Abstract
Posttraumatic stress disorder (PTSD) is a psychiatric illness whose prevalence in
women is more than twice the rate as men. Despite a burgeoning literature characterizing
sex differences in PTSD incidence and its disproportionate burden on society, there
is a dearth of literature describing biological mechanisms underlying these disparities.
However, the recent identification of biomarkers of PTSD by translational neuroscientists
offers a promising opportunity to explore sex interactions in PTSD phenotypes. A notable
observation is that individuals with PTSD show deficits in their ability to inhibit
conditioned fear responding after extinction training. Given that extinction procedures,
via exposure-based cognitive behavioral therapy, make up one of the predominant modes
of treatment in PTSD, there is a critical need for more research on sex interactions
in this form of fear regulation. An emerging hypothesis is that fluctuating gonadal
hormones, especially estrogen, in the menstrual cycle may play a critical role in
fear extinction and, hence, PTSD vulnerability and symptom severity in women. The
current review discusses how the study of putative activational effects of estrogen
on fear extinction may be harnessed to advance the search for better treatments for
PTSD in women. We conclude that estrogen treatment may be a putative pharmacologic
adjunct in extinction-based therapies and should be tracked in the menstrual cycle
during the course of PTSD treatment.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Gender differences in anxiety disorders: Prevalence, course of illness, comorbidity and burden of illness.J Psychiatr Res. 2011; 45: 1027-1035
- Sex differences in psychopathology: Of gonads, adrenals, and mental illness.Physiol Behav. 2009; 97: 250-258
- Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women.J Consult Clin Psychol. 1993; 61: 984-991
- Posttraumatic stress disorder in the National Comorbidity Survey.Arch Gen Psychiatry. 1995; 52: 1048-1060
- Trauma and posttraumatic stress disorder in the community: The 1996 Detroit Area Survey of Trauma.Arch Gen Psychiatry. 1998; 55: 626-632
- National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria.J Trauma Stress. 2013; 26: 537-547
- Posttraumatic stress disorder in an urban population of young adults: Risk factors for chronicity.Am J Psychiatry. 1992; 149: 671-675
- Rapid effects of estrogens on behavior: Environmental modulation and molecular mechanisms.Front Neuroendocrinol. 2014; 35: 447-458
- Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder.Biol Psychiatry. 2012; 72: 19-24
- Inhibition of fear is differentially associated with cycling estrogen levels in women.J Psychiatry Neurosci. 2013; 38: 120-129
- Sex differences in extinction recall in posttraumatic stress disorder: A pilot fMRI study.Neurobiol Learn Mem. 2014; 113: 101-108
- Sex differences in psychiatric disorders: Origins and developmental influences.Psychiatr Dev. 1987; 5: 1-23
- Why do many psychiatric disorders emerge during adolescence?.Nat Rev Neurosci. 2008; 9: 947-957
- Estradiol modulation of monoamine metabolism: One possible mechanism underlying sex differences in risk for depression and dementia.JAMA Psychiatry. 2014; 71: 869-870
- Women and anxiety disorders: Implications for diagnosis and treatment.CNS Spectr. 2004; 9: 1-16
- The symptomatology of puerperal illnesses.Br J Psychiatry. 1981; 139: 128-133
- Estrogen-related mood disorders: Reproductive life cycle factors.ANS Adv Nurs Sci. 2005; 28: 364-375
- Anxiety disorders in women.Psychiatr Clin N Am. 2003; 26: 621-672
- The clinical nature and formal diagnosis of premenstrual, postpartum, and perimenopausal affective disorders.Curr Psychiatry Rep. 2002; 4: 419-428
- Anxiety symptoms and anxiety disorders: How are they related to premenstrual disorders?.J Clin Psychiatry. 1997; 58: 62-67
- Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging.J Neurosci. 2005; 25: 9309-9316
- Sex differences in stress response circuitry activation dependent on female hormonal cycle.J Neurosci. 2010; 30: 431-438
- Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP.Pharmacol Biochem Behav. 2000; 67: 587-596
- Chronic estradiol replacement to aged female rats reduces anxiety-like and depression-like behavior and enhances cognitive performance.Psychoneuroendocrinology. 2009; 34: 909-916
- Estrous cycle influences the response of female rats in the elevated plus-maze test.Physiol Behav. 2001; 74: 435-440
- Effects of the estrous cycle and ovarian hormones on behavioral indices of anxiety in female rats.Psychoneuroendocrinology. 1996; 21: 609-620
- Memory mechanisms in posttraumatic stress disorder.J Neuropsychiatry Clin Neurosci. 2002; 14: 254-261
- Animal models of anxiety based on classical conditioning: The conditioned emotional response (CER) and fear-potentiated startle effect.Pharmacol Ther. 1990; 47: 147-165
- Animal models of relevance to PTSD.Ann N Y Acad Sci. 1997; 821: 332-351
- A theory of Pavlovian conditioning: Variations in the effectiveness of reinforcement and nonreinforcement.in: Black A.H. Prokasy W.F. Classical Conditioning II: Current Theory and Research. Appleton-Century-Crofts, New York1972: 64-99
- Posttraumatic stress disorder may be associated with impaired fear inhibition: Relation to symptom severity.Psychiatry Res. 2009; 167: 151-160
- How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD.Am J Psychiatry. 2010; 167: 648-662
- Fear extinction in traumatized civilians with posttraumatic stress disorder: Relation to symptom severity.Biol Psychiatry. 2011; 69: 556-563
- Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors.Front Psychiatry. 2014; 5: 88
- Sex differences in hippocampal long-term potentiation (LTP) and Pavolvian fear conditioning in rats: Positive correlation between LTP and contextual learning.Brain Res. 1994; 661: 25-34
- Effect of sex on fear conditioning is similar for context and discrete CS in Wistar, Lewis and Fischer rat strains.Pharmacol Biochem Behav. 1999; 64: 753-759
- Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant-path long-term potentiation in adult male rats.Behav Brain Res. 1998; 92: 1-9
- Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats(1).Brain Res. 2001; 888: 356-365
- Prefrontal cortex lesions and sex differences in fear extinction and perseveration.Learn Mem. 2010; 17: 267-278
- Estrogen facilitates fear conditioning and increases corticotropin-releasing hormone mRNA expression in the central amygdala in female mice.Horm Behav. 2006; 49: 197-205
- Sex differences and estrous cycle changes in hippocampus-dependent fear conditioning.Psychobiology. 1997; 25: 246-252
- Behavioral and neural analysis of extinction.Neuron. 2002; 36: 567-584
- Hormonal modulation of extinction responses induced by sexual steroid hormones in rats.Life Sci. 1994; 54: PL363-PL367
- Chronic stress and sex differences on the recall of fear conditioning and extinction.Neurobiol Learn Mem. 2009; 91: 323-332
- Estrogen modulates sexually dimorphic contextual fear extinction in rats through estrogen receptor beta.Hippocampus. 2009; 19: 1142-1150
- Sex differences, gonadal hormones and the fear extinction network: Implications for anxiety disorders.Biol Mood Anxiety Disord. 2012; 2: 3
- Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans.Behav Neurosci. 2006; 120: 1196-1203
- Estrous cycle phase and gonadal hormones influence conditioned fear extinction.Neuroscience. 2009; 164: 887-895
- The influence of gonadal hormones on conditioned fear extinction in healthy humans.Neuroscience. 2010; 168: 652-658
- Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats.Biol Psychiatry. 2011; 70: 920-927
- Low levels of estradiol are associated with elevated conditioned responding during fear extinction and with intrusive memories in daily life.Neurobiol Learn Mem. 2014; 116: 145-154
- Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: A functional MRI study.Biol Psychiatry. 2000; 47: 769-776
- A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder.Arch Gen Psychiatry. 2005; 62: 273-281
- Neurons in medial prefrontal cortex signal memory for fear extinction.Nature. 2002; 420: 70-74
- Extinction learning in humans: Role of the amygdala and vmPFC.Neuron. 2004; 43: 897-905
- Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation.J Comp Neurol. 2005; 491: 81-95
- Estrogen receptor gene expression in relation to neuropsychiatric disorders.Ann N Y Acad Sci. 2003; 1007: 54-63
- Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders.Prog Neurobiol. 2001; 64: 251-267
- Estrogen receptor beta in the brain: From form to function.Brain Res Rev. 2008; 57: 309-320
- Estrogen actions in the brain and the basis for differential action in men and women: A case for sex-specific medicines.Pharmacol Rev. 2010; 62: 155-198
- Estrogen receptor-alpha distribution in the human hypothalamus in relation to sex and endocrine status.J Comp Neurol. 2002; 454: 115-139
- Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas.Horm Behav. 2010; 58: 415-426
- Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density.Front Neuroendocrinol. 2012; 33: 388-402
- Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton.Neuroscience. 2013; 239: 3-16
- Mechanisms underlying the interactions between rapid estrogenic and BDNF control of synaptic connectivity.Neuroscience. 2013; 239: 17-33
- Sex differences in hippocampal estradiol-induced N-methyl-D-aspartic acid binding and ultrastructural localization of estrogen receptor-alpha.Neuroendocrinology. 2005; 81: 391-399
- Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory.Nat Neurosci. 2008; 11: 334-343
- Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein.J Neurosci. 2005; 25: 5066-5078
- Membrane-localised oestrogen receptor alpha and beta influence neuronal activity through activation of metabotropic glutamate receptors.J Neuroendocrinol. 2009; 21: 257-262
- Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS.Front Neuroendocrinol. 2006; 27: 415-435
- A genetic variant BDNF polymorphism alters extinction learning in both mouse and human.Science. 2010; 327: 863-866
- The association between menstural cycle and traumatic memories.J Affect Disord. 2011; 131: 398-401
- Sex-related influences on the neurobiology of emotionally influenced memory.Ann N Y Acad Sci. 2003; 985: 163-173
- Neural responses to masked fear faces: Sex differences and trauma exposure in posttraumatic stress disorder.J Abnorm Psychol. 2010; 119: 241-247
- Fear-related activity in subgenual anterior cingulate differs between men and women.Neuroreport. 2005; 16: 1233-1236
- Menstrual cycle phase effects on prepulse inhibition of acoustic startle.Psychophysiology. 2004; 41: 401-406
- Luteal-phase accentuation of acoustic startle response in women with premenstrual dysphoric disorder.Neuropsychopharmacology. 2007; 32: 2190-2198
- Tools for translational neuroscience: PTSD is associated with heightened fear responses using acoustic startle but not skin conductance measures.Depress Anxiety. 2011; 28: 1058-1066
- Impaired fear inhibition is a biomarker of PTSD but not depression.Depress Anxiety. 2010; 27: 244-251
- Sex differences in fear conditioning in posttraumatic stress disorder.J Psychiatr Res. 2013; 47: 64-71
- Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.Nature. 2011; 470: 492-497
- PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus.Proc Natl Acad Sci U S A. 2014; 111: 3158-3163
- ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females.Am J Med Genet B Neuropsychiatr Genet. 2013; 162B: 262-272
- PAC1 receptor (ADCYAP1R1) genotype is associated with dark-enhanced startle in children.Mol Psychiatry. 2012; 18: 742-743
- Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment.Depress Anxiety. 2013; 30: 251-258
- No association between ADCYAP1R1 and post-traumatic stress disorder in two independent samples.Mol Psychiatry. 2012; 17: 239-241
- Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women.Biol Psychiatry. 2013; 73: 371-378
- A randomized, double-blind evaluation of d-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan war veterans.Am J Psychiatry. 2014; 171: 640-648
- Estrogen replacement in perimenopause-related depression: A preliminary report.Am J Obstet Gynecol. 2000; 183: 414-420
- Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: A double-blind, randomized, placebo-controlled trial.Arch Gen Psychiatry. 2001; 58: 529-534
- The influence of emergency contraception on post traumatic stress symptoms following sexual assault.J Forensic Nurs. 2012; 8: 122-130
- Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear.Arch Gen Psychiatry. 2004; 61: 1136-1144
- Extinction-reconsolidation boundaries: Key to persistent attenuation of fear memories.Science. 2009; 324: 951-955
- Preventing the return of fear in humans using reconsolidation update mechanisms.Nature. 2009; 463: 49-53
- Human fear extinction and return of fear using reconsolidation update mechanisms: The contribution of on-line expectancy ratings.Neurobiol Learn Mem. 2014; 113: 165-173
- Hormone replacement therapy: Risks and benefits.Nurse Prescribing. 2008; 6: 433-439
- Hormones, heart disease, and health: Individualized medicine versus throwing the baby out with the bathwater.Depress Anxiety. 2011; 28: E1-E15
Article info
Publication history
Published online: February 16, 2015
Accepted:
February 4,
2015
Received in revised form:
January 6,
2015
Received:
September 5,
2014
Identification
Copyright
Published by Elsevier Inc.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Sex, Steroids, and FearBiological PsychiatryVol. 78Issue 3
- PreviewPsychiatric illness is not an “equal opportunity” disease. For example, the lifetime prevalence of posttraumatic stress disorder (PTSD) is twice as high in women than in men. In recent years, gonadal steroids have moved into the spotlight as a potential key to understanding this sex difference in vulnerability to trauma-related and stress-related disorders (1,2). Many preclinical and clinical studies have implicated ovarian hormones, including estrogen and progesterone, in the modulation of fear and anxiety in women (2).
- Full-Text
- Preview
