HHS Public Access: Anxiety Disorders Among Women: A Female Lifespan Approach

HHS Public Access
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Focus (Am Psychiatr Publ). Author manuscript; available in PMC 2018 April 10.
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Published in final edited form as:

Focus (Am Psychiatr Publ). 2017 ; 15(2): 162–172. doi:10.1176/appi.focus.20160042.
Anxiety Disorders Among Women: A Female Lifespan Approach

Dr. Liisa Hantsoo, Ph.D. and
Clinical Psychologist & Instructor, Penn Center for Women’s Behavioral Wellness, Perelman
School of Medicine, University of Pennsylvania
Dr. C. Neill Epperson, M.D.

Professor of Psychiatry and Obstetrics and Gynecology, Perelman School of Medicine, University
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of Pennsylvania and Director of the Penn Center for Women’s Behavioral Wellness and Penn
PROMOTES Research on Sex and Gender in Health, Perelman School of Medicine, University of
Pennsylvania
Abstract
Anxiety symptoms may present differently between women and men, and at different points in the
female lifespan. The female lifespan includes distinct epochs of hormonal function, including
puberty, the premenstruum, in some women pregnancy or postpartum, and the menopausal
transition. These stages give rise to important treatment considerations when treating anxiety in
women. When making assessments, the clinician should consider reproductive events and
hormonal status, as well as sex differences in anxiety presentation. This review is structured to: 1)
Define major epochs of the female lifespan, 2) Provide a brief summary of the major anxiety
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disorders, with a focus on prevalence and presentation in the context of sex differences and at
points in the female lifespan, 3) Describe potential biopsychosocial underpinnings of anxiety
disorders among women, 4) Provide guidelines for assessment and differential diagnosis, and 5)
Describe treatment options with attention to reproductive events such as pregnancy.
Keywords
premenstrual; perinatal; postpartum; menopause; puberty; ovarian hormones
INTRODUCTION
Women experience markedly greater prevalence of anxiety disorders than men, including
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generalized anxiety disorder (GAD), panic disorder (PD), and specific phobias. In a study of
over 20,000 individuals in the United States, the Collaborative Psychiatric Epidemiology
Studies (CPES) found higher rates of lifetime diagnosis for nearly all anxiety disorders
among women (1). Core features of the anxiety disorders include subjective anxiety or fear
experience, physiologic reactivity, and often avoidance behavior (2). Anxiety disorders are
characterized by anxious apprehension or fear in response to a perceived threat (3; 4).
Anxiety or anxious apprehension is a future-oriented state in which one is concerned about
Address correspondence to Dr. Hantsoo (LiisaHa2@mail.med.upenn.edu).

The authors report no financial relationships with commercial interests.
Hantsoo and Epperson Page 2
potential threats, while fear occurs in response to an immediate threat (5). Anxiety disorders
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in women often precipitate or worsen at times of hormonal fluctuation, including puberty,

the premenstruum, pregnancy or postpartum, and the menopausal transition (Figure 1). In
this review, we address each of these pivotal timepoints in the female lifespan and how
anxiety disorders present and may be treated at each timepoint.
THE FEMALE LIFESPAN

Puberty
Puberty represents a vulnerable developmental window for the occurrence of anxiety
disorders (6). It is at puberty that sex differences in anxiety begin to emerge, with a higher
rate among girls as they enter adolescence independent of age (7; 8). A recent cohort study
of nearly one million Danish youth found that prior to puberty, males had higher rates of
anxiety disorders, but this trend reversed with puberty, showing females with higher rates of
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anxiety disorders (9). In the U.S., a longitudinal community study annually assessed 1420
youth from age nine through 16 years and found higher three month percent prevalence of
most anxiety disorders in females (10). Among German youth aged 14–24 years, panic
disorder was more prevalent in females than in males, with an earlier age of onset (11).
Puberty in women is marked by the initiation of menses (menarche) and its accompanying
monthly fluctuations in ovarian steroid hormones, described below. Ovarian steroids (e.g.
estradiol, progesterone) and their metabolites are neuroactive, impacting neurotransmission
at a number of receptors in the central nervous system (CNS). Hormonal fluctuations
initiating with puberty may play a role in the etiology of anxiety disorders, however, further
research in this area is needed (7). Puberty may also be a time of increased psychosocial
stress, also described below, which may contribute to occurrence of anxiety symptoms.
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The Menstrual Cycle

The simplest characterization of the menstrual cycle is that it includes two stages, the
follicular and luteal phases. However, ovarian hormone levels are quite variable within as
well as between phases. At onset of menstruation, typically considered Day 1 of the cycle,
ovarian hormones estradiol and progesterone are both low. However, under conditions of
rising follicle stimulating hormone (FSH) secreted from the pituitary, ovarian estradiol levels
increase and peak at ovulation, approximately Day 14. With ovulation, progesterone levels
begin to rise, increasing over 20-fold over the course of the luteal phase. Estradiol levels
decline immediately after ovulation but then rise again in concert with mid-luteal phase
progesterone. Finally, during the late luteal phase, progesterone and estradiol levels
precipitously drop if pregnancy has not occurred, followed by menses and the next cycle
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(12).
As many as 80% of reproductive aged women experience at least one physical, mood, or
anxiety symptom in the luteal phase (13–16). Approximately 20% experience significant
premenstrual symptoms (13; 14; 16). A smaller subset of women, 5–8%, experience
premenstrual dysphoric disorder (PMDD), a mood disorder that often has a strong anxiety
symptom component (13; 17–19). In fact, Nillni and colleagues suggest common
biopsychosocial pathways between anxiety disorders and PMDD (20). Increased anxiety
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sensitivity and perceived control over anxiety-related events are potential contributors (21).
Women with anxiety disorders may also experience premenstrual exacerbation of symptoms,
described below.
Pregnancy & Postpartum

During pregnancy, estrogen and progesterone levels increase exponentially, then drop
rapidly within hours of delivery. Stress or depression during pregnancy can have profound
effects on both the woman and fetus, with implications for development through childhood
and into adulthood (22–24). Literature on the impact of prenatal anxiety on offspring is
relatively small. Antenatal anxiety had an effect independent of depression on offspring
behavioral and emotional concerns, in a large longitudinal study (25). Women with the most
severe anxiety during pregnancy had children with a twofold increased risk for a behavioral
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or mental health disorder after controlling for confounders including postnatal maternal
mood and paternal pre- and postnatal mood, which would be more consistent with genetic
effects (26). Given this potential for intergenerational transmission of stress, clinicians
should be aware of the impact of untreated anxiety on both mother and offspring, and be
attentive to emergence of anxiety symptoms during pregnancy. A 2014 systematic review
revealed a high prevalence of anxiety disorders during pregnancy, with GAD, phobias, and
PD being among the most prevalent (27). A meta-analysis suggested that there may be an
association between anxiety disorders and preterm birth or low birth weight, however,
anxiety assessments were heterogeneous (28).
Menopausal Transition
As menopause approaches, ovarian hormones fluctuate erratically and periods become
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irregular. The PENN-5 staging system divides the menopause transition into five stages:
premenopausal (regular menstrual cycles of 21–35 days); late premenopausal (one observed
change in cycle length of at least 7 days), early transition (at least two cycles with cycle
length changes of at least 7 days), late transition (greater than or equal to 3 months of
amenorrhea) and postmenopausal (greater than or equal to 12 months of amenorrhea) (29).
Anxiety may heighten with the menopausal transition, then decrease.
Indeed, the Study of Women’s Health Across the Nation (SWAN), a multi-site longitudinal
epidemiologic study, found that even women with low levels of anxiety were likely to
experience an increase in anxiety symptoms across the menopausal transition (30). The
menopausal transition may be a time of increased stress, as women experience a life
transition accompanied by physical symptoms such as hot flashes and insomnia. In fact,
research strongly suggests a link between perimenopausal hot flashes and anxiety symptoms
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(31–33). For women in the SWAN study who did not have high levels of baseline anxiety,
vasomotor symptoms such as hot flashes increased the odds of having high anxiety across
the stages of menopause transition (30).
EPIDEMIOLOGY OF ANXIETY DISORDERS ACROSS THE FEMALE

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LIFESPAN
In this section, we describe each of the major anxiety disorders, focusing on sex differences
and symptom presentation across the female lifespan.
Generalized Anxiety Disorder (GAD)

GAD is characterized by constant, nonspecific, difficult to control worry (17). Lifetime
prevalence of GAD is greater in women (about 6%) than in men (about 3%) (34).
Perinatally, GAD prevalence ranged from 0 to 10% in a systematic review (27). Compared
with men, women with GAD often present with somatic complaints such as fatigue, muscle
tension, or gastrointestinal symptoms. Women often have comorbid mood disorders, while
men have comorbid alcohol or drug abuse (35; 36).
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The Avon Longitudinal Study of Parents and Children (ALSPAC) followed a population-
based cohort in the United Kingdom from the ages of 7 to 13 years. The peak frequency of
“worry cognitions” occurred at age 10 in boys and girls. Among girls, highest level of
interference with daily life occurred at age 13, while it decreased in boys (37). While this
study did not assess GAD specifically, worry cognitions are a key facet of GAD. Literature
on premenstrual exacerbation of GAD is limited. One study of women with GAD found that
more than half experienced worsening of anxiety symptoms premenstrually, based on
clinical interview (38). The literature on GAD during pregnancy and postpartum is much
richer. Misri (39) and Goodman (27) both published recent reviews of perinatal GAD.
Briefly, GAD is fairly prevalent perinatally (27), but symptoms can be difficult to discern
from normal aspects of pregnancy and postpartum (e.g. insomnia, fatigue, difficulty
concentrating) (39). Women with a history of GAD are more likely to have a recurrence
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perinatally; in one study, women with four or more previous GAD episodes were
significantly more likely to experience GAD in pregnancy (40). Women with postpartum
GAD were at higher risk for later MDD (41). A study from the Menopause Strategies:
Finding Lasting Answers for Symptoms and Health (MsFLASH) trials found that 16.6% of
perimenopausal women had mild anxiety symptoms and 4.4% had moderate or severe
symptoms, based on the GAD-7 scale (42).
Panic Disorder (PD)

PD’s core feature is an unexpected but brief burst of fear accompanied by physical “fight or
flight” symptoms (e.g. tachycardia, chest pain, nausea), and followed by excessive concern
about additional attacks or their consequences (17). PD is at least twice as common in
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women as in men (34). Women often present with fear associated with the physical
symptoms of panic, while men may focus more on the social consequences of a panic attack
(43).
As girls progress through puberty, the likelihood of panic attack increases. For each increase
in Tanner stage, there was a two-fold increase in rates of panic attack in a sample of nearly
1000 peripubertal girls (44). Those with high levels of anxiety sensitivity may be
particularly vulnerable to panic attacks. Adolescents self-reported higher anxiety sensitivity
in the early stages of puberty than in the later stages, but did not report sex differences (45).
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In a study of healthy adolescents ages 12–17 years, those with more advanced pubertal
status and increased emotional reactivity were most likely to experience panic symptoms in
a hyperventilation challenge, after controlling for age and gender (46).
Premenstrually, women with PD report increased state anxiety, anxiety sensitivity, and
anxiety concerning bodily sensations or illness, compared with controls (47). They are also
physiologically more reactive to anxiety, showing greater increases in skin conductance in
the luteal phase compared to the follicular phase (47). In a small sample of women with PD,
patients retrospectively reported increased panic symptoms premenstrually, but this was not
confirmed by prospective symptom ratings (48). In fact, findings indicate that panic
symptoms may not commonly be exacerbated premenstrually among women diagnosed with
PD (49). However, some propose commonalities between PD and PMDD, as those with
either diagnosis are more prone to panic attacks in laboratory challenge studies (50).
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First onset of PD occurs perinatally in 3–11% of women with the disorder (51; 52). New
onset PD in pregnancy is associated with a higher risk of relapse in subsequent pregnancies
(53). Women with a previous diagnosis of PD or another anxiety disorder are at increased
risk for PD perinatally (54). Women who experienced panic attacks during pregnancy had a
2.29-fold increased risk of having a small-for-gestational-age infant, and a 2.54-fold
(adjusted odds ratio) increased risk for preterm birth compared with healthy controls (55).
Women with PD who did not have a panic attack during pregnancy had similar risk for
preterm birth as women without PD (55). Interestingly, some women with PD experience
improvement of symptoms during pregnancy (56). In the longitudinal study of over 2500
pregnant women, PD was not associated with increased risk for preterm birth in analyses
adjusted for factors such as other psychiatric disorders, nicotine or alcohol use, race/
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ethnicity and previous pregnancy history, to name a few (57).
During perimenopause, PD may arise or worsen (58). Intriguingly, there may be a link
between hot flashes and panic attacks (32). Hot flashes are experienced as a feeling of
flushing or heat, often with perspiration; the onset is sudden and peaks rapidly, as in panic
attacks. Both may include sweating, heart palpitations, dyspnea, and nausea, both can be
triggered experimentally by yohimbine (59; 60), and both respond to treatment with
clonidine, gabapentin, selective serotonin reuptake inhibitors (SSRIs) and selective
norepinephrine reuptake inhibitors (SNRIs).
Specific Phobia
Specific phobia is an excessive, unreasonable fear of a specific object or situation (17).
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Lifetime prevalence of specific phobia is about twice the rate in women (12–27%) compared
to men (6–12%) (34; 61; 62). Women tend to have more animal and environmental phobias
than men. Onset is often prior to puberty (63) and is not associated with reproductive events
in the female lifespan, suggesting that the higher prevalence among women is not due to
ovarian steroids (64). There is little research on pubertal status and specific phobias. Among
adults, females had four times greater prevalence of a specific phobia (emetophobia; fear of
vomiting), with onset most frequently in late puberty (65). A large study of Korean women
found that those with PMDD had comorbid specific phobia relatively frequently (16.9%)
(66). Case studies describe women who experience onset or worsening of phobias during
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pregnancy, but there is little literature on this topic. Pregnancy-related phobias have been
described, including emetophobia, tokophobia (fear of pregnancy or childbirth itself) (67–
69), and blood and injection phobia (70–72). There is similarly little research on specific
phobias in the perimenopause or menopause specifically.
Social Anxiety Disorder (SAD)

SAD is characterized by excessive fear of social or performance situations in which one
might be judged by others (17). Lifetime prevalence is slightly higher in women (about 5–
15%) than men (about 4–11%) (34; 73). The National Epidemiologic Survey on Alcohol and
Related Conditions assessed over 43,000 adults in the United States using DSM-IV criteria,
and found a prevalence of 5.67% for women and 4.20% for men (74). Women’s anxieties
often focus on performance (e.g. scrutiny from authority figures, eating and drinking in front
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of others) (75), and women often present with comorbid mood disorders (74).
SAD typically has onset prior to age 18; one study found that nearly 80% of individuals with
a diagnosis of SAD experienced onset prior to age 18 (76). However, whether SAD onset
occurs more frequently with puberty or earlier in development is debated (77). A
longitudinal study of over 1000 peripubertal girls, using a time-varying pubertal timing
model, found less advanced pubertal status was associated with greater self-reported social
anxiety symptoms (78). While this is supported by other studies (79), earlier puberty has
also been associated with increased social anxiety symptomatology (80). In a longitudinal
study that followed boys and girls from age 9 up to age 16, the transition to adolescence
brought an increase in social anxiety rates for girls, but not in boys (10). Among
reproductive aged women with social anxiety disorder, 45% experienced more severe
anxiety symptoms in the premenstrual phase in a small sample (81). Symptoms decreased
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during pregnancy in one sample, returning to pre-pregnancy levels postpartum (81). Little is
known about the course of social anxiety during perimenopause.
Anxiety in the Context of Menstrual Cycle Disorders

Women experience normal monthly fluctuations in neuroactive steroids with their menstrual
cycles. A subset of women, about five to eight percent, appear to be more sensitive to these
fluctuations than others and present with PMDD. PMDD itself has a strong anxiety
component (18), and women with PMDD often have a comorbid anxiety disorder. In a
review of the literature, women with PMDD had comorbid GAD (up to 40%), PD (25%),
and social anxiety disorder (approximately 20%) (82). Thus, when assessing women who
present with premenstrual syndrome (PMS) or other premenstrual mood symptoms (e.g.
PMDD), clinicians should consider whether there is an accompanying anxiety component.
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Women with polycystic ovarian syndrome (PCOS), characterized by increased androgen

levels and irregular menstrual cycles, are at risk for mood and anxiety disorders (83–85).
Women with PCOS and irregular menstrual cycles with hirsutism, had higher anxiety
symptoms but not depressive symptoms than control women (86). Among women with
PCOS who lost weight during a 16 week intervention with oral contraceptive pills or a
lifestyle modification program, anxiety symptoms decreased significantly (87). Clinicians
should be aware when treating ovarian hormone related disorders, such as PCOS, that
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anxiety or affective symptoms may also occur.
BIOPSYCHOSOCIAL UNDERPINNINGS
A combination of biological and social factors influence the sex differences and course of
anxiety disorders over the female lifespan. Women may be more likely to experience
stressors contributing to anxiety disorders (88), have coping or cognitive styles more prone
to rumination and worry (89), or have biological predispositions such as anxiety sensitivity
and hormonal fluctuations that propagate anxiety disorders.
Stressors
Childhood sexual abuse occurs twice as often in girls as in boys, and girls experience
multiple forms of childhood abuse, neglect or household dysfunction at a higher rate than
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boys (88; 90). The Nurses’ Health Study II, which included 68,505 women, found that 57%
reported some form of physical or sexual abuse in childhood (91). The pubertal window may
represent a period of increased vulnerability to the programming of lifetime risk for stress-
related psychiatric disorders. While pubertal timing itself may play a role in development of
anxiety disorders (92), the occurrence of stress relative to puberty may also have an
influence (93). In a sample of 2,899 girls from the National Comorbidity Survey Replication
– Adolescent Supplement, traumatic stress during the pubertal window (dating back up to
three years prior to menarche) increased risk for anxiety disorders, compared to stress during
preadolescence, which increased risk for mood disorders (93).
In adulthood, women experience trauma at a similar rate as men but experience sexual
assault at ten times the rate of men (94). Women may also be more sensitive to interpersonal
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stress than men, potentially contributing to the higher prevalence of depression in girls after
puberty (95). As described above, women with PMDD are more likely to have a trauma
history. Finally, women may be more physiologically reactive to stressors, contributing to
increased risk of anxiety or other neuropsychiatric disorders (96–98).
Coping and Cognitive Styles

During childhood and adolescence, girls exhibit more anxious coping and more emotional
distress in response to stressors than boys (95; 99; 100). In a prospective multiwave study of
adolescents, a negative cognitive style or rumination in combination with a stressor
accounted for an increasing trajectory of anxious arousal symptoms over the course of
adolescence in girls (101). In adulthood, women exhibit a ruminative coping style (102), and
often seek support from others in times of stress (103). Women exhibit greater anxiety
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sensitivity than men, defined by catastrophic interpretations of bodily sensations such as

heart pounding or dizziness. Susceptibility to, for example, panic disorder in women is likely
due to an interaction of anxiety sensitivity, cognitive factors, and neuroactive steroid
fluctuations (20).
Biological Factors
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While all women experience the hormonal fluctuations of puberty, the menstrual cycle, and
menopause (and some pregnancy), not all women develop anxiety disorders in response to
these fluctuations. Thus, determining the biological contributors that make certain women
vulnerable to hormonal fluctuations is critical. Women with reproductive mood or anxiety
disorders do not differ in peripheral hormone levels from women without these disorders.
Thus, it is not hormone levels per se, but their interaction with the central nervous system
that are implicated (104).
At puberty, ovarian hormone cycling initiates, with monthly fluctuations of neuroactive

hormones including estradiol and progesterone. Significant brain remodeling also occurs at
puberty, including areas implicated in anxiety disorders, such as the amygdala (105–107).
This remodeling may program the brain’s responsivity to stress hormones and neuroactive
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steroids, persisting through adulthood (108; 109). Puberty engenders both organizational and
activational effects of neuroactive hormones that may be implicated in the development of
anxiety disorders among females (108; 110).
Among the neuroactive steroid hormones, particularly relevant to anxiety disorders is

allopregnanolone (ALLO), a metabolite of progesterone and a strong agonist of the GABAA
receptor, with anxiolytic properties similar to a benzodiazepine. Some propose that altered
interactions between ALLO and the GABAA receptor across the menstrual cycle may
contribute to anxiety and affective disorders (111; 112). For instance, some propose that
panic and PMDD share common biological pathways, with ALLO as a key component (20;
113). Indeed, panic patients had higher levels of ALLO during the follicular phase compared
to controls, which Brambilla and colleagues propose was hypersecreted to offset HPA axis
activity (114). Estrogens may also play a role in anxiety disorders. Milad and colleagues
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propose that estradiol modulates fear learning and fear extinction, giving it a potential role in
anxiety or trauma-related disorders (115; 116).
ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

There are a number of tools specialized to identify symptoms in women across the lifespan.
In addition, a thorough clinical interview should be conducted, assessing the patient’s family
history, reproductive history including querying about affective or anxiety symptoms (e.g.
past episodes of postpartum depression), and medication history including psychiatric
medications and hormonal contraceptives or hormone therapy.
In terms of diagnostic criteria, the DSM-5 provides the most up to date guidelines for
diagnosing anxiety disorders. Accordingly, the Anxiety Disorders Workgroup developed
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several brief self-report scales to assess the major anxiety disorders with focus on the core
components of anxiety disorders - subjective fear experiences, physiological reactivity and
avoidance behavior. These scales are available free of charge on the American Psychiatric
Association’s website.
Premenstrual Anxiety
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To identify a pattern of premenstrual worsening of anxiety, it is ideal to obtain prospective

daily ratings from the patient for at least two menstrual cycles. The Daily Record of Severity
of Problems (DRSP) is the gold standard for prospective tracking (117). It includes anxiety
symptoms of feeling tense or on edge, difficulty concentrating, fatigue, and some physical
symptoms. The patient rates each symptom daily on a scale of “none” to “extreme;” the
provider can then compare the follicular and luteal phase to see if there is a luteal increase in
symptoms. The provider may ask the patient to also record specific anxiety symptoms that
she experiences, such as panic attacks.
The Carolina Premenstrual Assessment Scoring System (C-PASS) is a new instrument that
provides a means of scoring DRSP data (118). It is available for download as a worksheet or
statistical package macro. While it is designed to assess DSM-5 criteria for PMDD
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diagnoses, and not anxiety, it may provide a general impression of symptoms across the
cycle. Mobile applications may also provide a convenient means for patients to track daily
symptoms, however, many of these are not empirically supported and have not been
validated for clinical accuracy, i.e. compared with a diagnosis provided by a professional.
Perinatal Anxiety
Anxiety symptoms are fairly prevalent perinatally (27), but can be difficult to discern from
normal aspects of pregnancy and postpartum (e.g. insomnia, fatigue, difficulty
concentrating) (39; 119). Thus, a careful diagnostic interview should be conducted. A
promising new scale is the Postpartum Specific Anxiety Scale (PSAS), which shows good
validity and properly identified women with a current clinical diagnosis of anxiety (120).
Another recently developed tool is the Perinatal Anxiety Screening Scale (PASS) (121),
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which reliably identified women at risk of anxiety using a clinical cut-off score (122). Scales
not designed specifically for the perinatal population may be an option; one study found that
Beck Anxiety Inventory (BAI) items on feeling panicky, restlessness, and sleep difficulty
estimated GAD prevalence at 20.2% compared to the clinician-diagnosed 15.7% prevalence
among postpartum women, and had high (83%) specificity (123). Factors such as lack of
partner support, low social support, abuse history, an unplanned or unwanted pregnancy, and
pregnancy complications or loss were factors associated with prenatal anxiety, and should be
considered in the clinical assessment (124).
Perimenopausal Anxiety
The Women’s Health Questionnaire (WHQ) was developed in a sample of women ages 45 –
65. The scale asks women to report on physical and emotional symptoms, some specific to
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menopause (125). While not geared specifically toward assessing anxiety, it does include
four items on anxiety symptoms. Clinicians should assess reproductive mood history, as
women with premenstrual symptoms are more likely to develop anxiety perimenopausally
(126). The clinician should also assess vasomotor symptoms, as there may be a relationship
between anxiety and hot flashes. During the menopausal transition, women with high levels
of somatic anxiety had more than three times the risk of hot flashes than those with low
levels of somatic anxiety; this occurred in a time-lagged fashion, such that anxiety predicted
hot flashes (31).
TREATMENT AND OUTCOMES

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Treating Anxiety in the Premenstruum

Continuous and luteal phase treatment with selective serotonin reuptake inhibitors (SSRIs)
have both shown efficacy in treating PMDD (127–129). In luteal phase treatment, the
woman takes SSRI only during her luteal phase, which the clinician may mark via time of
ovulation, time predicted until next menses, or simply time of symptom onset. Treatment
response is generally rapid, and often a low dose is sufficient (130; 131). However, some
women do not respond to SSRIs, and side effects may occur. There is little research on
SSRIs specifically for premenstrual anxiety, although one small study showed a significant
45.4% decrease in Hamilton Anxiety Scale (HAM-A) score after four weeks of sertraline
treatment among women with PMDD (132). While hormonal contraceptives may influence
aspects of anxiety response, there is limited evidence for the efficacy of hormonal treatment
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for premenstrual mood symptoms (133–135). Some women report worsening of

premenstrual mood symptoms with hormonal contraceptives (136–138). In fact, a recent
prospective cohort study of over one million Danish women found that women who were
prescribed a hormonal contraceptive had a greater risk ratio for subsequently being
prescribed an antidepressant or being diagnosed with depression compared with non-users
(139). However, anxiety diagnoses were not assessed in that study. Among women with
PMS, continuous dosing of hormonal contraceptive may be effective over the typical 21/7
dosing schedule, avoiding hormonal fluctuations. In one study, women initiated a 21/7
dosing schedule, then crossed over to a continuous regimen of 3 mg of drosperinone and 30
micrograms of ethinyl estradiol. Their premenstrual symptoms decreased more in the
continuous phase than the 21/7 phase (140). Yaz (Bayer AG Pharmaceuticals), which
contains 3 mg drosperinone and 30 micrograms ethinyl estradiol on a 24/4 dosing schedule
is FDA approved for treating PMDD (141). Clinicians should be aware of the potential risks
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and side effects of hormonal contraceptives. Gonadotropin releasing hormone (GnRH)

agonists and inhibitors are another hormonal treatment option, reducing levels of estradiol,
progesterone, and ALLO to postmenopausal levels (142–144). Benzodiazepines are often
prescribed for anxiety symptoms, but women with PMDD show decreased sensitivity to
benzodiazepines (145); whether this is true for women with premenstrual exacerbation of
anxiety is not known, and the potential for misuse is a consideration.
Perinatal Anxiety – Balancing the Risks

For women who are pregnant or postpartum, treatment considerations include potential
impact of medication on the fetus (146), and transmission of medication via breastmilk (147;
148). For detailed information on placental and breastmilk transmission of medications,
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providers may refer to resources such as ReproTox.org, an online database that provides
summaries of medication effects on pregnancy, reproduction, and development (149).
Providers should consider the potential risks of medication versus the potential impact of
untreated anxiety on the pregnancy. A recent review of treatments concluded that in terms of
pharmacotherapy, SSRIs and tricyclic antidepressants had some evidence for effectiveness in
treating anxiety disorders in the perinatal period (150). For women who do not want to use
medication during pregnancy, cognitive behavioral therapy (CBT) may be a good alternative,
particularly for women with panic disorder or specific phobias (150; 151).
There are clear recommendations for the treatment of depression during pregnancy, with use
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of antidepressants for moderate to severe depression and psychotherapy as a first-line

intervention for milder depression (152). While anxiety is frequently comorbid with
depression, no clear recommendations have been made for the treatment of specific anxiety
disorders during pregnancy. As 50% of pregnancies in the United States are unplanned, it
behooves the patient and clinician to have a discussion regarding the risks and benefits of
continuing to take psychotropic medications during pregnancy early in the therapy. For
instance, benzodiazepines, which are often prescribed during the acute stages of managing
anxiety and/or insomnia, fall into Class D which indicates evidence of human fetal risk,
however, potential benefits may warrant use of the drug in pregnant women despite these
potential risks. As discussed previously, active anxiety disorders during pregnancy are not
without their risk even in the absence of psychotropic medication exposures. If the mother’s
psychological stability would be jeopardized by tapering off of the medication, a
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consultation with a reproductive psychiatrist would help the woman and her partner to better
comprehend the literature regarding risks associated with specific medications and whether
there are relatively safer alternatives. Fortunately, most antidepressants that are most
frequently used to treat anxiety disorders are not considered teratogenic with first trimester
exposure (152). Hence, the patient and her health care provider do not need to panic should
the patient become pregnant unexpectedly.
Perimenopausal Anxiety – A Role for Hormones?

Among perimenopausal women, treatment options for anxiety may include
pharmacotherapy, hormone therapy (HT), or psychotherapy (153). In terms of
pharmacotherapy, most research has focused on depressive symptoms, not anxiety. In a chart
review of over 150,000 perimenopausal women, those with an anxiety diagnosis were
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significantly more likely to be prescribed HT than those without anxiety (154). However,
whether HT is effective in treating perimenopausal affective or anxiety symptoms is debated
(155). In the Kronos Early Estrogen Prevention Study (KEEPS), recently-postmenopausal
women randomized to 0.45 mg/d oral conjugated equine estrogens (o-CEE) showed
improvement of depressive and anxiety symptoms compared to placebo over a four year
treatment period (156). Women with past episodes of perimenopausal depression who were
treated with transdermal estradiol (100 μg/d) remained free of mood symptoms, while those
who were withdrawn from estradiol developed depressive symptoms in a randomized
placebo-controlled trial (157). Perimenopausal women with a diagnosed depressive disorder
who used transdermal 17beta-estradiol (100 μg) in a 12-week double-blind, placebo-
controlled study had significantly greater remission of depression than depressed women on
placebo (158). Again, these studies focused on depressive symptoms, not anxiety. Some
Author Manuscript
studies have shown an advantage for SSRIs or SNRIs over HT for perimenopausal mood or
vasomotor symptoms (159; 160). There is evidence for SSRIs reducing hot flashes (161–
163), and paroxetine has been approved by the Food and Drug Administration (FDA) to treat
moderate to severe menopausal vasomotor symptoms (164). Gabapentin also reduces both
anxiety and hot flashes, and thus may be a treatment option for women experiencing both
(165; 166).
CONCLUSIONS & FUTURE DIRECTIONS

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In sum, the female lifespan encompasses several distinct epochs, each with a characteristic
hormonal milieu and psychosocial features. Clinically, there is a need for better screening –
while prenatal depression screening is becoming more common, only 20% of Ob-Gyns
surveyed reported actively screening for anxiety during pregnancy (167). When making
assessments and treatment recommendations, the clinician should consider developmental
stage, reproductive events and hormonal status, as well as differences in presentation
between women and men. Important treatment considerations include assessing anxiety in
the context of the menstrual cycle, differentiating anxiety symptoms from normal changes
associated with pregnancy or postpartum, considering pregnancy and breastfeeding status
when prescribing pharmacotherapy, and attending to HT and vasomotor symptoms when
diagnosing and treating in the perimenopause. To note, while the DSM-5 no longer classifies
post-traumatic stress disorder (PTSD) or obsessive compulsive disorder (OCD) as anxiety
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disorders, there is a rich literature on these disorders in women. While beyond the scope of
this article, we encourage providers to explore this area of research. Finally, as the bulk of
the literature on psychiatric sex differences focuses on depression, future research should
address anxiety disorders specifically.
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Figure 1. Anxiety Disorders Across the Female Lifespan

The female lifespan includes distinct hormonal and psychosocial epochs, including puberty,
the premenstruum, pregnancy or postpartum, and the menopausal transition. These stages
give rise to important assessment and treatment considerations. The clinician should
consider reproductive events, hormonal status, and potential sex differences in anxiety
presentation.
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Anxiety Disorders Among Women: A Female Lifespan Approach

Dr. C. Neill Epperson, M.D.

Address correspondence to Dr. Hantsoo (LiisaHa2@mail.med.upenn.edu).

in women often precipitate or worsen at times of hormonal fluctuation, including puberty,

THE FEMALE LIFESPAN

The Menstrual Cycle

Pregnancy & Postpartum

EPIDEMIOLOGY OF ANXIETY DISORDERS ACROSS THE FEMALE

Generalized Anxiety Disorder (GAD)

Panic Disorder (PD)

ethnicity and previous pregnancy history, to name a few (57).

Social Anxiety Disorder (SAD)

Anxiety in the Context of Menstrual Cycle Disorders

Women with polycystic ovarian syndrome (PCOS), characterized by increased androgen

anxiety or affective symptoms may also occur.

Coping and Cognitive Styles

sensitivity than men, defined by catastrophic interpretations of bodily sensations such as

At puberty, ovarian hormone cycling initiates, with monthly fluctuations of neuroactive

Among the neuroactive steroid hormones, particularly relevant to anxiety disorders is

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

To identify a pattern of premenstrual worsening of anxiety, it is ideal to obtain prospective

TREATMENT AND OUTCOMES

Treating Anxiety in the Premenstruum

for premenstrual mood symptoms (133–135). Some women report worsening of

and side effects of hormonal contraceptives. Gonadotropin releasing hormone (GnRH)

Perinatal Anxiety – Balancing the Risks

of antidepressants for moderate to severe depression and psychotherapy as a first-line

Perimenopausal Anxiety – A Role for Hormones?

CONCLUSIONS & FUTURE DIRECTIONS

Endicott J, Epperson CN, Halbreich U, Reid R, Rubinow D, Schmidt P, Yonkers K, Consensus

American Psychiatric Publishing; Arlington VA: 2013.

review. J Clin Psychiatry. 2014; 75:e1153–1184. [PubMed: 25373126]

Nation (SWAN). Menopause N Y N. 2013; 20:488–495.

Psychiatry. 1989; 146:1299–1303. [PubMed: 2782474]

47:1937–1945. [PubMed: 22538387]

students. Riv Psichiatr. 2015; 50:295–301. [PubMed: 26780203]

Obstet Gynecol. 2008; 111:1175–1182. [PubMed: 18448752]

Randomized Clinical Trial. JAMA Psychiatry. 2015; 72:1037–1044. [PubMed: 26351969]

combined oral contraceptive. Psychoneuroendocrinology. 2013; 38:1133–1144. [PubMed:

Figure 1. Anxiety Disorders Across the Female Lifespan

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