Series

Women’s mental health 2

Why are women so vulnerable to anxiety, trauma-related and
stress-related disorders? The potential role of sex hormones
Sophie H Li, Bronwyn M Graham

Increased prevalence, severity, and burden of anxiety, trauma-related and stress-related disorders in women compared Lancet Psychiatry 2017;
with men has been well documented. Evidence from a variety of fields has emerged suggesting that sex hormones, 4: 73–82
particularly oestradiol and progesterone, play a significant part in generation of these sex differences. In this Series Published Online
November 14 , 2016
paper, we aim to integrate the literature reporting on the effects of sex hormones on biological, behavioural, and
http://dx.doi.org/10.1016/
cognitive pathways, to propose two broad mechanisms by which oestradiol and progesterone influence sex differences S2215-0366(16)30358-3
in anxiety disorders: augmentation of vulnerability factors associated with anxiety disorder development; and See Comment page 8
facilitation of the maintenance of anxious symptoms post-development. The implications for future research, along This is the second in a Series of
with novel approaches to psychological and pharmacological treatment of anxiety disorders, are also considered. four papers on Women’s mental
health
Introduction these hormones have been the most widely studied in this School of Psychology, The
Clear data show increased prevalence of anxiety and regard. Because increases in oestradiol precede and then University of New South Wales,
Sydney, NSW, Australia
trauma-related and stress-related disorders, along with overlap with increases in progesterone during the (S Li PhD, B M Graham PhD)
increased symptom severity, comorbidity, and burden of menstrual cycle (figure 1), it can be difficult to draw
Correspondence to:
illness, in women compared with men.1 Although conclusions with regards to the exact role of each hormone Dr Bronwyn M Graham, School
reporting biases, socioeconomic role biases, and on the basis of findings from studies that have examined of Psychology, The University of
differences in trauma exposure probably contribute to naturally cycling rodents and women, unless pharma- New South Wales Australia,
Sydney, NSW 2052, Australia
these gender discrepancies,2 several sources suggest cological interventions or separate correlations for each
bgraham@psy.unsw.edu.au
organic factors are also at play, including fluctuating hormone have been conducted. Throughout this Series
levels of sex hormones such as oestradiol and paper we highlight where such uncertainty exists, and
progesterone. For example, several reports3–5 indicate that where more definitive conclusions can be made regarding
sex differences in anxiety emerge at puberty (although the role of each hormone.
Anderson and colleagues6 report evidence of an earlier
emergence of sex differences during childhood) and Sex hormonal influences on endogenous
women have an elevated risk of development of anxiety anxiolytics
disorders, or exacerbation of current anxiety symptoms, Role of serotonin and allopregnanolone in anxiety
during phases of their reproductive cycle marked by Anxiety and trauma-related and stress-related disorders
reduced hormone levels (figure 1).7–10 Furthermore, are characterised by aberrations in multiple molecular
investigations into the role of sex hormones in the signals, many of which are modulated by sex hormones.12–15
regulation of mood and anxiety symptoms in Of particular note are the neurotransmitter serotonin, and
premenstrual dysphoric disorder, although beyond the the neurosteroid allopregnanolone. Downregulations in
scope of this Series paper, highlight the importance of serotonergic functioning and allopregnanolone activity are
sex hormones in the regulation of mood states.11
In this Series paper, we propose two broad mechanisms Human menstrual cycle Rat oestrous cycle
by which sex hormonal fluctuations could influence the
Naturally Hormonal
gender imbalance in anxiety. The first mechanism is by
Oestradiol

cycling contraceptive
augmentation of vulnerability factors associated with the
development of anxiety disorders—eg, by down-regulation
of neurobiological systems that regulate stress, or by
Progesterone

promotion of the overconsolidation of traumatic

memories, or both. The second mechanism is facilitation
of the maintenance of anxiety disorders post-
development—eg, by exacerbation of symptom severity, or
by alterations of responsiveness to psychological and
pharmacological treatments, or both. In this Series paper,
we identify candidate biological, behavioural, and cognitive
pathways by which sex hormones might exert these
influences. We restrict our focus to the role of oestradiol
(the main oestrogen derivative) and progesterone, because
Follicular phase Luteal phase Follicular phase Luteal phase Metestrus Pro-oestrus
Figure 1: Human menstrual cycle versus rat oestrous cycle
(A) Fluctuations in peripheral oestradiol and progesterone levels across the month-long menstrual cycle in human
women. Peripheral (endogenous) oestradiol and progesterone levels are chronically low in women using hormonal
contraceptives. (B) Fluctuations in peripheral oestradiol and progesterone levels across the 4 day oestrous cycle in
female rodents. In women and rodents, periods of low sex hormones (eg, the early-follicular and metestrus
phases) are characterised by an intensification of anxious symptoms, relative to periods of high sex hormones
(eg, the mid-luteal and pro-oestrus phases).

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 Series
implicated in the development and expression of anxiety.
For example, transgenic mice that do not have the
serotonin transporter gene exhibit increased anxiety-like
behaviour,16 and reductions in central serotonin binding
have been observed in panic disorder17 and post-traumatic
stress disorder (PTSD).18 Likewise, reduced allopreg-
nanolone concentrations in serum or plasma and CSF
have been observed in a range of anxiety disorders and
PTSD19 (although basal allopregnanolone concentrations
are increased in people with panic disorder20). Notably,
allopregnanolone increases in response to acute stress in
rodents,21 although investigations of the association
between allopregnanolone and acute stress in people have
yielded inconclusive results.22 allopregnanolone negatively
modulates hypothalamic-pituitary-adrenal (HPA) axis
activity and allopregnanolone might serve a homoeostatic
function in the regulation of acute distress.19,22 Furthermore,
in rodents, administration of allopregnanolone is acutely
anxiolytic, whereas blockade of allopregnanolone synthesis
induces anxiety—opposing effects probably driven by
allopregnanolone’s positive allosteric modulation of the
GABAA receptor19 as well as its modulation of HPA axis
activity. For example, the anxiolytic or antidepressant
effects of allopregnanolone have been associated with a
normalisation of stress-induced HPA axis dysfunction
in rodents.21
Modulation of serotonin and allopregnanolone also
appear to be key to the efficacy of pharmacological treat-
ments for anxiety. SSRIs have been established as the
first-line pharmacological treatment for anxiety disorders,23
and are believed to regulate affect and cognition by
prevention of serotonin re-uptake, resulting in an increase
in serotonin bioavailability.24 SSRIs might also exert their
effects via upregulation of allopregnanolone, as has been
demonstrated in animal models,21 and as suggested by the
finding that effective treatment with SSRIs normalises
allopregnanolone deficiencies in people with depression.25
Findings demonstrating the modulation of serotonin and
allopregnanolone by oestradiol and progesterone highlight
clear molecular pathways by which these sex hormones
might influence the vulnerability and maintenance of
anxiety disorders in women.
Effect of oestradiol and progesterone on serotonin and
allopregnanolone regulation
Oestradiol has powerful stimulatory effects on
serotonergic neurotransmission. For example, oestradiol
treatment in ovariectomised rodents and non-human
primates facilitates serotonin neurotransmission by
inhibition of monoamine oxidases (MAOs, enzymes that
deaminate monoamines including serotonin, dopamine,
and norepinephrine), increasing tryptophan hydroxylase
expression (the rate-limiting enzyme in serotonin
synthesis), and increasing gene expression of the
serotonin reuptake transporter, in brain regions
associated with affect regulation.26,27 Similarly, a PET study
showed that MAO-A (a MAO subtype that is primarily
74
responsible for breaking down serotonin) has a greater
binding distribution volume in perimenopausal and
menopausal women than in premenopausal women.28
This finding suggests that reduced oestradiol associated
with reproductive senescence might contribute to
reduced serotonergic transmission via attenuated MAO
inhibition. Like serotonin, allopregnanolone is similarly
positively modulated by both oestradiol and progesterone.
Allopregnanolone is synthesised centrally and
peripherally from progesterone, and in cycling rats and
women, peripheral allopregnanolone fluctuates across
the oestrous or menstrual cycles, with highest
allopregnanolone during periods of peak progesterone.29,30
Similarly, suppression of oestradiol and progesterone
through hormonal contraceptive use is associated with
diminished allopreg-nanolone in women.31 Central
allopregnanolone expression also fluctuates across the
oestrous cycle in rats, with greatest hippocampal
allopregnanolone expression during periods of peak
progesterone.30,32 Increased allopreg-nanolone expression
can also be stimulated by oestradiol, indirectly via
oestradiol’s serotonergic regulation, and directly, as
suggested by rodent studies demonstrating increased
central allopregnanolone expression following oestradiol
administration.33
Serotonin and allopregnanolone as potential pathways
for sex hormone influences on anxiety vulnerability and
maintenance
Research suggests that serotonin and allopregnanolone
might function as endogenous anxiolytics, promoting
adaptive responses to stress, and that oestrogen and
progesterone contribute to the regulation of serotonin
and allopregnanolone. Therefore, periods of low
oestradiol and progesterone associated with menstruation,
hormonal contraceptive use, as well as post partum or
menopause, could result in less effective stress regulation
because of decreased serotonergic synthesis and turnover,
reduced allopregnanolone synthesis, and in turn, reduced
GABAergic inhibitory tone or less efficient HPA axis
regulation. Such periodic fluctuations in emotion
regulation efficacy might contribute to women’s increased
vulnerability to anxiety disorder development, and also
maintain pathological symptoms post-development by
intermittently exacerbating symptom severity. In support
of this idea, healthy women report a consistent fluctuation
in affect across the menstrual cycle, including a
premenstrual increase in non-pathological anxiety.34
Similarly, premenstrual worsening of symptoms occurs
in panic disorder,7 obsessive-compulsive disorder,8 and
generalised social anxiety disorder.9
In addition to the potential detrimental effects of normal
declines in sex hormones across the menstrual cycle and
lifespan, women might also be more susceptible to stress-
induced abnormal serotonin or allopregnanolone
downregulation. For example, a common source of
reproductive dysfunction in women is stress-induced
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functional hypothalamic amenorrhea, a condition
associated with abnormally reduced sex hormone levels
due to stress-induced downregulation in hypothalamic-
pituitary-gonadal axis functioning.35,36 Reductions in sex
hormones caused by conditions such as stress-induced
functional hypothalamic amenorrhea might increase
women’s vulnerability to anxiety development, or
exacerbate pre-existing anxious symptoms, by leading
to pathological downregulation of serotonin or allo-
pregnanolone. Preclinical evidence suggests that the
susceptibility to stress-induced serotonin or allopreg-
nanolone downregulation might be further mediated by
individual differences in pre-stress basal oestradiol and
progesterone levels, as shown by studies in monkeys that
exhibit phenotypic differences in the extent to which stress
disrupts oestrous cycling.37,38 Stress-sensitive monkeys
(that exhibit disrupted oestrous cycling after a single bout
of stress) exhibit lower peak oestradiol and progesterone
across the oestrous cycle than do high-stress resistant
monkeys (that show no disruptions in oestrous cycling
even after repeated stress), even before stress onset.39
Furthermore, compared with high-stress resistant
monkeys, stress-sensitive monkeys exhibited reduced
expression of several genes associated with synthesis and
turnover of serotonin, as well as reduced serotonin
neuronal expression.37,38 To our knowledge, no studies have
assessed whether individual differences in peak hormonal
levels during the menstrual cycle are similarly associated
with stress-induced infertility or anxiety-relevant processes
in women.
We further hypothesise that fluctuating hormonal
levels might lead to variance in women’s responsiveness
to SSRIs because of changes in basal regulation of
allopregnanolone and serotonin transmission. Unfor-
tunately, to our knowledge, this hypothesis has not been
assessed, and treatment response studies are generally
underpowered to adequately assess even sex-specific
effects of pharmacotherapies. Despite this, some
evidence for sex differences does exist in response to
SSRI treatment for depression. For example, it has been
shown that young women are more responsive to SSRIs
than to tricyclic antidepressants, compared with men
and women older than 44 years (a period in the lifespan
marked by reduced sex hormones) who show no
difference.40,41 These sex-specific effects in pharma-
cotherapy are due, at least in part, to sex differences in
pharmacokinetics that are accentuated by sex
hormones.42,43 Furthermore, some evidence suggests that
the efficacy of SSRI treatment for depression in peri-
menopausal and post-menopausal women is elevated
when administered in conjunction with oestradiol.44,45
However, Shapira and colleagues46 found that oestrogen
supplementation had no effect on imipramine treatment
efficacy in pre-menopausal or post-menopausal women.
Together, these findings suggest that the efficacy of SSRI
treatment for anxiety could similarly be influenced by sex
and hormonal status.
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Sex hormonal influences on emotional memory
formation
Evidence from fear conditioning studies
In addition to biological vulnerabilities noted above,
anxiety, trauma-related and stress-related disorders are
also associated with cognitive processes including
emotional memory formation. For example, PTSD is by
definition precipitated by exposure to trauma. Subsequent
symptoms including avoidance and hypervigilance are
thought to be due in part to fear conditioning processes
whereby cues and contextual information present at the
time of the trauma acquire the capacity to trigger intense
emotional reactions. This fear conditioning process can
be modelled in the laboratory by pairing a neutral
conditioned stimulus (eg, a light or tone) with a biologically
significant unconditioned stimulus (eg, a shock) until the
conditioned stimulus elicits fear responses. Although not
always the result of direct trauma exposure, fear
conditioning processes are thought to be relevant to the
cause of many anxiety disorders,47 and aberrations in fear
conditioning have been documented across several anxiety
subtypes;48 thus, laboratory studies of fear conditioning
might reveal factors associated with individual differences
in anxiety disorder propensity.
Sex differences in fear conditioning have been
documented in rodents using a range of tasks, (eg, after
puberty, female rats exhibit more rapid eyeblink
conditioning than do males, a difference that is particularly
marked during high oestradiol oestrous phases).49 By
contrast, although sex differences are generally not
observed in cued fear conditioning, male rodents exhibit
better contextual fear conditioning than do female
rodents,50,51 an effect which might be modulated by
oestrous cycle.52 Studies in healthy people have yielded
equally inconsistent results, with some reporting that
men exhibit stronger conditioned skin conductance
responses than women,53,54 and others indicating no sex
differences.55 Although these results indicate that in
healthy populations, sex differences in fear conditioning
exist, and might be in part mediated by sex hormones, the
direction of these differences is dependent on both the
task and the particular fear response being assessed.
Moreover, because most fear conditioning studies have
not taken sex hormones into account, it is difficult to
ascertain the exact nature of the sex differences reported
in the existing literature.
Evidence from studies of non-associative emotional
memory formation
A clearer picture emerges from a different body of
experimental research that has examined sex hormonal
influences on non-associative emotional memory via
clinical analogue studies in which healthy human
participants are exposed to stimuli such as aversive
images and film clips in laboratory settings. Cahill and
colleagues56–58 have shown that memory and subsequent
spontaneous intrusive recollections of inherently
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aversive stimuli are stronger when women are exposed
to such stimuli during mid-luteal phases of the
menstrual cycle, an effect that seems to be primarily
positively associated with salivary concentrations of
progesterone. A subsequent study59 further showed that
women’s salivary oestradiol to progesterone ratio at the
time of viewing an aversive film clip negatively correlated
with intrusion frequency, suggesting that a combination
of low oestradiol and high progesterone levels might
increase the propensity to experience intrusions. The
mechanisms by which progesterone, and potentially
oestradiol, might enhance the formation of emotional
memories are largely unknown. One possibility is that
progesterone might increase functional activation of
neural circuits involved in emotional processing and
memory. Indeed, progesterone administration in healthy
women increased amygdala activity, and increased
functional coupling of the amygdala with the dorsal
anterior cingulate cortex, a circuitry that is integral to the
acquisition of fearful associations.60 Additionally, rodent
research has shown that both oestradiol and progesterone
facilitate molecular signalling processes and synaptic
plasticity (eg, increased dendritic spine density, long-
term potentiation, and neurogenesis) within brain
regions that are responsible for memory consolidation,
such as the hippocampus.61,62
Evidence from naturalistic studies of trauma exposure
Together, evidence we have described in this Series
paper lead to the hypothesis that greater progesterone
at the time of trauma might contribute to a more deeply
encoded, or overconsolidated memory for the event,
potentially via hormonal-enhanced synaptic plasticity
within neural circuits responsible for emotional
processing. Memory overconsolidation is thought to
lead to subsequent intrusive recollections of trauma,
and is proposed to be a key factor in the development of
disorders such as PTSD.63 Indeed, preliminary support
for such a hypothesis comes from two studies
undertaken in naturalistic settings. The first study64
reported that women in the mid-luteal phase of the
menstrual cycle (assessed by retrospective self-report)
at the time they were admitted to hospital after a
traumatic injury had more numerous flashbacks to the
event during the following week, compared with
women who were not in the mid-luteal phase. The
second study65 reported that naturally cycling women
who refused emergency contraception following sexual
assault reported increased post-trauma stress reactions
relative to those who took emergency contraception or
were currently using hormonal contraceptives. Because
both forms of contraception suppress progesterone
synthesis (as well as oestradiol), these interventions
could have served a protective function against memory
overconsolidation and the development of subsequent
intrusions, thus reducing the overall emotional effect of
the trauma.
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Sex hormonal influences on fear extinction
Fear extinction as a model of anxiety vulnerability and
treatment
Avoidance of situations and objects that are perceived to
be highly threatening (because of previous conditioning
events or other causes) has long been acknowledged as a
key behavioural process in the development and
maintenance of anxiety and trauma-related and stress-
related disorders.66 The value of exposure therapy in
counteraction of such behavioural avoidance has long
been acknowledged and constitutes a large part of
cognitive behavioural therapy (CBT), the first-line
psychological treatment for anxiety and trauma-related
and stress-related disorders.67 Exposure therapy requires
the patient to confront the feared situation or object
without escape, which usually occurs in a graded fashion
where remaining in the feared situation becomes
increasingly challenging. The success of exposure
therapy is thought to depend on the patient acquiring
corrective information about the realistic level of danger
associated with the situation or object, as well as their
coping ability in the situation.66 During the past two
decades much research has examined fear extinction,
the laboratory model of exposure therapy, as a means of
elucidating the mechanisms underlying the loss of fear
to a feared situation or object.68
Fear extinction is a robust process in both rodents and
people, and involves the repeated presentation of a
feared conditioned stimulus (eg, a light or tone that was
previously paired with shock) in the absence of an
aversive outcome until fear responses decline (figure 2).
In addition to formation of the procedural and
theoretical basis of exposure therapy, individual
differences in fear extinction are thought to partly
underlie one’s vulnerability to the development of
anxiety. Although most people exhibit symptoms of
PTSD or other anxiety disorders in the weeks
immediately after trauma exposure, these symptoms
subside in almost all people, which is potentially
because of natural extinction processes occurring upon
incidental exposure to reminders and cues associated
with the trauma.69 A failure in natural extinction might
be partly responsible for the small proportion of
individuals who do not recover, and who are
subsequently diagnosed with PTSD.69 In support of this
theory, a prospective study in firefighters showed that
heightened fear responding in a laboratory fear
extinction task accounted for 31% of the variance
associated with PTSD symptoms 24 months later.70
Similarly, a range of anxiety and trauma-related and
stress-related disorders, including specific phobia, panic
disorder, and PTSD, have been associated with
impairments in laboratory fear extinction.48 Thus, fear
extinction is an ideal model with which to assess the
mechanisms underlying the development of anxiety
disorders, their treatment, and potential means to
improve both resilience and treatment response.
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Effect of sex, oestradiol, and progesterone on fear
extinction
Most rodent studies on fear extinction have been done in
males, and human studies have ignored the potential
influence of sex. Few studies have directly compared fear
extinction in males versus females, and similar to
outcomes from studies that have examined fear
conditioning, these have produced inconsistent findings,
with some reporting no sex differences in rats71,72 or healthy
people,53,54 and others reporting deficits in fear extinction
learning (ie, heightened fear responding) or its recall, or
both, in female rodents compared with male rodents.73,74
When the hormonal status of women and female animals
is taken into account (ie, menstrual or oestrous cycle stage
and hormonal contraceptive use), the results appear more
consistent (figure 2). For example, Milad and colleagues54,71
showed that cycling healthy human and rodent females
exhibit poorer extinction recall than do males when
extinguished during periods of low cycling oestradiol and
progesterone, and this difference is abolished when
females are extinguished during periods of high cycling
oestradiol and progesterone. The same association
between cycling sex hormones and fear extinction in rats
and healthy women has been shown by multiple
laboratories, indicating a robust effect.75–79 The results
from naturally cycling subjects are corroborated by the
finding that hormonal contraceptives, which inhibit
oestradiol and progesterone production, impair fear
extinction in female rats and healthy women.80 Evidence
for a specific role of oestradiol in fear extinction comes
from studies showing that pharmacological blockade of
the oestrogen receptor impairs fear extinction in female
rats;72 conversely, administration of oestradiol enhances
extinction recall in healthy women during the early
follicular phase,80 and selective oestrogen receptor agonists
reverse extinction impairments in rats during the
metestrus phase (marked by low oestradiol and
progesterone concentrations), as well as rats treated with
hormonal contraceptives.71,80,81 Together, these pharma-
cological studies show that oestradiol is both necessary
for, and can enhance, fear extinction in female rats and
healthy women. The exact mechanisms by which
oestradiol modulates fear extinction are yet to be identified.
However, given that fear extinction depends on the
formation of a new safety memory, and in view of
oestradiol’s well established influence on the molecular
signalling processes involved in long-term memory
consolidation,62 oestradiol probably promotes enhanced
consolidation of the fear extinction memory.
By contrast with studies investigating the role of
oestradiol in extinction, the few studies that have
investigated progesterone’s role in this regard have yielded
inconsistent results, with studies in healthy women
suggesting no effect of cycling progesterone,54,81 and studies
in rats suggesting either a beneficial effect71 or no effect75 of
progesterone administration on extinction recall. In our
2016 study,77 we used an oestradiol and progesterone
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Fear conditioning: Extinction learning: Extinction recall:
CS paired with US CS presented alone CS presented alone
Fear responses
High oestradiol
(eg, pro-oestrus/mid-luteal phase or oestrogen
receptor agonists) during extinction learning
facilitates the loss of conditioned fear responses
Low oestradiol
(eg, metestrus/follicular phase, oestrogen receptor
antagonist and hormonal contraceptives) during extinction
learning impairs the loss of conditioned fear responses
Figure 2: Standard cross-species fear conditioning and extinction laboratory
procedure
Fear responses increase in the presence of an initially neutral CS that is paired
with an aversive US during fear conditioning. Extinction learning involves the
repeated, non-reinforced presentation of the CS, which results in a decrement in
fear responses because of the formation of a new safety memory. The strength
of the extinction memory can be assessed at a later time by again presenting the
non-reinforced CS. Good extinction recall is indexed by low fear responses and
poor extinction recall is indexed by high (ie, relapsed) fear responses. Oestradiol
levels at the time of extinction learning influence the strength of the extinction
memory. CS=conditioned stimulus. US=unconditioned stimulus.
replacement regimen that mimics the oestrous cycle in
ovariectomised female rats and showed that oestradiol
enhances fear extinction, whereas progesterone has
biphasic effects. Progesterone augmented the facilitation
of fear extinction by oestradiol when administered 6 h
before extinction training, and antagonised oestradiol’s
beneficial effects on fear extinction when administered
24 h before extinction training. Indeed, prevention of
progesterone receptor activation during the progesterone
surge in cycling rats successfully rescued the extinction
impairments in these rats when they were subsequently in
the metestrus phase of their oestrous cycle, suggesting
that progesterone might be responsible for the cyclic
impairments in extinction ability. Although these results
need to be translated to women, they highlight the
existence of a complex association between oestradiol,
progesterone, and fear extinction, and the need for future
research to consider potential effects of the interactions
between these hormones as well as how these effects
might differ according to temporal factors.
Fear extinction as a potential pathway for sex hormone
influences on anxiety vulnerability and maintenance
The clear involvement of oestradiol in fear extinction raises
novel hypotheses with regards to how oestradiol
fluctuations during the menstrual cycle, as well as the
influence of pharmacological agents and developmental
stages that alter oestradiol synthesis, might result in phasic
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changes in both the propensity to develop anxiety
disorders, as well as in the responsiveness to exposure-
based treatments for anxiety disorders. Specifically, periods
of low oestradiol (eg, premenstrual, post partum, peri-
menopausal and post-menopausal, and during use of
hormonal contraceptives) might lead to impairments in
the natural extinction of emotional responses in the
aftermath of trauma, which could increase avoidance of
trauma reminders, which is, as already noted, a key factor
in the development and maintenance of PTSD and anxiety
disorders. Similarly, the effectiveness of exposure therapy
might be compromised during periods of low oestradiol,
and augmented during periods of high oestradiol (eg,
ovulation and pregnancy). This limitation is particularly
relevant to one-session-treatment protocols for anxiety
disorders such as specific phobia, but also of potential
relevance to the treatment of more complex anxiety and
stress-related disorders, such as PTSD, social anxiety
disorder, and generalised anxiety disorder, which require
treatment over multiple sessions. For instance, an
unsuccessful exposure session during a period of low
oestradiol might reduce motivation to engage in treatment,
or even prompt treatment dropout. Additionally, phasic
reductions in the effectiveness of exposure therapy would
dictate the need for an extended duration of treatment,
increasing the time and cost investment by the patient.
To date, no studies have tested these hypotheses.
However, evidence is emerging that the cyclic influence of
sex hormones on fear extinction in female rodents and
healthy women also extends to women with anxiety, and
trauma-related and stress-related disorders. For example,
reflexive startle responses were heightened throughout
extinction learning in PTSD-diagnosed women with low
oestradiol relative to those with high oestradiol
(progesterone concentrations were not assessed).82 A
subsequent 2016 study83 replicated the finding that trauma-
exposed healthy women exhibit worse extinction retention
during the follicular phase, compared with the midluteal,
menstrual cycle phase; notably, the opposite pattern of
results was observed in women with PTSD, who exhibited
worse extinction recall during the midluteal phase,
compared with the follicular phase. In a study84 focusing
on women with and without arachnophobia, we have
shown that extinction recall is equally impaired during
periods of low, relative to high, oestradiol, irrespective of
clinical status (no association was found between
progesterone and fear extinction in this study).
Observations that hormonal influences on fear extinction
have been conserved across species, and are observed
across multiple anxiety and trauma-related and stress-
related disorders, provide preliminary support for the
hypothesis that oestradiol might influence the development
of anxiety disorders and treatment responsiveness in
women via its effects on extinction processes. We are
investigating this issue by assessing whether the
effectiveness of exposure therapy for arachnophobia
depends on levels of cycling oestradiol across the menstrual
78
cycle, or hormonal contraceptive use (ClinicalTrials.gov
identifier NCT02622087). We are capitalising on the fact
that long-lasting symptom reduction for individuals with
specific phobia can be achieved with a single prolonged
session of exposure therapy, taking place within a discrete
hormonal phase for women.85 This trial presents a unique
opportunity to empirically evaluate whether hormonal
levels at the time of treatment affect long-term maintenance
of treatment gains.
Sex hormonal influences on anxious cognitions
and emotion regulation
Behavioural avoidance in anxiety disorders is thought to
be driven by catastrophic beliefs about the likelihood and
cost of the occurrence of negative events. Such beliefs are
integral to the development of anxiety disorders but also
play a key role in maintenance of anxious symptoms via
their effects on behaviour (ie, promotion of avoidance,
which prevents the disconfirmation of catastrophic
beliefs).86 In addition to reducing behavioural avoidance
via extinction processes, CBT also aims to alter these
cognitive processes via facilitation of adaptive emotion
regulation strategies such as cognitive reappraisal
(reducing unrealistic evaluations of the threat associated
with the object or situation), and elimination of
maladaptive emotion regulation strategies, including
worry and rumination (repetitive, abstract thoughts
focused on the causes of one’s symptoms).87
Some evidence suggests that the maladaptive cognitive
processes exhibited in anxious patients are influenced by
sex hormones. For example, rumination predicts anxiety
and depression scores and is consistently reported more
often by women in community samples compared with
men.88 Additionally, anxious women report premenstrual
worsening of physiological and cognitive symptoms of
anxiety,7,89,90 and such fluctuations have also been reported
in women with high anxiety sensitivity (ie, a tendency to
respond fearfully to anxiety symptoms). Specifically,
women with high anxiety sensitivity reported increased
cognitive symptoms of panic (ie, misinterpretation and
catastrophisation of physical symptoms) in the
premenstrual phase compared with the follicular phase
of the menstrual cycle89 and also engaged in more
avoidant oriented-coping (eg, mental and behavioural
disengagement, alcohol or drugs, denial) during the
premenstrual phase compared with other phases.90
Similarly, women with PTSD exhibit increased physical
and psychological symptoms in the early follicular phase,
compared with the mid-luteal phase.91
We hypothesise that phasic increases in anxious
cognitions, maladaptive emotion regulation strategies,
and avoidant behaviour, could lead to increased
vulnerability to the development of anxiety but also
intermittently exacerbate symptom severity, serving to
maintain anxious symptoms. Similarly, we expect that
such phasic increases, particularly in avoidant behaviour,
would be detrimental to treatment efficacy. For example,
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exposure therapy would be compromised if adequate
exposure to the feared object or situation could not be
maintained. Furthermore, cognitive therapy could be
similarly compromised by the tendency to engage in
maladaptive emotion regulation strategies. Of the
numerous studies to determine the effectiveness of
cognitive-based interventions for anxiety, few, if any, have
assessed for sex-specific effects, and none have assessed
the potential influence of hormonal status. Nonetheless,
the higher prevalence of anxiety disorders among women
is also accompanied by an increased incidence of post-
treatment relapse in women relative to men92—an effect
that is consistent with the hypothesised influence of sex
hormones on treatment processes. Whether women’s
hormonal status moderates their increased risk of post-
treatment relapse should be assessed in future research.
Conclusions and future directions
The influence of sex hormones on the many factors
underlying anxiety is profound, spanning biological,
behavioural, and cognitive processes. The evidence we
present in this Series paper highlights a complex
association between sex hormones and anxiety, whereby
periods of heightened oestradiol and progesterone can be
both protective as well as increase vulnerability,
depending on the particular cognitive or behavioural
process occurring at the time of hormonal change.
Increased allopregnanolone
Increased serotonin
Effective extinction
High levels
Facilitates trauma memory consolidation
progesterone
Progesterone
Oestradiol/
Oestradiol
Reduced allopregnanolone
Reduced serotonin
Low levels
Impaired extinction
Increased maladaptive behaviours
Increased maladaptive cognitions
Figure 3: Hypothesised model of the influence of sex hormones on biological, behavioural, and cognitive pathways that promote or reduce anxiety disorder
vulnerability and maintenance in women
High or low levels of oestradiol (light blue shading), progesterone (purple shading), or both (light green shading), mediate the effect specified in the second column
of boxes, which reduces vulnerability in healthy women and reduces maintenance of symptoms in anxious women (dark blue shading), or increases vulnerability in
healthy women and promotes maintenance of symptoms in anxious women (orange shading). CBT=cognitive behavioural therapy.
www.thelancet.com/psychiatry Vol 4 January 2017
Series
We hypothesise a model by which the different pathways
described in this Series paper could interact to influence
the gender imbalance in anxiety prevalence (figure 3). We
propose that normal fluctuations in sex hormones
(because of the menstrual cycle, reproductive status, or
age) and the resulting modification of basal endogenous
anxiolytics (ie, serotonin and allopregnanolone activity)
could lead to intermittent periods of heightened
vulnerability to anxiety, due to periodic declines in the
ability to regulate anxious emotions, independent of
environmental context. Hormonal-induced fluctuations in
these endogenous anxiolytics might similarly inter-
mittently exacerbate pre-existing anxious symptoms, and
contribute to instability in the efficacy of pharmacotherapy.
Alongside these ongoing fluctuations in emotion
regulation, oestradiol and progesterone might influence
cognitive and behavioural processes to moderate the effect
of environmental events. High levels of sex hormones,
particularly progesterone, at the time of trauma exposure
might facilitate the development of anxiety and PTSD,
possibly because of an overconsolidation of the traumatic
memory via the excitatory effect of sex hormones on the
molecular processes underlying long-term memory.
Conversely, low levels of sex hormones, particularly
oestradiol, at the time of re-exposure to fear-eliciting cues
and situations (either incidentally or during exposure
therapy) might obstruct natural or therapeutic reductions
Improved symptoms Reduced vulnerability: protects
against the development of an
anxiety disorder
Increased SSRI efficacy
Effective natural extinction
Reduced maintenance: improves
treatment response and reduces
Increased exposure therapy efficacy anxiety symptoms
Increased symptom severity
Increased symptom severity
Reduced SSRI efficacy Increased vulnerability: more likely
to develop an anxiety disorder
Poor natural exinction
Reduced exposure therapy efficacy
Increased maintenance: impairs
treatment response so anxiety
Avoidance and reduced cognitive flexibility symptoms are maintained
Reduced CBT efficacy
79
 Series
Search strategy and selection criteria
We identified references for this review by searching PubMed
for articles without publication date or language restrictions,
with the search terms “sex differences”, “anxiety”, “fear
extinction”, “fear conditioning”, “estradiol”, “progesterone”,
“allopregnanlone”, and “neuroactive steroid”. We identified
other relevant articles by searching our personal files and
Google Scholar. We reviewed articles resulting from these
searches and relevant references cited in those articles.
in anxiety and behavioural avoidance, because of an
impaired molecular consolidation of fear extinction
memories. Such a process would both prevent natural
recovery (ie, increase vulnerability) and also periodically
compromise the efficacy of exposure therapy (ie, facilitate
maintenance of pre-existing symptoms). Finally, periods
of reduced synaptic plasticity associated with low levels of
sex hormones might lead to reduced engagement of
adaptive emotion regulation strategies, such as cognitive
reappraisal, exacerbating cognitive biases that underlie
anxiety (thus increasing vulnerability and exacerbating
symptom severity) and potentially intermittently
compromising psychological treatments that depend on
restructuring of anxious cognitions. We further speculate
that pharmacological agents that suppress endogenous
sex hormone production (eg, hormonal contraceptives)
might mimic the effects of the early follicular phase of the
menstrual cycle on the above processes. However, this
speculation is based on only a small body of research
examining the influence of hormonal contraceptives on
fear extinction and on spontaneous intrusive memories of
trauma. The implications of hormonal contraceptive use
are probably complex, given that they suppress
endogenous hormone production and simultaneously
elevate synthetic levels of sex hormones. More thorough
investigations of the effect of different hormonal
contraceptive formulations are required.
Throughout this Series paper we have highlighted the
dearth of literature systematically assessing the influence
of sex hormones on processes relevant to the development
and treatment of anxiety. Crucially, many of the
speculations and assumptions in our model are yet to be
tested in clinical populations, although they come from a
solid base of preclinical experimental research in both
rodents and healthy women. In particular, our predictions
regarding how sex hormones might lead to fluctuations in
the efficacy of pharmacological and psychological
treatments should be assessed in future research, as part
of the wider drive to develop personalised treatments for
mental illness. We suggest that much of the data required
to assess these predictions probably already exist as part of
information that is routinely collected in clinical treatment
trials, and we encourage researchers to consider re-
analysing existing databases with these predictions
in mind.
80
We also suggest that irrespective of whether future
research supports the model depicted in figure 3, the
evidence reviewed nonetheless points to multiple strategies
by which existing treatments for anxiety could be improved
by taking women’s hormonal status into account. Such
strategies include intensification of cognitive restructuring
during the premenstrual period (when such symptoms are
most severe), and psychoeducation around menstrual cycle
regulation of anxiety symptoms, as well as targeting of
exposure sessions during periods of heightened oestradiol
levels. Similarly, hormonal adjuncts to enhance the efficacy
of psychological and pharmacological treatments (Soares
and colleagues93 provide an example of oestradiol being
used successfully as an adjunct to SSRI treatment of
depression), and modification of pharmacotherapy dose in
accordance with basal fluctuations in sex hormones, might
also be areas worthy of future investigation.
Finally, the small body of research that has examined the
influence of sex hormones on anxiety-relevant processes
has focused on the consequences of high versus low
hormonal levels, as defined by group median splits, or by
self-reported menstrual cycle stage. However, some
evidence suggests that individual differences in basal or
peak levels of oestradiol and progesterone might also
influence vulnerability, as might individual differences in
responses to changing hormonal levels, in which some
people react adversely to normal hormonal fluctuations
(Bloch and colleagues94 propose a similar theory with
respect to post-partum depression). As such, the absolute
value of the hormone concentration might only be one part
of the puzzle. Future research (both experimental and
clinical) should therefore focus on within-subject designs—
repeated measures designs that track symptom changes
across time—and map these onto individual differences in
basal hormonal levels and fluctuations in both men and
women. Indeed, a key assumption of the model we present
in figure 3 is that women might be more vulnerable to
anxiety disorders than men because of their greater
monthly and life-span hormonal fluctuation (leading to
instability in emotion regulation and treatment efficacy),
rather than differences in the absolute level of sex
hormones and neurosteroids, but evidence for this
assumption is currently absent. Continued investigation of
sex-specific and hormonal-specific mechanisms underlying
the cause and maintenance of anxiety disorders will be
essential to ensure the development of individualised,
evidence-based preventions and interventions for anxiety
that are optimally effective in both men and women.
Contributors
Both authors contributed equally to the literature search, drafting of the
manuscript, critical revision of the manuscript, and approval of the
version of the manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
This study was funded by MQ: Transforming Mental Health Fellowship
(MQ13002) to BMG. The MQ: Transforming Mental Health Fellowship
had no involvement in the preparation of this manuscript.
www.thelancet.com/psychiatry Vol 4 January 2017

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