Please cite this article in press as: van Wingen GA, et al.

, Gonadal hormone regulation of the emotion circuitry in humans, Neurosci-

ence (2011), doi: 10.1016/j.neuroscience.2011.04.042

Neuroscience xx (2011) xxx

REVIEW
GONADAL HORMONE REGULATION OF THE EMOTION CIRCUITRY IN
HUMANS
G. A. VAN WINGEN,a,b* L. OSSEWAARDE,a,c Key words: sex, gonadal, hormone, steroids, amygdala, pre-
T. BÄCKSTRÖM,d E. J. HERMANSa,e AND frontal.
G. FERNÁNDEZa,f
a
Donders Institute for Brain, Cognition and Behaviour, Radboud Uni- Contents
versity Nijmegen, Nijmegen, The Netherlands Gonadal hormones and psychiatric disorders 1
b
The menstrual cycle and affect 2
Department of Psychiatry, Academic Medical Center, University of
The emotion regulation circuitry 2
Amsterdam, Amsterdam, The Netherlands
Sex, gonadal hormones, and brain structure 3
c
GGNet, Institute for Mental Health Care, Department of Medical Psy- Gonadal hormone influences on brain activity 3
chology, Zutphen, The Netherlands The menstrual cycle 3
d
Umeå Neurosteroid Research Center, Department of Clinical Sci- Progesterone 4
ences, University of Umeå, Umeå, Sweden Estrogens 4
e
Testosterone 5
Department of Psychology, New York University, New York, NY, USA
Common and divergent gonadal hormone effects 5
f
Department for Cognitive Neuroscience, Radboud University Nijme- Conclusion 6
gen Medical Centre, Nijmegen, The Netherlands References 6

Abstract—Gonadal hormones are known to influence the reg-
ulation of emotional responses and affective states. Whereas
fluctuations in progesterone and estradiol are associated
with increased vulnerability for mood disorders, testosterone
is mainly associated with social dominance, aggressive, and
antisocial behavior. Here, we review recent functional neuro-
imaging studies that have started to elucidate how these
hormones modulate the neural circuitry that is important for
emotion regulation, which includes the amygdala and the
medial prefrontal (mPFC) and orbitofrontal cortex (OFC). The
amygdala is thought to generate emotional responses, and
the prefrontal brain regions to regulate those responses.
Overall, studies that have investigated women during differ-
ent phases of the menstrual cycle suggest that progesterone
and estradiol may have opposing actions on the amygdala
and prefrontal cortex. In addition, the influence of exogenous
progesterone appears to be dose-dependent. Endogenous
testosterone concentrations are generally positively corre-
lated to amygdala and OFC responses, and exogenous tes-
tosterone increases amygdala reactivity. Whereas the admin-
istration of progesterone increases amygdala reactivity and
its connectivity with the mPFC, testosterone administration
increases amygdala reactivity but decreases its connectivity
with the OFC. We propose that this opposing influence on
amygdala-prefrontal coupling may contribute to the diver-
gent effects of progesterone and testosterone on emotion
regulation and behavioral inhibition, respectively, which may
promote the differential vulnerability to various psychiatric
disorders between women and men. © 2011 IBRO. Published
by Elsevier Ltd. All rights reserved.
*Correspondence to: G. A. van Wingen, Department of Psychiatry,
Academic Medical Center, University of Amsterdam, PO Box 22660,
1100 DD Amsterdam, The Netherlands. Tel: ⫹31-20-8913523.
E-mail address: guidovanwingen@gmail.com (G. A. van Wingen).
Abbreviations: mPFC, medial prefrontal cortex; OFC, orbitofrontal cor-
tex.
0306-4522/11 $ - see front matter © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuroscience.2011.04.042
Men and women are equally affected by mental health
problems, but the kind of symptomatology they most often
experience is strikingly different between the sexes.
Women suffer more from mood and anxiety disorders,
whereas men suffer more from impulse-control and sub-
stance use disorders (Kessler et al., 2005). Although var-
ious sociocultural influences likely contribute to the vari-
ability in the prevalence of many psychiatric disorders
between the sexes, this sexual dimorphism may in part be
explained by the profound hormonal differences between
men and women. Recent human neuroimaging studies
have started to investigate how these hormones influence
the neurocircuitry that underlies the regulation of emotional
responses and affective states including mood. The central
aim of this paper is to review the evidence for the hormonal
regulation of this circuitry during the processing of emo-
tional stimuli, and to discuss how this could contribute to
the differential vulnerability to various psychiatric disorders
between men and women. First, we will shortly describe
the link between gonadal hormones and psychiatric disor-
ders, and introduce the neural circuitry that could mediate
this link. Second, we will highlight sex differences and
hormonal influences on brain structures within this neuro-
circuitry, before turning to the hormonal regulation of neu-
ral activity during various emotional challenges.
GONADAL HORMONES AND PSYCHIATRIC
DISORDERS
The sex difference in the prevalence of mood disorders
starts during puberty and reduces in the years after
menopause (Steiner et al., 2003; Weissman and Olfson,

1
2 G. A. van Wingen et al. / Neuroscience xx (2011) xxx
1995). This suggests that fluctuations in the female go-
nadal hormones such as progesterone and estradiol
have a major impact on the susceptibility to mood dis-
orders in women. Indeed, the hormonal changes during
the menstrual cycle induce depressive symptoms in
women with premenstrual syndrome (Schmidt et al.,
1998), which is discussed further below. Furthermore,
rates of depression are higher during pregnancy (Ben-
nett et al., 2004), and the menopausal transition is as-
sociated with a more than two-fold increase in the oc-
currence of depression (Freeman et al., 2006). At the
same time, the male gonadal hormone testosterone is
positively associated with aggressive behavior and sub-
stance abuse (Dabbs and Morris, 1990), which are pre-
sumably mediated by its effect on social dominance
(Tarter et al., 2007), and negatively associated with
depressive mood. Meta-analyses have demonstrated
positive correlations between testosterone concentra-
tions and aggressive and antisocial behavior, both in
men and women (Archer, 1991; Book et al., 2001), and
testosterone levels during puberty predict later sub-
stance abuse (Tarter et al., 2007). However, low testos-
terone in elderly men and women is associated with
more depressive symptoms (Almeida et al., 2008;
Morsink et al., 2007). These associations suggest that
whereas progesterone and/or estradiol promote the vul-
nerability to mood disorders, testosterone protects
against mood disorders but increases the risk for devel-
oping impulse-control and substance use disorders.
THE MENSTRUAL CYCLE AND AFFECT
The natural hormone fluctuations during the menstrual
cycle offer an opportunity to investigate the influence of
female gonadal hormones on the brain and behavior, as
different phases of the menstrual cycle are character-
ized by different concentrations of progesterone and
estradiol (see Fig. 1). On the basis of these hormone
levels, the menstrual cycle can be divided into at least
four distinct phases: the menstrual or early follicular
phase during the first week, with the lowest levels of
progesterone and estradiol; the mid-cycle or ovulatory
phase at the end of the second and beginning of the
third week, with high estradiol but relatively low proges-
Fig. 1. Fluctuations of progesterone (red) and estradiol (blue) con-
centrations across the menstrual cycle. Data are adapted from Sher-
man and Korenman (1975).
Please cite this article in press as: van Wingen GA, et al., Gonadal hormone regulation of the emotion circuitry in humans, Neurosci-
ence (2011), doi: 10.1016/j.neuroscience.2011.04.042
terone levels; the luteal phase during the third and fourth
weeks, with the highest progesterone and moderate
estradiol levels; and the premenstrual or late luteal
phase during the end of the fourth week, with declining
levels of mainly progesterone. This latter phase with
high and declining levels of progesterone is associated
with negative mood symptoms in women with premen-
strual syndrome (PMS) or premenstrual dysphoric dis-
order (PMDD) (Bäckström et al., 1983), and to a lesser
extent also in healthy women (Sveindóttir and Bäck-
ström, 2000). This period is also associated with in-
creased responsivity to psychological stressors (Kirsch-
baum et al., 1999), which may facilitate the development
of negative mood. The heightened stress responsivity is
more pronounced in women with PMDD (Epperson et
al., 2007), and appears to be mediated by progesterone
(Roca et al., 2003). These studies highlight how the
natural hormone fluctuations during the menstrual cycle
could be used to investigate the combined effects of
progesterone and estradiol on the brain.
THE EMOTION REGULATION CIRCUITRY
The association of male and female gonadal hormones
with various emotion regulation disorders suggests a pos-
sible common underlying neural circuitry. Indeed, a similar
neurocircuitry underlies mood and anxiety disorders as
well as impulse-control and substance abuse disorders. A
key brain structure involved in emotion processing is the
amygdala, which is located within the medial temporal lobe
(see Fig. 2). It consists of several nuclei that appear to form
distinct anatomical and functional units (Swanson and
Petrovich, 1998). However, typical noninvasive human im-
aging methods lack the spatial resolution to separate the
contribution of these distinct nuclei and the amygdala is
therefore considered one entity throughout this review, of
which the basolateral nuclei form the largest component.
But the amygdala has such dense intrinsic connections
that it may be considered one structure (see Aggleton,
2000). It is involved in the detection of potential threat and
responds to signals of anger and fear, projects to brain
stem nuclei that are responsible for fight or flight responses
(Davis and Whalen, 2001; Sergerie et al., 2008), and ac-
tivates the stress system (Herman et al., 2003). It is part of
a larger neural circuitry that is implicated in the control of
emotion, most notably including the prefrontal cortex (PFC;
Quirk and Beer, 2006; Sotres-Bayon and Quirk, 2010). The
parts of the PFC that are most often associated with emo-
tion regulation are its orbital (OFC) and medial (mPFC)
surfaces (see Fig. 2). Dysregulation within this prefrontal-
amygdala circuitry is associated with various psychiatric
disorders, including mood and anxiety disorders (Phillips et
al., 2003) as well drug abuse (Koob and Volkow, 2010) and
violent behavior (Blair, 2010; Davidson et al., 2000). Go-
nadal hormone regulation of this circuitry may therefore
contribute to the vulnerability or resilience for these
disorders.
 G. A. van Wingen et al. / Neuroscience xx (2011) xxx
Fig. 2. Core brain regions involved in the emotion circuitry. The amygdala (red) is involved in the detection of potential threat and responds to signals
of anger and fear, and projects to brain stem nuclei that are responsible for fight or flight responses. The medial prefrontal cortex (mPFC; green) and
orbitofrontal cortex (OFC; blue) are involved in emotion regulation.
SEX, GONADAL HORMONES, AND BRAIN
STRUCTURE
Sex differences in brain structures suggest that gonadal
hormones have organizational effects during development
on the emotion circuitry. Sexual dimorphisms in brain
structure have been reported in both the amygdala and
PFC, with relatively larger amygdala volumes in men than
women, and variable sex differences within different re-
gions of the PFC (Goldstein et al., 2001; Witte et al., 2010).
Although hormonal concentrations are correlated with re-
gional brain volume in these brain regions during puberty
(Neufang et al., 2009; Peper et al., 2009) (for a review, see
Peper et al., in press), no significant correlations have
been observed during adulthood (Witte et al., 2010). This
indicates that circulating hormones have the largest effect
on individual differences in these brain structures during
puberty. However, the hormonal fluctuations during the
menstrual cycle do influence structural plasticity during
adulthood. Menstrual cycle-dependent volume changes
have been reported in the hippocampus (Protopopescu et
al., 2008a) and parahippocampal gyrus (Pletzer et al.,
2010). This suggests that the organizational effects of
hormones but also their influence on structural plasticity
during the menstrual cycle may contribute to their activa-
tional effects on neural activity within the emotion circuitry,
which is discussed next.
GONADAL HORMONE INFLUENCES ON BRAIN
ACTIVITY
The menstrual cycle
Most studies have compared neural responses to emo-
tional stimuli between the follicular phase and luteal phase,
reflecting phases with relatively low versus high estradiol
and progesterone concentrations, respectively (see
above). One study specifically focused on the mid-cycle
phase that is characterized by high estradiol but low pro-
gesterone concentrations (Goldstein et al., 2005), and is
therefore discussed separately.
The majority of studies that have investigated neural
responsivity during relatively passive emotional challenges
have found higher amygdala reactivity during the luteal
phase than follicular phase. Amygdala reactivity was
higher to angry, fearful, and happy faces during the late
luteal phase than the late follicular phase (Ossewaarde et
Please cite this article in press as: van Wingen GA, et al., Gonadal hormone regulation of the emotion circuitry in humans, Neurosci-
ence (2011), doi: 10.1016/j.neuroscience.2011.04.042
3
al., 2010), as well as to negative pictures (relative to neu-
tral pictures) during the mid-luteal than early follicular
phase (Andreano and Cahill, 2010). Higher amygdala re-
activity during the luteal than follicular phase has also been
observed during the anticipation of a painful heat stimulus
(Choi et al., 2006). In contrast, higher amygdala reactivity
was observed during the follicular than luteal phase in a
study in which the participants were requested to label the
emotional expression of faces semantically (Derntl et al.,
2008). However, the difference in task instruction may
explain this apparent inconsistency. Semantic labeling of
emotions requires the retrieval of semantic knowledge,
which is associated with recruitment of a semantic network
including the left inferior frontal gyrus and left temporal
cortex (Hagoort, 2005). Importantly, this process also re-
duces amygdala activity in healthy individuals (Hariri et al.,
2000). This indicates that the influence of gonadal hor-
mones may be dependent on the task instructions that
presumably moderate the relative involvement of the PFC
(see below) and the level of amygdala activity.
Whereas these studies using relatively passive emotional
challenges suggest hormonal influences on amygdala activ-
ity, they provide little support for menstrual cycle-dependent
effects on the PFC. However, two studies suggest that its
influence on the PFC may only become apparent under
stress. Whereas mPFC responsivity to emotional faces
was larger in the late luteal phase than late follicular
phase in a neutral situation, mPFC activity was lower in
the luteal than follicular phase after the induction of
psychological stress (Ossewaarde et al., 2010). Simi-
larly, mPFC activity was also lower in the luteal than fol-
licular phase during the anticipation and experience of a
painful heat stimulus (Choi et al., 2006).
Additional evidence for menstrual cycle-dependent ef-
fects on the PFC comes from two studies that have inves-
tigated PFC functioning during emotional go/no-go tasks,
in which participants have to respond to emotional words in
go-trials and withhold their response in no-go trials. One
study observed increased activity in the mPFC and dorso-
lateral PFC during the luteal phase when compared to the
early follicular phase during the response inhibition to pos-
itive stimuli (Amin et al., 2006). Another study observed a
shift in OFC activity between the late follicular and late
luteal phase during behavioral responding or response
inhibition to negative words in healthy women (Protopo-
pescu et al., 2005), which was altered in women with
4 G. A. van Wingen et al. / Neuroscience xx (2011) xxx

Fig. 3. Divergent effects of progesterone and testosterone on functional connectivity of the amygdala with the prefrontal cortex. (a) Progesterone
administration increases amygdala coupling with the medial prefrontal cortex (mPFC; data from van Wingen et al., 2008b). (b) Testosterone
administration decreases amygdala coupling with the orbitofrontal cortex (OFC; data from van Wingen et al., 2010).

PMDD (Protopopescu et al., 2008b). These studies sug-
gest that the female gonadal hormones influence PFC
activity in tasks that require cognitive control over behav-
ior.
The only study that specifically investigated the mid-
cycle phase measured neural activity during the attentive
viewing of negative pictures, and compared activity during
this phase to the low hormone early follicular phase (Gold-
stein et al., 2005). In contrast to the studies that investi-
gated amygdala reactivity during the luteal phase, this
study observed reduced amygdala and mPFC reactivity.
These midcycle deactivations appear more pronounced in
women with a history of depression, and are associated
with gonadal hormonal dysregulation (Holsen et al., in
press). Because the mid-cycle phase of the menstrual
cycle is characterized by high estradiol but relatively low
progesterone levels, this suggests that estradiol may re-
duce amygdala activity. At the same time, this also sug-
gests that mainly progesterone or its interaction with es-
tradiol could induce the increased amygdala activity that is
observed during the luteal phase. However, these men-
strual cycle studies do not provide direct evidence for a
dissociation between progesterone and estradiol effects
on brain activity.
Progesterone
More direct evidence for the causal relation between hor-
monal levels and neural activity comes from placebo-con-
trolled progesterone administration studies. In one study, a
single dose of progesterone was administered to healthy
young women during the early follicular phase, which in-
creased progesterone levels to those observed during the
luteal phase (van Wingen et al., 2008b). This led to an
increase in amygdala reactivity to threatening faces, which
suggests that increased amygdala reactivity during the
luteal phase is indeed mediated by progesterone. Further-
more, progesterone increased functional coupling of the
amygdala with the mPFC, indicating that progesterone
influences the communication between the amygdala and
mPFC (see Fig. 3a). In contrast to these findings, a higher
progesterone concentration, similar to that observed dur-
ing pregnancy, led to a reduction in amygdala activity
during the memorization of happy and neutral faces (van
Wingen et al., 2007). These results suggest that the influ-
ence of progesterone on amygdala reactivity is dose-de-
pendent, increasing its activity at moderate levels but de-
creasing its activity at high levels. Interestingly, this non-
linear response to progesterone is also observed in clinical
studies (Andréen et al., 2006) and is presumably mediated
by progesterone’s metabolite allopregnanolone that influ-
ences neuronal activity via its action on the GABAA recep-
tor (Andréen et al., 2009, and Bäckström et al., in press).
However, this nonlinear effect on amygdala reactivity re-
mains to be tested formally, and the response to proges-
terone may be different across different phases of the
menstrual cycle (Sundström et al., 1998). Nevertheless,
these neuroimaging studies indicate that luteal phase
progesterone levels may be responsible for increasing
amygdala reactivity.
Estrogens
Even though several neuroimaging studies have investi-
gated the influence of estrogens on various cognitive func-
tions (e.g. Berman et al., 1997), and many animal studies
have demonstrated that estrogens influence emotional be-
havior (for review, see Walf and Frye, 2006), only one
placebo-controlled study has investigated the influence of
estrogens on emotion processing in humans. Healthy post-
menopausal women received 4 weeks of combined estro-
gen-progestin hormone therapy, which increased neural
responses to negative pictures in the OFC, but decreased
responses to both negative and positive pictures in the
mPFC (Love et al., 2010). Although this study suggests
that hormonal replacement therapy influences PFC activity
during emotion processing, it remains unknown whether
this is the result of prolonged hormone treatment, and

Please cite this article in press as: van Wingen GA, et al., Gonadal hormone regulation of the emotion circuitry in humans, Neurosci-
ence (2011), doi: 10.1016/j.neuroscience.2011.04.042
 G. A. van Wingen et al. / Neuroscience xx (2011) xxx
whether this is an estrogen, progestin, or combined estro-
gen-progestin effect. Furthermore, the neural effect of hor-
mone treatment is likely different in premenopausal
women. In light of the well established effects of estrogens
on emotional behavior in animals, the limited knowledge
about how estrogens influence the emotion circuitry in
humans highlights the need for additional studies.
Testosterone
The majority of studies that have investigated the influence
of testosterone on neural responsivity have used a corre-
lational approach across individuals with variable endoge-
nous testosterone concentrations, which are discussed
first. In addition, exogenous testosterone has been admin-
istrated in placebo-controlled studies to identify a causal
relation between testosterone and neural functioning,
which is discussed second.
Most studies have reported positive correlations be-
tween endogenous testosterone concentrations and neu-
ral responsivity to threatening faces in the amygdala and
OFC in men, and in the amygdala in women. Increased
reactivity in individuals with higher testosterone concentra-
tions has been observed in healthy young (Derntl et al.,
2009) and middle-aged men (Manuck et al., 2010), and in
healthy young to middle-aged women (van Wingen et al.,
2009) as well as young women when taking their endog-
enous cortisol concentrations into account (Hermans et al.,
2008). In addition, a direct comparison between young and
middle-aged women showed that the young women, who
have higher androgen levels (Zumoff et al., 1995), also
have higher amygdala reactivity (van Wingen et al., 2009).
Only one study reported conflicting results, with no corre-
lation between testosterone levels in women and a nega-
tive correlation in the amygdala in a small sample of men,
whereas the correlation with OFC activity was positive
(Stanton et al., 2009). Another study observed a negative
correlation between testosterone and OFC activity, but this
result may be complementary rather than conflicting be-
cause this association was found during a task that is not
readily comparable to the other studies, in which partici-
pants had to split money with virtual others (Mehta and
Beer, 2010).
To assess a couple of causal link between testoster-
one and neural activity, studies have investigated the in-
fluence of exogenous testosterone in healthy women and
hypogonadal men. Using placebo-controlled designs, a
single testosterone dose has been found to increase
amygdala reactivity to threatening faces in healthy young
women (Hermans et al., 2008) as well as middle-aged
women, which increased their amygdala reactivity to the
young adulthood level (van Wingen et al., 2009). Whereas
testosterone also increased OFC activity in the young
women, no significant difference between the testosterone
and placebo conditions was observed in the middle-aged
women, in whom the drug-induced testosterone levels cor-
related negatively with OFC activity. The difference in tes-
tosterone’s influence on the OFC may be explained by the
difference in prefrontal activity between these age groups
(van Wingen et al., 2009). Furthermore, even though tes-
Please cite this article in press as: van Wingen GA, et al., Gonadal hormone regulation of the emotion circuitry in humans, Neurosci-
ence (2011), doi: 10.1016/j.neuroscience.2011.04.042
5
tosterone increased amygdala reactivity, it reduced func-
tional coupling between the amygdala and OFC in the
middle-aged women (van Wingen et al., 2010), suggesting
that testosterone attenuates the communication between
the amygdala and OFC (see Fig. 3b). This result is in line
with findings from an electroencephalography (EEG)
study, in which testosterone reduced the coupling between
subcortically generated oscillations in the delta frequency
range and cortically generated oscillations in the beta fre-
quency range (Schutter and van Honk, 2004). Taken to-
gether, these studies demonstrate that testosterone regu-
lates amygdala and OFC activity and their communication
during the processing of threatening faces. However, sim-
ilar testosterone administrations did not influence those
brain regions significantly during the listening to crying
infants (Bos et al., 2010) or the memorization of faces,
which was mainly associated with altered hippocampal
processing (van Wingen et al., 2008a). In addition to these
studies in women, one study investigated neural re-
sponses to visual sexual stimuli in healthy and hypogo-
nadal men, who were investigated once on and once off
androgen treatment (Redoute et al., 2005). Untreated pa-
tients demonstrated lower OFC activity than healthy indi-
viduals, and treatment increased OFC and amygdala ac-
tivity. Overall, these studies show that testosterone in-
creases amygdala and OFC reactivity, mainly in response
to potentially threatening or rewarding stimuli.
Although a discussion about the cellular action of tes-
tosterone is beyond the focus of the present review, it
remains important to note that testosterone could influence
neuronal activity via different pathways. Both testosterone
and its metabolite dihydrotestosteone (DHT) have their
primary action on the androgen receptor. However, testos-
terone is also metabolized into the neuroactive steroid
androstanediol that modulates the GABAA receptor
(Reddy and Jian, 2010), an action similar to that of the
progesterone metabolite allopregnanolone (see above).
Furthermore, testosterone is also aromatized into estra-
diol, which may occur locally within presynaptic terminals
(Balthazart and Ball, 2006). Therefore, the effects of tes-
tosterone that are discussed above may in part be medi-
ated via its conversion to other steroids.
COMMON AND DIVERGENT GONADAL
HORMONE EFFECTS
The studies reviewed above demonstrate that gonadal
hormones regulate the activity within the emotion circuitry.
Menstrual cycle studies suggest that progesterone in-
creases amygdala and mPFC reactivity to emotional stim-
uli. Although confirmatory evidence remains limited, this
conclusion is supported by a placebo-controlled study in
which a single dose of progesterone increased amygdala
reactivity and its connectivity to the mPFC (van Wingen et
al., 2008b). Evidence about the influence of estradiol on
this neurocircuitry is scarce. A single menstrual cycle study
indicates that estradiol may decrease neural activity within
these brain regions (Goldstein et al., 2005), but placebo-
controlled studies are required to provide support for this
6 G. A. van Wingen et al. / Neuroscience xx (2011) xxx
conclusion. More data are available about the neural ef-
fects of testosterone, which suggest that testosterone in-
creases amygdala and OFC reactivity to threatening stim-
uli (e.g. Hermans et al., 2008). However, if both proges-
terone and testosterone increase amygdala reactivity, how
could progesterone increase the vulnerability to mood and
anxiety disorders, whereas testosterone increases the vul-
nerability to impulse-control and substance use disorders?
The divergent influence of these hormones on psychiatric
vulnerability may in part be related to the preferential mod-
ulation of the mPFC by progesterone and the OFC by
testosterone. However, fluctuations in progesterone con-
centration across the menstrual cycle also influence OFC
functioning (e.g. Protopopescu et al., 2005). We propose
that the differential effect of gonadal hormones on the
neural circuitry involved in emotion and affect regulation
may be related to their influence on neural coupling with
the amygdala. Progesterone increases amygdala coupling
with the mPFC (van Wingen et al., 2008b), whereas tes-
tosterone decreases amygdala coupling with the OFC (van
Wingen et al., 2010) (see Fig. 3). Increased coupling with
the mPFC may influence the appraisal of emotional events
and promote rumination about negative affect (Ochsner
and Gross, 2005; Ray et al., 2005), whereas reduced
coupling with the OFC may reduce behavioral inhibition
and promote impulsivity and violence (Coccaro et al.,
2007; Meyer-Lindenberg et al., 2006). However, more ev-
idence is required to provide additional empirical support
for this hypothesis.
CONCLUSION
The neuroimaging studies that are discussed in this review
highlight the activational effects of gonadal hormones on
the amygdala and PFC. In addition to the organizational
effects of these hormones, these studies strongly suggest
that activational effects contribute to sex differences in this
neurocircuitry underlying the regulation of emotion and
affect (Cahill, 2006; Goldstein et al., 2010; Sergerie et al.,
2008). Recent studies indicate that progesterone and tes-
tosterone have diverging effects on the communication
between the amygdala and PFC (van Wingen et al., 2010;
van Wingen et al., 2008b), which may contribute to sex
differences in the vulnerability to various psychiatric disor-
ders (Kessler et al., 2005).
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(Accepted 16 April 2011)

Please cite this article in press as: van Wingen GA, et al., Gonadal hormone regulation of the emotion circuitry in humans, Neurosci-
ence (2011), doi: 10.1016/j.neuroscience.2011.04.042
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