculinisation (6, 7). Three distinct cellular
events occur here during the perinatal sensitive period; (i) cells in
the female sexually dimorphic nucleus (SDN) die as a result of a
lack of oestradiol; (ii) cells in the female anteroventral periventricular (AVPV) nucleus survive due to a lack of oestradiol; and (iii) neurones in the medial preoptic nucleus of males form approximately
twice as many dendritic spines containing excitatory synapses. Each
one of these events involves distinct non-overlapping cellular
mechanisms. Perhaps the least understood is the SDN where oestradiol prevents apoptosis, resulting in males having three-fold
more neurones than females (8). The cell death in females is classic
BAX ⁄ caspase 3 apopotic cell death and higher levels of Bcl2 in
males affords protection, but how BAX and Bcl2 are regulated is
not yet clear. Several proteins of interest have been implicated
including NMDA receptor glutamatergic signalling and neurotrophic
proteins such as RNA binding motif protein 3 and alpha-tubulin
(9, 10).
A far greater understanding has been achieved for the basis of
the sex difference in the volume of the AVPV. Tumour necrosis factor (TNF)-a is a proinflammatory cytokine that activates nuclear
factor (NF)-kB receptors and promotes cell survival. This pathway is
constitutively active in AVPV neurones of neonatal females but
repressed in their male littermates. The suppression in males is the
result of higher expression of an associated protein called TRIP (TNF
receptor associated-associated factor 2-inhibiting protein) which
inhibits both the TNFa-NF-kB survival pathway and the anti-apoptotic protein, bcl-2 (11). Whether the down-regulation of TRIP in
males is directly a result of oestrogen action has not been established, although it has been determined that these events are
exclusive to GABAergic neurones of the AVPV, and, equally importantly, TRIP is not expressed in the SDN-POA, which consists largely
of GABAergic neurones (12). The selective involvement of GABA
neurones of the AVPV is complemented by a parallel effect of oestrogen-induced activation of caspase-dependent cell death in the
dopaminergic neurones of the AVPV, reducing the number of this
class of neurones in males as well (13). The combination of oestra-
ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 22, 736–742
738
M. M. McCarthy
fever (14). The cyclo-oxygenase enzymes, COX-1 and COX-2 limit
the rate of prostaglandin synthesis, which includes up to eight distinct prostanoids determined by distinct synthetic enzymes from
short-lived precursors (15). In the developing preoptic area, oestradiol induces a two-fold increase in COX-1 and -2 and a correspondingly greater increase in the prostaglandin, PGE2, but not
other prostanoids (16).
Making the connection from prostaglandins to changes in dendritic spine density involves the glutamate system of neurotransmission. AMPA ⁄ kainate and NMDA glutamate receptors are highly
enriched on the surface of dendritic spines, the site at which an
diol effects results in a male AVPV with significantly fewer dopaminergic and GABAergic neurones, comprising the two principle cell
types in this nucleus, and appears to underlie at least in part the
inability of males to respond to rising oestradiol in adulthood with
positive feedback and a surge of luteinising hormone (LH) release.
There has also been considerable progress made in elucidating
the cellular pathway to greater dendritic spine density on male preoptic area neurones, which has direct implications for the control
of male sexual behaviour. Prostaglandins are a class of lipid membrane-derived signalling molecules that subserve normal cellular
functions relevant to reproduction, inflammation, hyperalgesia and
(A)
(B)
Mean spine density (per microrn)
0.16
Male
Female
0.12
Male + Indo
Female + E2
0.08
Female + PGE2
0.04
0
Vehicle E2
PGE2 E2+PGE2 E2+
lndomethacin
(C)
Sex
Prostaglandin
synthesis
POA Neurone
Behaviour
PGD2
PGF2alpha
AA
COX-2
PGE2
PGI2
TXA2
Feminisation
PGD2
PGF2alpha
AA
COX-2
PGE2
PGI2
Masculinisation
TXA2
Fig. 2. Prostaglandin E2 mediates masculinisation of preoptic area (POA) neurones and adult sexual behaviour of rats. The density of dendritic spines, and the
excitatory synapses associated with these structures, is two- to three-fold higher on POA neurones in males than females. Oestradiol permanently organises
this sex difference during the perinatal sensitive period. (A) Treatment of females with oestradiol (E2) or prostaglandin E2 (PGE2) significantly increases the density of dendritic spines, to the same level as seen in males. The effects of E2 and PGE2 are not additive, and the effects of E2 are completely blocked by the
co-administration of the COX-2 inhibitor, indomethacin (indo). COX-2 is a key enzyme in prostaglandin synthesis (38). (B) Golgi impregnation of POA neurones
further reveals the sex difference in dendritic spines and regulation by prostaglandins. These neurones were visualised in 20-day-old animals that had been
treated with oestradiol, PGE2 or indomethacin on days 1 and 2 of life. The higher density of spines in males compared to females is evident, as is the induction of spines by E2 or PGE2 treatment of females. Treatment of males with indomethacin permanently down-regulated dendritic spines on POA neurones (16).
(C) Schematic representation of the role of prostaglandins in masculinisation. Males have higher levels of the COX-2 enzyme, resulting in five-fold higher levels
of the prostaglandin, PGE2, but not other prostanoids. Through a mechanism that at least partly involves the AMPA receptor, but that remains poorly understood, PGE2 permanently increases the density of dendritic spines on POA neurones. The resulting sex difference in neuronal morphology is correlated with
(and presumably determines) adult sex differences in reproductive behaviour. However, the changes in brain regions outside the POA contributing to the
change in behaviour cannot be ruled out.
ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 22, 736–742
Organisational effects of hormones on the developing brain
estimated 95% of excitatory neurotransmission in the brain occurs.
PGE2 signalling is propagated by G-protein coupled receptors
named EP1–4 (17). Convergent evidence indicates EP2 and EP4 are
required for PGE2-mediated masculinisation (18). Both receptors
recruit protein kinase A (PKA) which helps to maintain AMPA ⁄ kainate receptor expression in the post-synaptic density of the dendritic spine (19). In the developing POA, activation of PKA increases
the density of dendritic spines and inhibition of the AMPA ⁄ kainate
glutamate receptors prevents this PKA-induced dendritic spine formation. (20). Taken together, these data allow us to construct a
working model in which oestradiol increases the synthesis of COX-1
and -2 to promote PGE2 production in either neurones or glia
(Fig. 2). PGE2 binds to EP2 and EP4 receptors, activating adenlyl
cyclase, increasing cAMP and activating PKA, which assures the
AMPA ⁄ kainate receptors are anchored in the dendritic spine. The
induction and stabilisation of dendritic spines is aided by functional
AMPA receptors. Disruption of any step in the above process, such
as inhibiting the COX enzymes, blocking PKA activation or antagonising the AMPA glutamate receptors, will impair adult male rat sexual behaviour. More importantly, newborn female rats treated with
PGE2 readily exhibit male sexual behaviour when given testosterone
in adulthood, and the same effect can be achieved by activating
the AMPA receptor during the critical period. Thus, both male sexual behaviour and its neurological underpinnings are organised by
(A)
oestradiol-induced prostaglandin synthesis, which alters glutamatergic neurotransmission during a perinatal sensitive period.
Oestradiol mediates synaptogenesis in developing
mediobasal hypothalamus by regulating glutamatergic
neurotransmission
The ventromedial nucleus (VMN) located in the mediobasal hypothalamus is a principle brain region controlling female sexual
behaviour (21). The dendrites of neurones in the male VMN branch
more frequently and therefore have more overall dendritic spine
synapses than females (22, 23). Oestradiol-mediated dendritic spine
formation begins with a rapid (approximately 1 h) ER-mediated
activation of phosphoinositide 3-kinase (PI3) kinase and enhanced
release of pre-synaptic glutamate (Fig. 3). The connection between
PI3 kinase activation and glutamate release remains poorly characterised but is independent of protein synthesis. Increased synaptic
glutamate leads to increased activation of post-synaptic NMDA
receptors followed by dendritic branching and construction and stabilisation of dendritic spines (24). The latter process is dependent
upon protein synthesis in the post-synaptic neurone, but does not
require ER in the post-synaptic neurone. Activity dependent dendritic growth and synaptogenesis is a common theme throughout
brain development but, in the case of sexual differentiation, it is
(B)
Paired-pulse stimulation
Veh
Males
Females
Females + E2
E2
50 pA
20 ms
(C)
739
Sex
Females + NMDA
Glutamate release
VMN neurone
Behaviour
Defeminised
Feminised
Fig. 3. Nongenomic steroid-induced organisation of the hypothalamus. Oestradiol rapidly induces glutamate release from hypothalamic neurones leading to
activation of post-synaptic glutamate receptors and induction of dendritic spines. (A) Paired pulse stimulation ratios indicate enhanced release of glutamate on
the second stimulation in neurones pretreated with oestradiol. The rate of destaining of FM4-64 visualised terminals confirms this, and the effect of oestradiol
is blocked by the highly specific oestrogen receptor antagonist, ICI 182,780. The effect of oestradiol on FM4-64 destaining is apparent within 1 h of treatment
and does not require protein synthesis but does require activation of phosphoinositide 3-kinase (PI3) kinase. (B) Golgi impregnated ventromedial nucleus (VMN)
neurones reveal a higher number of dendritic spines on the neurones of males or females treated with oestradiol compared to control females (*P < 0.05 compared to all other groups, ANOVA). Treatment with the glutamate agonist, NMDA, mimics the effect of oestradiol, confirming an essential role for glutamate
transmission in establishing sexually dimorphic dendritic morphology (25). (C) Schematic representation of the role of glutamate in defeminisation. Enhanced
glutamate release in male neurones results in increased dendritic spines, which is correlated with a loss of expression of female sexual behaviour expression in
adulthood. Treatment of neonatal females with NMDA successfully defeminises their adult behaviour, further confirming the role of glutamate in the organisational component of sexual differentiation.
ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 22, 736–742
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M. M. McCarthy
quite surprising that initiation begins with nongenomic effects of
oestradiol. The effects of oestradiol on the pre-synaptic neurone
are receptor mediated, and involve ERa. Thus, although the effects
of oestradiol are nontraditional, the receptor mediating the effects
are the classic ER. Moreover, these results illustrate the principle
that oestradiol-mediated sexual differentiation of the mammalian
brain is not a cell autonomous process in which only ER containing
neurones change morphology in response to steroid exposure.
Instead, a neurotransmitter serves as a signalling factor that elicits
a morphological change in an entire population of cells, suggesting
that all neuronal inputs to sexually differentiated brain regions such
as the POA and VMN are considered and interpreted depending on
the animal’s sex, regardless of whether the incoming signals are
relevant to sex. The POA and VMN are two critical nodes in a larger
network of brain regions controlling sex behaviour and they exert
largely opposite influences. The POA is essential for expression of
male sexual behaviour, and therefore a principle brain region subject to masculinisation, whereas the VMN is essential for female
sexual behaviour and therefore presumably feminised. However,
there is a third developmental process, defeminisation, in which the
capacity for female sexual behaviour is suppressed. The observation
that oestradiol increases the amount of excitatory input into both
brain regions is consistent with the VMN being a principle brain
region mediating defeminisation, and behavioural studies further
support that view (25).
Feminisation is an active process but difficult to study
Understanding the cellular basis of feminisation is difficult on multiple levels. The definition of a feminised brain is one that supports
the expression of female reproductive behaviour and oestradiol-initiated positive feedback control of LH release. Although the female
brain is the default, it is not merely the absence of masculinisation.
The fact that defeminisation is a distinct and active process negates
the notion that the female brain is an undifferentiated brain. How
do we gain an understanding of what cellular processes mediate
feminisation? One approach is to identify factors that are inhibited
or suppressed by the hormones mediating masculinisation, such as
testosterone and oestradiol. A novel set of signalling molecules
implicated as potential mediators of feminisation come from study
of metastatic cancer, focal adhesion kinase (FAK) and its associated
protein, paxillin. Both these proteins regulate cell adhesion and
interaction with the extracellular matrix, and are therefore essential
for dendritic and axonal growth and branching (26) as well as dendritic spine morphology (27). Newborn females have higher hypothalamic FAK and paxillin content than their male counterpoints,
and treatment of females with oestradiol drives down levels to that
of males (28). Higher FAK and paxillin is associated with reduced
dendritic branching (26), and may be the basis for the fewer number of dendritic branches on the VMN neurones of females (Fig. 4).
The above approach relies on the assumption that feminisation
proceeds in the complete absence of gonadal steroids, although
there has long been evidence that oestradiol plays an active but
poorly understood role in feminisation (29). The advent of genetically modified mice has allowed for further exploration and support
of this view (30). When considering the hormonal basis of sexual
differentiation of the human brain, it is worth noting that an active
role for oestradiol in feminisation has never been excluded.
The organisational ⁄ activational hypothesis does not
always strictly apply
Behaviours directly associated with reproduction but not sexual
behaviour per se are also often highly sexually dimorphic, with the
best example being singing by male song birds, with females singing relatively little. Elaborate courtship displays, scent marking, territorial defence, mate guarding are all related behaviours shown by
males to attract and then protect females. Conversely, next building, maternal behaviour, maternal aggression are more female typical behaviours, particularly in mammals. Despite the clear
distinctions in motivation and division of labour between the sexes,
a strict application of the organisational ⁄ activational hypothesis to
explain the differences begins to break down and we instead
observe a complex interplay of early hormone and experience combined with adult context and hormonal influences. As we move further away from behaviours directly relevant to reproduction and
consider stress responding, pain perception, food preferences, learning and memory, drug addiction and so on, the applicability of the
hypothesis becomes even less. This is not to say that there are no
neural underpinnings that direct sex differences in behaviour, but
that a strict adherence to early organisational hormonal effects
activated by adult hormones does not satisfactorily explain the
basis of the sex difference. Additional variables, including recent
evidence for a genetic contribution (31), must be considered to create a more nuanced view of how and why males and females differ. Moreover, in some cases, what is taken for a sex difference is
not really a sex difference at all but rather an example of hormonally-mediated plasticity in the adult (32). Oestradiol exerts profound
effects on hippocampal morphology and function, inducing a 30%
increase in the density of dendritic spines, increased long-term
potentiation and enhanced spatial learning (33). These and similar
data are often interpreted as evidence for a sex difference that is
the result of sex differentiation, but, when males are considered,
they fall somewhere in between the measures for females with and
without oestradiol. Is this really a sex difference? The answer is
‘yes’ and ‘no’; there are some intrinsic sex differences in the hippocampus, and responses to extrinsic variables such as stress may
impact the hippocampus differently in males versus females (34),
but unambiguous evidence for classic sex differentiation is lacking.
The hippocampus may prove a brain region that exemplifies a mix
of hormonal, genetic and experiential influences to generate a sexspecific phenotype. Discerning the relative weight of each variable
and its impact on function will provide a valuable integrative view
of sex differences with relevance across a wide range of functions.
The value of research on sex differences is wide ranging
The motivation to incorporate sex differences into basic science
research remains low, with over 50% of studies published in the
field of neuroscience in 2009 being conducted either exclusively on
ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 22, 736–742
Organisational effects of hormones on the developing brain
(B)
7
6
5
4
3
2
Male
Female
1
0
2
(C) Sex
FAK level
FAK level
(A) 8
6 8 10
4
Days postnatal
FAK
Hypothalamic
neurone
Expression
FAK
FAK
M
F
M
741
F+E
100
80
60
40
20
0
Male Female+ Female
E2
Sex behaviour
Feminisation
Masculinisation
Fig. 4. Oestradiol down-regulates focal adhesion kinase (FAK) in the developing male brain. FAK is an important regulator of axonal growth and dendritic
branching in the developing brain. Neurones of the developing hypothalamus have more dendritic branches in males than in females, an effect mediated by
the higher levels of oestradiol in neonatal male brain, following its aromatisation from testicular androgens. (A) The level of FAK protein gradually increases in
the female hypothalamus during the sensitive period of sexual differentiation, peaking on postnatal day 6, at which point it is significantly higher than in the
male hypothalamus, where levels remain relatively constant. (B) Treatment of newborn females with oestradiol significantly reduces FAK levels within 24–48 h
when assessed by quantitative western blot (28). (C) Schematic representation of FAK, which interacts with the integrins to control cell adhesion, thereby
impacting on growth cone movement and branching. Increased FAK levels in females are speculated to decrease branching of hypothalamic neurones. The
resulting sex difference in neuronal morphology is considered as a permanently organised change that is then activated by adult circulating gonadal steroids
to regulate sexually dimorphic reproductive behaviour.
males or with sex unspecified (35). Even in areas where there is a
clear sex bias in the frequency or severity of a neurologic or mental
health disorder, there remains a preponderance of research on only
one sex and this is often not the sex that is dominantly afflicted by
the disorder. Yet, the value of comparing physiology and behaviour
of males and females has proven itself time and time again. Our
discovery of a fundamental role for prostaglandins in masculinisation of the preoptic area is the first demonstration that this ubiquitous signalling molecule plays a role in normal brain development.
Research in pain sensitivity identified a unique signalling pathway
that is only active in females and could be the basis for novel therapeutic approaches (36). These are just two examples of the discovery potential inherent in comparing males versus females. This
principle potentially extends to determining the sex bias in disorders
such as autism, dyslexia, attention deficit disorder and early onset
schizophrenia, all of which disproportionally afflict males (37).
An additional pervading principle can also be extracted from our
current knowledge of how steroid hormones act on the developing
brain. There is a popular view that males have one kind of brain,
whereas females have another, and never the twain shall meet.
However, if we step back and consider what our data tells us, this
uniform view of the male versus female brain conflicts with the
discovery that the cellular mechanisms mediating steroid hormone
action are extraordinarily diverse both within and between brain
regions. Steroids are just the first step in highly complex cellular
processes and variation at each node along the way could provide
important variation to the final phenotypic outcome. For example,
allelic variation in the expression or functionality of glutamate
receptors, COX enzymes, PKA, TNFa, to name a few, would be predicted to impact on the effect that steroids have on the brain. As a
result, the brain of one male is likely to be much different from that
of another male because some regions or endpoints will be strongly
masculinised, whereas others will be less male-like or even somewhat feminised. Likewise, specific females will have some brain
regions that undergo a degree of masculinisation as a result of hormonal exposure from their male siblings in utero, or the natural processes of feminisation will vary depending on their genetic makeup.
As a result, each brain is an individually specific mosaic of maleness
and femaleness, and doesn’t that just fit perfectly with how we
think of all the boys and girl, men and women we know and love?
Received: 22 April 2010,
revised 3 May 2010,
accepted 3 May 2010
ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 22, 736–742
742
M. M. McCarthy
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ª 2010 The Author. Journal Compilation ª 2010 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 22, 736–742
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