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Sex Differences in Vulnerability and Resilience to Stress Across the Life Span

  • Georgia E. Hodes
    Correspondence
    Address correspondence to Georgia E. Hodes, Ph.D., Virginia Polytechnic Institute and State University, School of Neuroscience, 1981 Kraft Drive, Blacksburg, VA 24060.
    Affiliations
    School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
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  • C. Neill Epperson
    Affiliations
    Department of Psychiatry, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
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      Abstract

      Susceptibility and resilience to stress depend on 1) the timing of the exposure with respect to development, 2) the time across the life span at which effects are measured, and 3) the behavioral or biological phenotype under consideration. This translational review examines preclinical stress models that provide clues to causal mechanisms and their relationship to the more complex phenomenon of stress-related psychiatric and cognitive disorders in humans. We examine how genetic sex and epigenetic regulation of hormones contribute to the proximal and distal effects of stress at different epochs of life. Stress during the prenatal period and early postnatal life puts male offspring at risk of developing diseases involving socialization, such as autism spectrum disorder, and attention and cognition, such as attention-deficit/hyperactivity disorder. While female offspring show resilience to some of the proximal effects of prenatal and early postnatal stress, there is evidence that risk associated with developmental insults is unmasked in female offspring following periods of hormonal activation and flux, including puberty, pregnancy, and perimenopause. Likewise, stress exposures during puberty have stronger proximal effects on girls, including an increased risk of developing mood-related and stress-related illnesses, such as depression, anxiety, and posttraumatic stress disorder. Hormonal changes during menopause and andropause impact the processes of memory and emotion in women and men, though women are preferentially at risk for dementia, and childhood adversity further impacts estradiol effects on neural function. We propose that studies to determine mechanisms for stress risk and resilience across the life span must consider the nature and timing of stress exposures as well as the sex of the organism under investigation.

      Keywords

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      References

        • Menard C.
        • Pfau M.L.
        • Hodes G.E.
        • Russo S.J.
        Immune and neuroendocrine mechanisms of stress vulnerability and resilience.
        Neuropsychopharmacology. 2017; 42: 62-80
        • McEwen B.S.
        Sex, stress and the hippocampus: Allostasis, allostatic load and the aging process.
        Neurobiol Aging. 2002; 23: 921-939
        • Russo S.J.
        • Murrough J.W.
        • Han M.H.
        • Charney D.S.
        • Nestler E.J.
        Neurobiology of resilience.
        Nat Neurosci. 2012; 15: 1475-1484
        • Brockhurst J.
        • Cheleuitte-Nieves C.
        • Buckmaster C.L.
        • Schatzberg A.F.
        • Lyons D.M.
        Stress inoculation modeled in mice.
        Transl Psychiatry. 2015; 5: e537
        • Hourani L.
        • Tueller S.
        • Kizakevich P.
        • Lewis G.
        • Strange L.
        • Weimer B.
        • et al.
        Toward preventing post-traumatic stress disorder: Development and testing of a pilot predeployment stress inoculation training program.
        Mil Med. 2016; 181: 1151-1160
        • Morrison K.E.
        • Narasimhan S.
        • Fein E.
        • Bale T.L.
        Peripubertal stress with social support promotes resilience in the face of aging.
        Endocrinology. 2016; 157: 2002-2014
        • Gillman L.
        • Adams J.
        • Kovac R.
        • Kilcullen A.
        • House A.
        • Doyle C.
        Strategies to promote coping and resilience in oncology and palliative care nurses caring for adult patients with malignancy: A comprehensive systematic review.
        JBI Database System Rev Implement Rep. 2015; 13: 131-204
        • Domhardt M.
        • Munzer A.
        • Fegert J.M.
        • Goldbeck L.
        Resilience in survivors of child sexual abuse: A systematic review of the literature.
        Trauma Violence Abuse. 2015; 16: 476-493
        • Jackson A.
        • Cavanagh J.
        • Scott J.
        A systematic review of manic and depressive prodromes.
        J Affect Disord. 2003; 74: 209-217
        • Savill M.
        • D’Ambrosio J.
        • Cannon T.D.
        • Loewy R.L.
        Psychosis risk screening in different populations using the Prodromal Questionnaire: A systematic review.
        Early Interv Psychiatry. 2018; 12: 3-14
        • Secinti E.
        • Thompson E.J.
        • Richards M.
        • Gaysina D.
        Research review: Childhood chronic physical illness and adult emotional health—a systematic review and meta-analysis.
        J Child Psychol Psychiatry. 2017; 58: 753-769
        • Zucker I.
        • Beery A.K.
        Males still dominate animal studies.
        Nature. 2010; 465: 690
        • Kessler R.C.
        • McGonagle K.A.
        • Swartz M.
        • Blazer D.G.
        • Nelson C.B.
        Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence.
        J Affect Disord. 1993; 29: 8-96
        • Kessler R.C.
        Epidemiology of women and depression.
        J Affect Disord. 2003; 74: 5-13
        • Brown A.S.
        • Susser E.S.
        • Lin S.P.
        • Neugebauer R.
        • Gorman J.M.
        Increased risk of affective disorders in males after second trimester prenatal exposure to the Dutch hunger winter of 1944-45.
        Br J Psychiatry. 1995; 166: 601-606
        • Franzek E.J.
        • Sprangers N.
        • Janssens A.C.
        • Van Duijn C.M.
        • Van De Wetering B.J.
        Prenatal exposure to the 1944-45 Dutch ‘hunger winter’ and addiction later in life.
        Addiction. 2008; 103: 433-438
        • Hoek H.W.
        • Brown A.S.
        • Susser E.
        The Dutch famine and schizophrenia spectrum disorders.
        Soc Psychiatry Psychiatr Epidemiol. 1998; 33: 373-379
        • St Clair D.
        • Xu M.
        • Wang P.
        • Yu Y.
        • Fang Y.
        • Zhang F.
        • et al.
        Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961.
        JAMA. 2005; 294: 557-562
        • Dantzer R.
        Cytokine-induced sickness behaviour: A neuroimmune response to activation of innate immunity.
        Eur J Pharmacol. 2004; 500: 399-411
        • Hart B.L.
        Biological basis of the behavior of sick animals.
        Neurosci Biobehav Rev. 1988; 12: 123-137
        • Clifton V.L.
        • Murphy V.E.
        Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth.
        Placenta. 2004; 25: S45-S52
        • Clifton V.L.
        Review: Sex and the human placenta: Mediating differential strategies of fetal growth and survival.
        Placenta. 2010; 31: S33-S39
        • Murphy V.E.
        • Gibson P.G.
        • Giles W.B.
        • Zakar T.
        • Smith R.
        • Bisits A.M.
        • et al.
        Maternal asthma is associated with reduced female fetal growth.
        Am J Respir Crit Care Med. 2003; 168: 1317-1323
        • Murphy V.E.
        • Smith R.
        • Giles W.B.
        • Clifton V.L.
        Endocrine regulation of human fetal growth: The role of the mother, placenta, and fetus.
        Endocr Rev. 2006; 27: 141-169
        • Torche F.
        • Kleinhaus K.
        Prenatal stress, gestational age and secondary sex ratio: The sex-specific effects of exposure to a natural disaster in early pregnancy.
        Hum Reprod. 2012; 27: 558-567
        • Brown A.S.
        Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.
        Dev Neurobiol. 2012; 72: 1272-1276
        • Khashan A.S.
        • Abel K.M.
        • McNamee R.
        • Pedersen M.G.
        • Webb R.T.
        • Baker P.N.
        • et al.
        Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events.
        Arch Gen Psychiatry. 2008; 65: 146-152
        • Kinney D.K.
        • Miller A.M.
        • Crowley D.J.
        • Huang E.
        • Gerber E.
        Autism prevalence following prenatal exposure to hurricanes and tropical storms in Louisiana.
        J Autism Dev Disord. 2008; 38: 481-488
        • Ronald A.
        • Pennell C.E.
        • Whitehouse A.J.
        Prenatal maternal stress associated with ADHD and autistic traits in early childhood.
        Front Psychol. 2010; 1: 223
        • Jouda J.
        • Wohr M.
        • Del Rey A.
        Immunity and ultrasonic vocalization in rodents.
        Ann N Y Acad Sci. 2019; 1437: 68-82
        • Malkova N.V.
        • Yu C.Z.
        • Hsiao E.Y.
        • Moore M.J.
        • Patterson P.H.
        Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism.
        Brain Behav Immun. 2012; 26: 607-616
        • Shi L.
        • Fatemi S.H.
        • Sidwell R.W.
        • Patterson P.H.
        Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring.
        J Neurosci. 2003; 23: 297-302
        • Holloway T.
        • Moreno J.L.
        • Umali A.
        • Rayannavar V.
        • Hodes G.E.
        • Russo S.J.
        • et al.
        Prenatal stress induces schizophrenia-like alterations of serotonin 2A and metabotropic glutamate 2 receptors in the adult offspring: Role of maternal immune system.
        J Neurosci. 2013; 33: 1088-1098
        • Goel N.
        • Bale T.L.
        Examining the intersection of sex and stress in modelling neuropsychiatric disorders.
        J Neuroendocrinol. 2009; 21: 415-420
        • Mueller B.R.
        • Bale T.L.
        Sex-specific programming of offspring emotionality after stress early in pregnancy.
        J Neurosci. 2008; 28: 9055-9065
        • Mueller B.R.
        • Bale T.L.
        Early prenatal stress impact on coping strategies and learning performance is sex dependent.
        Physiol Behav. 2007; 91: 55-65
        • Weinstock M.
        The long-term behavioural consequences of prenatal stress.
        Neurosci Biobehav Rev. 2008; 32: 1073-1086
        • McCormick C.M.
        • Smythe J.W.
        • Sharma S.
        • Meaney M.J.
        Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats.
        Brain Res Dev Brain Res. 1995; 84: 55-61
        • Alonso S.J.
        • Arevalo R.
        • Afonso D.
        • Rodriguez M.
        Effects of maternal stress during pregnancy on forced swimming test behavior of the offspring.
        Physiol Behav. 1991; 50: 511-517
        • Reynaert M.L.
        • Marrocco J.
        • Mairesse J.
        • Lionetto L.
        • Simmaco M.
        • Deruyter L.
        • et al.
        Hedonic sensitivity to natural rewards is affected by prenatal stress in a sex-dependent manner.
        Addict Biol. 2016; 21: 1072-1085
        • Samuelsson A.M.
        • Jennische E.
        • Hansson H.A.
        • Holmang A.
        Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning.
        Am J Physiol Regul Integr Comp Physiol. 2006; 290: R1345-R1356
        • Semple B.D.
        • Blomgren K.
        • Gimlin K.
        • Ferriero D.M.
        • Noble-Haeusslein L.J.
        Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species.
        Prog Neurobiol. 2013; 106–107: 1-16
        • Nugent B.M.
        • Wright C.L.
        • Shetty A.C.
        • Hodes G.E.
        • Lenz K.M.
        • Mahurkar A.
        • et al.
        Brain feminization requires active repression of masculinization via DNA methylation.
        Nat Neurosci. 2015; 18: 690-697
        • Bogdanovic O.
        • Veenstra G.J.
        DNA methylation and methyl-CpG binding proteins: Developmental requirements and function.
        Chromosoma. 2009; 118: 549-565
        • Chan J.C.
        • Nugent B.M.
        • Bale T.L.
        Parental advisory: Maternal and paternal stress can impact offspring neurodevelopment.
        Biol Psychiatry. 2018; 83: 886-894
        • Rodgers A.B.
        • Morgan C.P.
        • Leu N.A.
        • Bale T.L.
        Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.
        Proc Natl Acad Sci U S A. 2015; 112: 13699-13704
        • Vassoler F.M.
        • White S.L.
        • Schmidt H.D.
        • Sadri-Vakili G.
        • Pierce R.C.
        Epigenetic inheritance of a cocaine-resistance phenotype.
        Nat Neurosci. 2013; 16: 42-47
        • White S.L.
        • Vassoler F.M.
        • Schmidt H.D.
        • Pierce R.C.
        • Wimmer M.E.
        Enhanced anxiety in the male offspring of sires that self-administered cocaine.
        Addict Biol. 2016; 21: 802-810
        • Dietz D.M.
        • Laplant Q.
        • Watts E.L.
        • Hodes G.E.
        • Russo S.J.
        • Feng J.
        • et al.
        Paternal transmission of stress-induced pathologies.
        Biol Psychiatry. 2011; 70: 408-414
        • Stein A.D.
        • Pierik F.H.
        • Verrips G.H.
        • Susser E.S.
        • Lumey L.H.
        Maternal exposure to the Dutch famine before conception and during pregnancy: Quality of life and depressive symptoms in adult offspring.
        Epidemiology. 2009; 20: 909-915
        • Sagi-Schwartz A.
        • van I.M.H.
        • Bakermans-Kranenburg M.J.
        Does intergenerational transmission of trauma skip a generation? No meta-analytic evidence for tertiary traumatization with third generation of Holocaust survivors.
        Attach Hum Dev. 2008; 10: 105-121
        • Kassai S.C.
        • Motta R.W.
        An investigation of potential Holocaust-related secondary traumatization in the third generation.
        Int J Emerg Ment Health. 2006; 8: 35-47
        • Zerach G.
        • Solomon Z.
        Low levels of posttraumatic stress symptoms and psychiatric symptomatology among third-generation Holocaust survivors whose fathers were war veterans.
        J Psychiatr Res. 2016; 73: 25-33
        • Yehuda R.
        • Daskalakis N.P.
        • Bierer L.M.
        • Bader H.N.
        • Klengel T.
        • Holsboer F.
        • et al.
        Holocaust exposure induced intergenerational effects on FKBP5 methylation.
        Biol Psychiatry. 2016; 80: 372-380
        • Bierer L.M.
        • Bader H.N.
        • Daskalakis N.P.
        • Lehrner A.L.
        • Makotkine I.
        • Seckl J.R.
        • et al.
        Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure.
        Psychoneuroendocrinology. 2014; 48: 1-10
        • Ellis B.H.
        • Fisher P.A.
        • Zaharie S.
        Predictors of disruptive behavior, developmental delays, anxiety, and affective symptomatology among institutionally reared romanian children.
        J Am Acad Child Adolesc Psychiatry. 2004; 43: 1283-1292
        • Zeanah C.H.
        • Egger H.L.
        • Smyke A.T.
        • Nelson C.A.
        • Fox N.A.
        • Marshall P.J.
        • et al.
        Institutional rearing and psychiatric disorders in Romanian preschool children.
        Am J Psychiatry. 2009; 166: 777-785
        • Fareri D.S.
        • Tottenham N.
        Effects of early life stress on amygdala and striatal development.
        Dev Cogn Neurosci. 2016; 19: 233-247
        • Palmer F.B.
        • Anand K.J.
        • Graff J.C.
        • Murphy L.E.
        • Qu Y.
        • Volgyi E.
        • et al.
        Early adversity, socioemotional development, and stress in urban 1-year-old children.
        J Pediatr. 2013; 163: 1733-1739.e1731
        • Van Niel C.
        • Pachter L.M.
        • Wade Jr., R.
        • Felitti V.J.
        • Stein M.T.
        Adverse events in children: predictors of adult physical and mental conditions.
        J Dev Behav Pediatr. 2014; 35: 549-551
        • Felitti V.J.
        • Anda R.F.
        • Nordenberg D.
        • Williamson D.F.
        • Spitz A.M.
        • Edwards V.
        • et al.
        Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study.
        Am J Prev Med. 1998; 14: 245-258
        • Nephew B.C.
        • Bridges R.S.
        Effects of chronic social stress during lactation on maternal behavior and growth in rats.
        Stress. 2011; 14: 677-684
        • Rice C.J.
        • Sandman C.A.
        • Lenjavi M.R.
        • Baram T.Z.
        A novel mouse model for acute and long-lasting consequences of early life stress.
        Endocrinology. 2008; 149: 4892-4900
        • Bolton J.L.
        • Molet J.
        • Ivy A.
        • Baram T.Z.
        New insights into early-life stress and behavioral outcomes.
        Curr Opin Behav Sci. 2017; 14: 133-139
        • Lotan A.
        • Lifschytz T.
        • Wolf G.
        • Keller S.
        • Ben-Ari H.
        • Tatarsky P.
        • et al.
        Differential effects of chronic stress in young-adult and old female mice: Cognitive-behavioral manifestations and neurobiological correlates.
        Mol Psychiatry. 2018; 23: 1432-1445
        • Bolton J.L.
        • Molet J.
        • Regev L.
        • Chen Y.
        • Rismanchi N.
        • Haddad E.
        • et al.
        Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene.
        Biol Psychiatry. 2018; 83: 137-147
        • Molet J.
        • Heins K.
        • Zhuo X.
        • Mei Y.T.
        • Regev L.
        • Baram T.Z.
        • et al.
        Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome.
        Transl Psychiatry. 2016; 6: e702
        • Bolton J.L.
        • Ruiz C.M.
        • Rismanchi N.
        • Sanchez G.A.
        • Castillo E.
        • Huang J.
        • et al.
        Early-life adversity facilitates acquisition of cocaine self-administration and induces persistent anhedonia.
        Neurobiol Stress. 2018; 8: 57-67
        • Kanatsou S.
        • Karst H.
        • Kortesidou D.
        • van den Akker R.A.
        • den Blaauwen J.
        • Harris A.P.
        • et al.
        Overexpression of mineralocorticoid receptors in the mouse forebrain partly alleviates the effects of chronic early life stress on spatial memory, neurogenesis and synaptic function in the dentate gyrus.
        Front Cell Neurosci. 2017; 11: 132
        • Brunson K.L.
        • Kramar E.
        • Lin B.
        • Chen Y.
        • Colgin L.L.
        • Yanagihara T.K.
        • et al.
        Mechanisms of late-onset cognitive decline after early-life stress.
        J Neurosci. 2005; 25: 9328-9338
        • Ivy A.S.
        • Rex C.S.
        • Chen Y.
        • Dube C.
        • Maras P.M.
        • Grigoriadis D.E.
        • et al.
        Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors.
        J Neurosci. 2010; 30: 13005-13015
        • Korten N.C.
        • Penninx B.W.
        • Pot A.M.
        • Deeg D.J.
        • Comijs H.C.
        Adverse childhood and recent negative life events: Contrasting associations with cognitive decline in older persons.
        J Geriatr Psychiatry Neurol. 2014; 27: 128-138
        • Kiecolt-Glaser J.K.
        • Gouin J.P.
        • Weng N.P.
        • Malarkey W.B.
        • Beversdorf D.Q.
        • Glaser R.
        Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation.
        Psychosom Med. 2011; 73: 16-22
        • Podcasy J.L.
        • Epperson C.N.
        Considering sex and gender in Alzheimer disease and other dementias.
        Dialogues Clin Neurosci. 2016; 18: 437-446
        • Radford K.
        • Delbaere K.
        • Draper B.
        • Mack H.A.
        • Daylight G.
        • Cumming R.
        • et al.
        Childhood stress and adversity is associated with late-life dementia in Aboriginal Australians.
        Am J Geriatr Psychiatry. 2017; 25: 1097-1106
        • Pena C.J.
        • Kronman H.G.
        • Walker D.M.
        • Cates H.M.
        • Bagot R.C.
        • Purushothaman I.
        • et al.
        Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.
        Science. 2017; 356: 1185-1188
        • Kaufman J.
        • Wymbs N.F.
        • Montalvo-Ortiz J.L.
        • Orr C.
        • Albaugh M.D.
        • Althoff R.
        • et al.
        Methylation in OTX2 and related genes, maltreatment, and depression in children.
        Neuropsychopharmacology. 2018; 43: 2204-2211
        • Morrison K.E.
        • Epperson C.N.
        • Sammel M.D.
        • Ewing G.
        • Podcasy J.S.
        • Hantsoo L.
        • et al.
        Preadolescent adversity programs a disrupted maternal stress reactivity in humans and mice.
        Biol Psychiatry. 2017; 81: 693-701
        • Shors T.J.
        • Tobomicronn K.
        • DiFeo G.
        • Durham D.M.
        • Chang H.Y.
        Sexual Conspecific Aggressive Response (SCAR): A model of sexual trauma that disrupts maternal learning and plasticity in the female brain.
        Sci Rep. 2016; 6: 18960
        • Manyema M.
        • Norris S.A.
        • Richter L.M.
        Stress begets stress: The association of adverse childhood experiences with psychological distress in the presence of adult life stress.
        BMC Public Health. 2018; 18: 835
        • Epperson C.N.
        • Sammel M.D.
        • Bale T.L.
        • Kim D.R.
        • Conlin S.
        • Scalice S.
        • et al.
        Adverse childhood experiences and risk for first-episode major depression during the menopause transition.
        J Clin Psychiatry. 2017; 78: e298-e307
        • Kaplan J.R.
        • Adams M.R.
        • Clarkson T.B.
        • Manuck S.B.
        • Shively C.A.
        Social behavior and gender in biomedical investigations using monkeys: studies in atherogenesis.
        Lab Anim Sci. 1991; 41: 334-343
        • Shanmugan S.
        • Loughead J.
        • Cao W.
        • Sammel M.D.
        • Satterthwaite T.D.
        • Ruparel K.
        • et al.
        Impact of tryptophan depletion on executive system function during menopause is moderated by childhood adversity.
        Neuropsychopharmacology. 2017; 42: 2398-2406
        • Shanmugan S.
        • Epperson C.N.
        Estrogen and the prefrontal cortex: Towards a new understanding of estrogen’s effects on executive functions in the menopause transition.
        Hum Brain Mapp. 2014; 35: 847-865
        • Khosravi S.
        • Ardebili H.E.
        • Larijani B.
        • Nedjat S.
        • Nikbakht Nasrabadi A.
        • Ardebili M.E.
        • et al.
        Are andropause symptoms related to depression?.
        Aging Clin Exp Res. 2015; 27: 813-820
        • Sato Y.
        • Tanda H.
        • Kato S.
        • Onishi S.
        • Nakajima H.
        • Nanbu A.
        • et al.
        Prevalence of major depressive disorder in self-referred patients in a late onset hypogonadism clinic.
        Int J Impot Res. 2007; 19: 407-410
        • Breslau J.
        • Gilman S.E.
        • Stein B.D.
        • Ruder T.
        • Gmelin T.
        • Miller E.
        Sex differences in recent first-onset depression in an epidemiological sample of adolescents.
        Transl Psychiatry. 2017; 7: e1139
        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Joinson C.
        • Heron J.
        • Lewis G.
        • Croudace T.
        • Araya R.
        Timing of menarche and depressive symptoms in adolescent girls from a UK cohort.
        Br J Psychiatry. 2011; 198: 17-23
        • Seney M.L.
        • Ekong K.I.
        • Ding Y.
        • Tseng G.C.
        • Sibille E.
        Sex chromosome complement regulates expression of mood-related genes.
        Biol Sex Differ. 2013; 4: 20
        • Puralewski R.
        • Vasilakis G.
        • Seney M.L.
        Sex-related factors influence expression of mood-related genes in the basolateral amygdala differentially depending on age and stress exposure.
        Biol Sex Differ. 2016; 7: 50
        • Schulz K.M.
        • Sisk C.L.
        The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development.
        Neurosci Biobehav Rev. 2016; 70: 148-158
        • De Lorme K.C.
        • Sisk C.L.
        The organizational effects of pubertal testosterone on sexual proficiency in adult male Syrian hamsters.
        Physiol Behav. 2016; 165: 273-277
        • Schulz K.M.
        • Richardson H.N.
        • Zehr J.L.
        • Osetek A.J.
        • Menard T.A.
        • Sisk C.L.
        Gonadal hormones masculinize and defeminize reproductive behaviors during puberty in the male Syrian hamster.
        Horm Behav. 2004; 45: 242-249
        • Bessa D.S.
        • Maschietto M.
        • Aylwin C.F.
        • Canton A.P.M.
        • Brito V.N.
        • Macedo D.B.
        • et al.
        Methylome profiling of healthy and central precocious puberty girls.
        Clin Epigenetics. 2018; 10: 146
        • Lomniczi A.
        • Wright H.
        • Castellano J.M.
        • Matagne V.
        • Toro C.A.
        • Ramaswamy S.
        • et al.
        Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression.
        Nat Commun. 2015; 6: 10195
        • Lomniczi A.
        • Loche A.
        • Castellano J.M.
        • Ronnekleiv O.K.
        • Bosch M.
        • Kaidar G.
        • et al.
        Epigenetic control of female puberty.
        Nat Neurosci. 2013; 16: 281-289
        • Foilb A.R.
        • Lui P.
        • Romeo R.D.
        The transformation of hormonal stress responses throughout puberty and adolescence.
        J Endocrinol. 2011; 210: 391-398
        • Romeo R.D.
        • Karatsoreos I.N.
        • McEwen B.S.
        Pubertal maturation and time of day differentially affect behavioral and neuroendocrine responses following an acute stressor.
        Horm Behav. 2006; 50: 463-468
        • Romeo R.D.
        • Lee S.J.
        • McEwen B.S.
        Differential stress reactivity in intact and ovariectomized prepubertal and adult female rats.
        Neuroendocrinology. 2004; 80: 387-393
        • Bourke C.H.
        • Neigh G.N.
        Behavioral effects of chronic adolescent stress are sustained and sexually dimorphic.
        Horm Behav. 2011; 60: 112-120
        • Kaplowitz E.T.
        • Savenkova M.
        • Karatsoreos I.N.
        • Romeo R.D.
        Somatic and neuroendocrine changes in response to chronic corticosterone exposure during adolescence in male and female rats.
        J Neuroendocrinol. 2016; 28: 12336
        • Weintraub A.
        • Singaravelu J.
        • Bhatnagar S.
        Enduring and sex-specific effects of adolescent social isolation in rats on adult stress reactivity.
        Brain Res. 2010; 1343: 83-92
        • Westfall N.C.
        • Nemeroff C.B.
        The preeminence of early life trauma as a risk factor for worsened long-term health outcomes in women.
        Curr Psychiatry Rep. 2015; 17: 90
        • McLaughlin K.A.
        • Koenen K.C.
        • Hill E.D.
        • Petukhova M.
        • Sampson N.A.
        • Zaslavsky A.M.
        • et al.
        Trauma exposure and posttraumatic stress disorder in a national sample of adolescents.
        J Am Acad Child Adolesc Psychiatry. 2013; 52: 815-830.e814
        • Herringa R.J.
        • Birn R.M.
        • Ruttle P.L.
        • Burghy C.A.
        • Stodola D.E.
        • Davidson R.J.
        • et al.
        Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence.
        Proc Natl Acad Sci U S A. 2013; 110: 19119-19124
        • Gamwell K.
        • Nylocks M.
        • Cross D.
        • Bradley B.
        • Norrholm S.D.
        • Jovanovic T.
        Fear conditioned responses and PTSD symptoms in children: Sex differences in fear-related symptoms.
        Dev Psychobiol. 2015; 57: 799-808
        • Garcia N.M.
        • Walker R.S.
        • Zoellner L.A.
        Estrogen, progesterone, and the menstrual cycle: A systematic review of fear learning, intrusive memories, and PTSD.
        Clin Psychol Rev. 2018; 66: 80-96
        • Pineles S.L.
        • Nillni YI
        • King M.W.
        • Patton S.C.
        • Bauer M.R.
        • Mostoufi S.M.
        • et al.
        Extinction retention and the menstrual cycle: Different associations for women with posttraumatic stress disorder.
        J Abnorm Psychol. 2016; 125: 349-355
        • Wegerer M.
        • Kerschbaum H.
        • Blechert J.
        • Wilhelm F.H.
        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
        • Hodes G.E.
        • Pfau M.L.
        • Purushothaman I.
        • Ahn H.F.
        • Golden S.A.
        • Christoffel D.J.
        • et al.
        Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress.
        J Neurosci. 2015; 35: 16362-16376
        • Labonte B.
        • Engmann O.
        • Purushothaman I.
        • Menard C.
        • Wang J.
        • Tan C.
        • et al.
        Sex-specific transcriptional signatures in human depression.
        Nat Med. 2017; 23: 1102-1111
        • Zhang S.
        • Zhang H.
        • Ku S.M.
        • Juarez B.
        • Morel C.
        • Tzavaras N.
        • et al.
        Sex differences in the neuroadaptations of reward-related circuits in response to subchronic variable stress.
        Neuroscience. 2018; 376: 108-116
        • LaPlant Q.
        • Chakravarty S.
        • Vialou V.
        • Mukherjee S.
        • Koo J.W.
        • Kalahasti G.
        • et al.
        Role of nuclear factor kappaB in ovarian hormone-mediated stress hypersensitivity in female mice.
        Biol Psychiatry. 2009; 65: 874-880
        • Rosenhauer A.M.
        • McCann K.E.
        • Norvelle A.
        • Huhman K.L.
        An acute social defeat stressor in early puberty increases susceptibility to social defeat in adulthood.
        Horm Behav. 2017; 93: 31-38
        • Solomon M.B.
        • Karom M.C.
        • Norvelle A.
        • Markham C.A.
        • Erwin W.D.
        • Huhman K.L.
        Gonadal hormones modulate the display of conditioned defeat in male Syrian hamsters.
        Horm Behav. 2009; 56: 423-428
        • Lorsch Z.S.
        • Loh Y.E.
        • Purushothaman I.
        • Walker D.M.
        • Parise E.M.
        • Salery M.
        • et al.
        Estrogen receptor alpha drives pro-resilient transcription in mouse models of depression.
        Nat Commun. 2018; 9: 1116
        • McCann K.E.
        • Sinkiewicz D.M.
        • Rosenhauer A.M.
        • Beach L.Q.
        • Huhman K.L.
        Transcriptomic analysis reveals sex-dependent expression patterns in the basolateral amygdala of dominant and subordinate animals after acute social conflict.
        Mol Neurobiol. 2019; 56: 3768-3779
        • LaPlant Q.
        • Vialou V.
        • Covington 3rd, H.E.
        • Dumitriu D.
        • Feng J.
        • Warren B.L.
        • et al.
        Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.
        Nat Neurosci. 2010; 13: 1137-1143
        • Elliott E.
        • Ezra-Nevo G.
        • Regev L.
        • Neufeld-Cohen A.
        • Chen A.
        Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice.
        Nat Neurosci. 2010; 13: 1351-1353
        • Bangasser D.A.
        • Eck S.R.
        • Ordones Sanchez E.
        Sex differences in stress reactivity in arousal and attention systems.
        Neuropsychopharmacology. 2019; 44: 129-139
        • Bangasser D.A.
        • Eck S.R.
        • Telenson A.M.
        • Salvatore M.
        Sex differences in stress regulation of arousal and cognition.
        Physiol Behav. 2018; 187: 42-50
        • Bangasser D.A.
        • Curtis A.
        • Reyes B.A.
        • Bethea T.T.
        • Parastatidis I.
        • Ischiropoulos H.
        • et al.
        Sex differences in corticotropin-releasing factor receptor signaling and trafficking: Potential role in female vulnerability to stress-related psychopathology.
        Mol Psychiatry 15. 2010; 877: 896-904
        • McAlinn H.R.
        • Reich B.
        • Contoreggi N.H.
        • Kamakura R.P.
        • Dyer A.G.
        • McEwen B.S.
        • et al.
        Sex differences in the subcellular distribution of corticotropin-releasing factor receptor 1 in the rat hippocampus following chronic immobilization stress.
        Neuroscience. 2018; 383: 98-113
        • Hu L.Y.
        • Shen C.C.
        • Hung J.H.
        • Chen P.M.
        • Wen C.H.
        • Chiang Y.Y.
        • et al.
        Risk of psychiatric disorders following symptomatic menopausal transition: A nationwide population-based retrospective cohort study.
        Medicine (Baltimore). 2016; 95: e2800
        • Freeman E.W.
        • Sammel M.D.
        • Boorman D.W.
        • Zhang R.
        Longitudinal pattern of depressive symptoms around natural menopause.
        JAMA Psychiatry. 2014; 71: 36-43
        • Saad F.
        • Gooren L.J.
        Late onset hypogonadism of men is not equivalent to the menopause.
        Maturitas. 2014; 79: 52-57
        • Woods N.F.
        • Carr M.C.
        • Tao E.Y.
        • Taylor H.J.
        • Mitchell E.S.
        Increased urinary cortisol levels during the menopausal transition.
        Menopause. 2006; 13: 212-221
        • Bale T.L.
        • Epperson C.N.
        Sex differences and stress across the lifespan.
        Nat Neurosci. 2015; 18: 1413-1420
        • Seeman T.E.
        • McEwen B.S.
        • Singer B.H.
        • Albert M.S.
        • Rowe J.W.
        Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging.
        J Clin Endocrinol Metab. 1997; 82: 2458-2465
        • Albert K.
        • Pruessner J.
        • Newhouse P.
        Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle.
        Psychoneuroendocrinology. 2015; 59: 14-24
        • Newhouse P.A.
        • Dumas J.
        • Wilkins H.
        • Coderre E.
        • Sites C.K.
        • Naylor M.
        • et al.
        Estrogen treatment impairs cognitive performance after psychosocial stress and monoamine depletion in postmenopausal women.
        Menopause. 2010; 17: 860-873
        • Herrera A.Y.
        • Hodis H.N.
        • Mack W.J.
        • Mather M.
        Estradiol therapy after menopause mitigates effects of stress on cortisol and working memory.
        J Clin Endocrinol Metab. 2017; 102: 4457-4466
        • Almela M.
        • Hidalgo V.
        • Villada C.
        • Espin L.
        • Gomez-Amor J.
        • Salvador A.
        The impact of cortisol reactivity to acute stress on memory: Sex differences in middle-aged people.
        Stress. 2011; 14: 117-127
        • Hodes G.E.
        • Shors T.J.
        Distinctive stress effects on learning during puberty.
        Horm Behav. 2005; 48: 163-171
        • Hodes G.E.
        • Shors T.J.
        Learning during middle age: A resistance to stress?.
        Neurobiol Aging. 2007; 28: 1783-1788
        • Shors T.J.
        • Falduto J.
        • Leuner B.
        The opposite effects of stress on dendritic spines in male vs. female rats are NMDA receptor-dependent.
        Eur J Neurosci. 2004; 19: 145-150
        • Tzeng W.Y.
        • Wu H.H.
        • Wang C.Y.
        • Chen J.C.
        • Yu L.
        • Cherng C.G.
        Sex differences in stress and group housing effects on the number of newly proliferated cells and neuroblasts in middle-aged dentate gyrus.
        Front Behav Neurosci. 2016; 10: 249
        • Ownby R.L.
        • Crocco E.
        • Acevedo A.
        • John V.
        • Loewenstein D.
        Depression and risk for Alzheimer disease: Systematic review, meta-analysis, and metaregression analysis.
        Arch Gen Psychiatry. 2006; 63: 530-538
        • Singh-Manoux A.
        • Dugravot A.
        • Fournier A.
        • Abell J.
        • Ebmeier K.
        • Kivimaki M.
        • et al.
        Trajectories of depressive symptoms before diagnosis of dementia: A 28-year follow-up study.
        JAMA Psychiatry. 2017; 74: 712-718
        • Mirza S.S.
        • Wolters F.J.
        • Swanson S.A.
        • Koudstaal P.J.
        • Hofman A.
        • Tiemeier H.
        • et al.
        10-year trajectories of depressive symptoms and risk of dementia: A population-based study.
        Lancet Psychiatry. 2016; 3: 628-635
        • Mielke M.M.
        • Vemuri P.
        • Rocca W.A.
        Clinical epidemiology of Alzheimer’s disease: Assessing sex and gender differences.
        Clin Epidemiol. 2014; 6: 37-48
        • Seshadri S.
        • Wolf P.A.
        • Beiser A.
        • Au R.
        • McNulty K.
        • White R.
        • et al.
        Lifetime risk of dementia and Alzheimer’s disease. The impact of mortality on risk estimates in the Framingham Study.
        Neurology. 1997; 49: 1498-1504
        • Dal Forno G.
        • Palermo M.T.
        • Donohue J.E.
        • Karagiozis H.
        • Zonderman A.B.
        • Kawas C.H.
        Depressive symptoms, sex, and risk for Alzheimer’s disease.
        Ann Neurol. 2005; 57: 381-387
        • Maccari S.
        • Darnaudery M.
        • Morley-Fletcher S.
        • Zuena A.R.
        • Cinque C.
        • Van Reeth O.
        Prenatal stress and long-term consequences: implications of glucocorticoid hormones.
        Neurosci Biobehav Rev. 2003; 27: 119-127
        • Babb J.A.
        • Carini L.M.
        • Spears S.L.
        • Nephew B.C.
        Transgenerational effects of social stress on social behavior, corticosterone, oxytocin, and prolactin in rats.
        Horm Behav. 2014; 65: 386-393
        • Kanatsou S.
        • Ter Horst J.P.
        • Harris A.P.
        • Seckl J.R.
        • Krugers H.J.
        • Joels M.
        Effects of mineralocorticoid receptor overexpression on anxiety and memory after early life stress in female mice.
        Front Behav Neurosci. 2015; 9: 374
        • Nephew B.C.
        • Febo M.
        • Huang W.
        • Colon-Perez L.M.
        • Payne L.
        • Poirier G.L.
        • et al.
        Early life social stress and resting state functional connectivity in postpartum rat anterior cingulate circuits.
        J Affect Disord. 2018; 229: 213-223