Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sex differences and stress across the lifespan

Abstract

Sex differences in stress responses can be found at all stages of life and are related to both the organizational and activational effects of gonadal hormones and to genes on the sex chromosomes. As stress dysregulation is the most common feature across neuropsychiatric diseases, sex differences in how these pathways develop and mature may predict sex-specific periods of vulnerability to disruption and increased disease risk or resilience across the lifespan. The aging brain is also at risk to the effects of stress, where the rapid decline of gonadal hormones in women combined with cellular aging processes promote sex biases in stress dysregulation. In this Review, we discuss potential underlying mechanisms driving sex differences in stress responses and their relevance to disease. Although stress is involved in a much broader range of diseases than neuropsychiatric ones, we highlight here this area and its examples across the lifespan.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Programming and maturation of the sexually dimorphic brain and importance in lifelong sex differences in stress circuitry.

Marina Corral Spence/Nature Publishing Group

Figure 2: Sex differences in stress-related neuropsychiatric disease across the lifespan.

Similar content being viewed by others

References

  1. Vale, W., Spiess, J., Rivier, C. & Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213, 1394–1397 (1981).

    Article  CAS  PubMed  Google Scholar 

  2. Rivier, C. & Vale, W. Effects of corticotropin-releasing factor, neurohypophyseal peptides, and catecholamines on pituitary function. Fed. Proc. 44, 189–195 (1985).

    CAS  PubMed  Google Scholar 

  3. Sawchenko, P.E. et al. The functional neuroanatomy of corticotropin-releasing factor. Ciba Found. Symp. 172, 5–21 (1993).

    CAS  PubMed  Google Scholar 

  4. Kirby, L.G., Rice, K.C. & Valentino, R.J. Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology 22, 148–162 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Rivier, C. & Vale, W. Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305, 325–327 (1983).

    Article  CAS  PubMed  Google Scholar 

  6. Goel, N. & Bale, T.L. Organizational and activational effects of testosterone on masculinization of female physiological and behavioral stress responses. Endocrinology 149, 6399–6405 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Handa, R.J., Burgess, L.H., Kerr, J.E. & O'Keefe, J.A. Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. Horm. Behav. 28, 464–476 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Walker, C.D., Perrin, M., Vale, W. & Rivier, C. Ontogeny of the stress response in the rat: role of the pituitary and the hypothalamus. Endocrinology 118, 1445–1451 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Brydges, N.M., Wood, E.R., Holmes, M.C. & Hall, J. Prepubertal stress and hippocampal function: sex-specific effects. Hippocampus 24, 684–692 (2014).

    Article  PubMed  Google Scholar 

  10. Ege, M.A., Messias, E., Thapa, P.B. & Krain, L.P. Adverse childhood experiences and geriatric depression: results from the 2010 BRFSS. Am. J. Geriatr. Psychiatry 23, 110–114 (2015).

    Article  PubMed  Google Scholar 

  11. Khan, A. et al. Childhood maltreatment, depression, and suicidal ideation: critical importance of parental and peer emotional abuse during developmental sensitive periods in males and females. Front. Psychiatry 6, 42 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. Kendler, K.S., Thornton, L.M. & Prescott, C.A. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am. J. Psychiatry 158, 587–593 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. McCarthy, M.M. & Nugent, B.M. Epigenetic contributions to hormonally mediated sexual differentiation of the brain. J. Neuroendocrinol. 25, 1133–1140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arnold, A.P. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm. Behav. 55, 570–578 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bale, T.L. et al. Early life programming and neurodevelopmental disorders. Biol. Psychiatry 68, 314–319 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Morgan, C.P. & Bale, T.L. Sex differences in microRNA regulation of gene expression: no smoke, just miRs. Biol Sex Differ 3, 22 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bale, T.L. Epigenetic and transgenerational reprogramming of brain development. Nat. Rev. Neurosci. 16, 332–344 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nugent, B.M. et al. Brain feminization requires active repression of masculinization via DNA methylation. Nat. Neurosci. 18, 690–697 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sandman, C.A., Glynn, L.M. & Davis, E.P. Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. J. Psychosom. Res. 75, 327–335 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kim, D.R., Bale, T.L. & Epperson, C.N. Prenatal programming of mental illness: current understanding of relationship and mechanisms. Curr. Psychiatry Rep. 17, 5 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  21. O'Connor, T.G., Heron, J., Golding, J., Beveridge, M. & Glover, V. Maternal antenatal anxiety and children's behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Br. J. Psychiatry 180, 502–508 (2002).

    Article  PubMed  Google Scholar 

  22. Heim, C. et al. Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Front. Behav. Neurosci. 3, 41 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Heim, C. & Nemeroff, C.B. The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biol. Psychiatry 46, 1509–1522 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Heim, C. & Nemeroff, C.B. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol. Psychiatry 49, 1023–1039 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Heim, C., Shugart, M., Craighead, W.E. & Nemeroff, C.B. Neurobiological and psychiatric consequences of child abuse and neglect. Dev. Psychobiol. 52, 671–690 (2010).

    Article  PubMed  Google Scholar 

  26. McEwen, B.S. & Morrison, J.H. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79, 16–29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Karatsoreos, I.N. & McEwen, B.S. Resilience and vulnerability: a neurobiological perspective. F1000Prime Rep. 5, 13 (2013).

    PubMed  PubMed Central  Google Scholar 

  28. Kelly, S.D., Harrell, C.S. & Neigh, G.N. Chronic stress modulates regional cerebral glucose transporter expression in an age-specific and sexually-dimorphic manner. Physiol. Behav. 126, 39–49 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Martin, E.I., Ressler, K.J., Binder, E. & Nemeroff, C.B. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Clin. Lab. Med. 30, 865–891 (2010).

    Article  PubMed  Google Scholar 

  30. Rodgers, A.B. & Bale, T.L. Germ cell origins of posttraumatic stress disorder risk: the transgenerational impact of parental stress experience. Biol. Psychiatry 78, 307–314 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Arborelius, L., Owens, M.J., Plotsky, P.M. & Nemeroff, C.B. The role of corticotropin-releasing factor in depression and anxiety disorders. J. Endocrinol. 160, 1–12 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Kornstein, S.G. Gender differences in depression: implications for treatment. J. Clin. Psychiatry 58, 12–18 (1997).

    Article  PubMed  Google Scholar 

  33. Kajantie, E. & Phillips, D.I. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31, 151–178 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Rohleder, N., Schommer, N.C., Hellhammer, D.H., Engel, R. & Kirschbaum, C. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom. Med. 63, 966–972 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Bangasser, D.A. & Valentino, R.J. Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front. Neuroendocrinol. 35, 303–319 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Goel, N. & Bale, T.L. Identifying early behavioral and molecular markers of future stress sensitivity. Endocrinology 148, 4585–4591 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Goel, N. & Bale, T.L. Sex differences in the serotonergic influence on the hypothalamic-pituitary-adrenal stress axis. Endocrinology 151, 1784–1794 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Goel, N., Plyler, K.S., Daniels, D. & Bale, T.L. Androgenic influence on serotonergic activation of the HPA stress axis. Endocrinology 152, 2001–2010 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Hiroi, R., McDevitt, R.A. & Neumaier, J.F. Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field. Biol. Psychiatry 60, 288–295 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Donner, N. & Handa, R.J. Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei. Neuroscience 163, 705–718 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Weiser, M.J., Goel, N., Sandau, U.S., Bale, T.L. & Handa, R.J. Androgen regulation of corticotropin-releasing hormone receptor 2 (CRHR2) mRNA expression and receptor binding in the rat brain. Exp. Neurol. 214, 62–68 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Weiser, M.J. & Handa, R.J. Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic-pituitary-adrenal axis via estrogen receptor alpha within the hypothalamus. Neuroscience 159, 883–895 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Mueller, B.R. & Bale, T.L. Sex-specific programming of offspring emotionality after stress early in pregnancy. J. Neurosci. 28, 9055–9065 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hanninen, V. & Aro, H. Sex differences in coping and depression among young adults. Soc. Sci. Med. 43, 1453–1460 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Protopopescu, X. et al. Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc. Natl. Acad. Sci. USA 102, 16060–16065 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Amin, Z., Epperson, C.N., Constable, R.T. & Canli, T. Effects of estrogen variation on neural correlates of emotional response inhibition. Neuroimage 32, 457–464 (2006).

    Article  PubMed  Google Scholar 

  47. Hong, D.S. et al. Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes. J. Neurosci. 34, 3509–3516 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hong, D.S., Bray, S., Haas, B.W., Hoeft, F. & Reiss, A.L. Aberrant neurocognitive processing of fear in young girls with Turner syndrome. Soc. Cogn. Affect. Neurosci. 9, 255–264 (2014).

    Article  PubMed  Google Scholar 

  49. Rose, A.B. et al. Effects of hormones and sex chromosomes on stress-influenced regions of the developing pediatric brain. Ann. NY Acad. Sci. 1032, 231–233 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Capel, B. Sex in the 90s: SRY and the switch to the male pathway. Annu. Rev. Physiol. 60, 497–523 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Newschaffer, C.J. et al. The epidemiology of autism spectrum disorders. Annu. Rev. Public Health 28, 235–258 (2007).

    Article  PubMed  Google Scholar 

  52. Gore, A.C., Martien, K.M., Gagnidze, K. & Pfaff, D. Implications of prenatal steroid perturbations for neurodevelopment, behavior, and autism. Endocr. Rev. 35, 961–991 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Davis, E.P. & Pfaff, D. Sexually dimorphic responses to early adversity: implications for affective problems and autism spectrum disorder. Psychoneuroendocrinology 49, 11–25 (2014).

    Article  PubMed  Google Scholar 

  54. Erskine, H.E. et al. Epidemiological modelling of attention-deficit/hyperactivity disorder and conduct disorder for the Global Burden of Disease Study 2010. J. Child Psychol. Psychiatry 54, 1263–1274 (2013).

    Article  PubMed  Google Scholar 

  55. van Os, J. & Selten, J.P. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br. J. Psychiatry 172, 324–326 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Khashan, A.S. et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch. Gen. Psychiatry 65, 146–152 (2008).

    Article  PubMed  Google Scholar 

  57. Beversdorf, D.Q. et al. Timing of prenatal stressors and autism. J. Autism Dev. Disord. 35, 471–478 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Gerardin, P. et al. Depression during pregnancy: is the developmental impact earlier in boys? a prospective case-control study. J. Clin. Psychiatry 72, 378–387 (2011).

    Article  PubMed  Google Scholar 

  59. Cowell, P.E., Kostianovsky, D.J., Gur, R.C., Turetsky, B.I. & Gur, R.E. Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am. J. Psychiatry 153, 799–805 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Gur, R.E. et al. A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia. Biol. Psychiatry 55, 512–517 (2004).

    Article  PubMed  Google Scholar 

  61. Goldstein, J.M., Cherkerzian, S., Tsuang, M.T. & Petryshen, T.L. Sex differences in the genetic risk for schizophrenia: history of the evidence for sex-specific and sex-dependent effects. Am. J. Med. Genet. 162, 698–710 (2013).

    Article  CAS  Google Scholar 

  62. Goldstein, J.M. et al. Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch. Gen. Psychiatry 59, 154–164 (2002).

    Article  PubMed  Google Scholar 

  63. Clarke, A.S. & Schneider, M.L. Prenatal stress has long-term effects on behavioral responses to stress in juvenile rhesus monkeys. Dev. Psychobiol. 26, 293–304 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Brunton, P.J. & Russell, J.A. Prenatal social stress in the rat programmes neuroendocrine and behavioural responses to stress in the adult offspring: sex-specific effects. J. Neuroendocrinol. 22, 258–271 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Kapoor, A. & Matthews, S.G. Short periods of prenatal stress affect growth, behaviour and hypothalamo-pituitary-adrenal axis activity in male guinea pig offspring. J. Physiol. (Lond.) 566, 967–977 (2005).

    Article  CAS  Google Scholar 

  66. Cottrell, E.C. & Seckl, J.R. Prenatal stress, glucocorticoids and the programming of adult disease. Front. Behav. Neurosci. 3, 19 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lyons, D.M., Parker, K.J., Katz, M. & Schatzberg, A.F. Developmental cascades linking stress inoculation, arousal regulation, and resilience. Front. Behav. Neurosci. 3, 32 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Lyons, D.M., Parker, K.J. & Schatzberg, A.F. Animal models of early life stress: implications for understanding resilience. Dev. Psychobiol. 52, 616–624 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Schneider, M.L., Moore, C.F., Kraemer, G.W., Roberts, A.D. & DeJesus, O.T. The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model. Psychoneuroendocrinology 27, 285–298 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Kapoor, A., Kostaki, A., Janus, C. & Matthews, S.G. The effects of prenatal stress on learning in adult offspring is dependent on the timing of the stressor. Behav. Brain Res. 197, 144–149 (2009).

    Article  PubMed  Google Scholar 

  71. Mueller, B.R. & Bale, T.L. Early prenatal stress impact on coping strategies and learning performance is sex dependent. Physiol. Behav. 91, 55–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Lemaire, V., Koehl, M., Le Moal, M. & Abrous, D.N. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl. Acad. Sci. USA 97, 11032–11037 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Weinstock, M. Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog. Neurobiol. 65, 427–451 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Mueller, B.R. & Bale, T.L. Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity. Physiol. Behav. 88, 605–614 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Richardson, H.N., Zorrilla, E.P., Mandyam, C.D. & Rivier, C.L. Exposure to repetitive versus varied stress during prenatal development generates two distinct anxiogenic and neuroendocrine profiles in adulthood. Endocrinology 147, 2506–2517 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Franklin, T.B. et al. Epigenetic transmission of the impact of early stress across generations. Biol. Psychiatry 68, 408–415 (2010).

    Article  PubMed  Google Scholar 

  77. Ivy, A.S., Brunson, K.L., Sandman, C. & Baram, T.Z. Dysfunctional nurturing behavior in rat dams with limited access to nesting material: a clinically relevant model for early-life stress. Neuroscience 154, 1132–1142 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Ivy, A.S. et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J. Neurosci. 30, 13005–13015 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Korosi, A. et al. Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone. J. Neurosci. 30, 703–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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 149, 4892–4900 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Meaney, M.J. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24, 1161–1192 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Meaney, M.J. et al. Individual differences in the hypothalamic-pituitary-adrenal stress response and the hypothalamic CRF system. Ann. NY Acad. Sci. 697, 70–85 (1993).

    Article  CAS  PubMed  Google Scholar 

  83. Barha, C.K., Pawluski, J.L. & Galea, L.A. Maternal care affects male and female offspring working memory and stress reactivity. Physiol. Behav. 92, 939–950 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. McCarthy, M.M. & Arnold, A.P. Reframing sexual differentiation of the brain. Nat. Neurosci. 14, 677–683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Baron-Cohen, S. et al. Elevated fetal steroidogenic activity in autism. Mol. Psychiatry 20, 369–376 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lombardo, M.V. et al. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J. Neurosci. 32, 674–680 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ruta, L., Ingudomnukul, E., Taylor, K., Chakrabarti, B. & Baron-Cohen, S. Increased serum androstenedione in adults with autism spectrum conditions. Psychoneuroendocrinology 36, 1154–1163 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Bingham, B. & Viau, V. Neonatal gonadectomy and adult testosterone replacement suggest an involvement of limbic arginine vasopressin and androgen receptors in the organization of the hypothalamic-pituitary-adrenal axis. Endocrinology 149, 3581–3591 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Pembrey, M., Saffery, R. & Bygren, L.O. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Genet. 51, 563–572 (2014).

    Article  PubMed  Google Scholar 

  90. Romeo, R.D. Pubertal maturation and programming of hypothalamic-pituitary-adrenal reactivity. Front. Neuroendocrinol. 31, 232–240 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Romeo, R.D. & McEwen, B.S. Stress and the adolescent brain. Ann. NY Acad. Sci. 1094, 202–214 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Kessler, R.C. Epidemiology of women and depression. J. Affect. Disord. 74, 5–13 (2003).

    Article  PubMed  Google Scholar 

  93. Gomez, F., Manalo, S. & Dallman, M.F. Androgen-sensitive changes in regulation of restraint-induced adrenocorticotropin secretion between early and late puberty in male rats. Endocrinology 145, 59–70 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Andersen, S.L. & Teicher, M.H. Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci. 31, 183–191 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Plant, T.M. & Barker-Gibb, M.L. Neurobiological mechanisms of puberty in higher primates. Hum. Reprod. Update 10, 67–77 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Viau, V. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes. J. Neuroendocrinol. 14, 506–513 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Morrison, K.E., Rodgers, A.B., Morgan, C.P. & Bale, T.L. Epigenetic mechanisms in pubertal brain maturation. Neuroscience 264, 17–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. De Bellis, M.D. et al. Sex differences in brain maturation during childhood and adolescence. Cereb. Cortex 11, 552–557 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Schmitt, J.E. et al. The dynamic role of genetics on cortical patterning during childhood and adolescence. Proc. Natl. Acad. Sci. USA 111, 6774–6779 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pfefferbaum, A. et al. A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch. Neurol. 51, 874–887 (1994).

    Article  CAS  PubMed  Google Scholar 

  101. Ahmed, E.I. et al. Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nat. Neurosci. 11, 995–997 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nuruddin, S. et al. Peri-pubertal gonadotropin-releasing hormone agonist treatment affects sex biased gene expression of amygdala in sheep. Psychoneuroendocrinology 38, 3115–3127 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Sapolsky, R.M., Meaney, M.J. & McEwen, B.S. The development of the glucocorticoid receptor system in the rat limbic brain. III. Negative-feedback regulation. Brain Res. 350, 169–173 (1985).

    Article  CAS  PubMed  Google Scholar 

  104. Meaney, M.J., Sapolsky, R.M. & McEwen, B.S. The development of the glucocorticoid receptor system in the rat limbic brain. I. Ontogeny and autoregulation. Brain Res. 350, 159–164 (1985).

    Article  CAS  PubMed  Google Scholar 

  105. Lund, T.D., Hinds, L.R. & Handa, R.J. The androgen 5alpha-dihydrotestosterone and its metabolite 5alpha-androstan-3beta, 17beta-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor beta-expressing neurons in the hypothalamus. J. Neurosci. 26, 1448–1456 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Goldstein, J.M., Jerram, M., Abbs, B., Whitfield-Gabrieli, S. & Makris, N. Sex differences in stress response circuitry activation dependent on female hormonal cycle. J. Neurosci. 30, 431–438 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Romeo, R.D. Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development. J. Neuroendocrinol. 15, 1185–1192 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Pechtel, P., Lyons-Ruth, K., Anderson, C.M. & Teicher, M.H. Sensitive periods of amygdala development: the role of maltreatment in preadolescence. Neuroimage 97, 236–244 (2014).

    Article  PubMed  Google Scholar 

  109. Heim, C. & Binder, E.B. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp. Neurol. 233, 102–111 (2012).

    Article  PubMed  Google Scholar 

  110. Gillespie, C.F., Phifer, J., Bradley, B. & Ressler, K.J. Risk and resilience: genetic and environmental influences on development of the stress response. Depress. Anxiety 26, 984–992 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bale, T.L. Sex differences in prenatal epigenetic programming of stress pathways. Stress 14, 348–356 (2011).

    Article  PubMed  Google Scholar 

  112. Barha, C.K., Brummelte, S., Lieblich, S.E. & Galea, L.A. Chronic restraint stress in adolescence differentially influences hypothalamic-pituitary-adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus 21, 1216–1227 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. van der Knaap, L.J. et al. Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study. Transl. Psychiatry 4, e381 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Araujo, A.B. & Wittert, G.A. Endocrinology of the aging male. Best Pract. Res. Clin. Endocrinol. Metab. 25, 303–319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nemeroff, C.B. Stress, menopause and vulnerability for psychiatric illness. Expert Rev. Neurother. 7, S11–S13 (2007).

    Article  PubMed  Google Scholar 

  116. Freeman, E.W., Sammel, M.D., Boorman, D.W. & Zhang, R. Longitudinal pattern of depressive symptoms around natural menopause. JAMA Psychiatry 71, 36–43 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Godar, S.C. & Bortolato, M. Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. Front. Behav. Neurosci. 8, 71 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schmitt, A., Malchow, B., Hasan, A. & Falkai, P. The impact of environmental factors in severe psychiatric disorders. Front. Neurosci 8, 19 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Rabinowitz, J., Levine, S.Z. & Hafner, H. A population based elaboration of the role of age of onset on the course of schizophrenia. Schizophr. Res. 88, 96–101 (2006).

    Article  PubMed  Google Scholar 

  120. Harsh, V., Schmidt, P.J. & Rubinow, D.R. The menopause transition: the next neuroendocrine frontier. Expert Rev. Neurother. 7, S7–S10 (2007).

    Article  PubMed  Google Scholar 

  121. Maki, P.M. et al. Summary of the National Institute on Aging-sponsored conference on depressive symptoms and cognitive complaints in the menopausal transition. Menopause 17, 815–822 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Shively, C.A. et al. Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys. Arch. Gen. Psychiatry 63, 396–403 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Lima, F.B. & Bethea, C.L. Ovarian steroids decrease DNA fragmentation in the serotonin neurons of non-injured rhesus macaques. Mol. Psychiatry 15, 657–668 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Bethea, C.L. & Reddy, A.P. Effect of ovarian hormones on genes promoting dendritic spines in laser-captured serotonin neurons from macaques. Mol. Psychiatry 15, 1034–1044 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Bethea, C.L., Reddy, A.P., Tokuyama, Y., Henderson, J.A. & Lima, F.B. Protective actions of ovarian hormones in the serotonin system of macaques. Front. Neuroendocrinol. 30, 212–238 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bethea, C.L., Reddy, A.P., Pedersen, D. & Tokuyama, Y. Expression profile of differentiating serotonin neurons derived from rhesus embryonic stem cells and comparison to adult serotonin neurons. Gene Expr. Patterns 9, 94–108 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. McEwen, B.S. Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. J. Appl. Physiol. 91, 2785–2801 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Suda, S., Segi-Nishida, E., Newton, S.S. & Duman, R.S. A postpartum model in rat: behavioral and gene expression changes induced by ovarian steroid deprivation. Biol. Psychiatry 64, 311–319 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Galea, L.A., Wide, J.K. & Barr, A.M. Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression. Behav. Brain Res. 122, 1–9 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Stoffel, E.C. & Craft, R.M. Ovarian hormone withdrawal-induced “depression” in female rats. Physiol. Behav. 83, 505–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. 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. 35, 847–865 (2014).

    Article  PubMed  Google Scholar 

  132. Newhouse, P.A. et al. Estrogen treatment impairs cognitive performance after psychosocial stress and monoamine depletion in postmenopausal women. Menopause 17, 860–873 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Dumas, J.A. et al. The effects of age and estrogen on stress responsivity in older women. Am. J. Geriatr. Psychiatry 20, 734–743 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Albert, K., Pruessner, J. & Newhouse, P. Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle. Psychoneuroendocrinology 59, 14–24 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Seeman, T.E., Singer, B., Wilkinson, C.W. & McEwen, B. Gender differences in age-related changes in HPA axis reactivity. Psychoneuroendocrinology 26, 225–240 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Kudielka, B.M. & Kirschbaum, C. Sex differences in HPA axis responses to stress: a review. Biol. Psychol. 69, 113–132 (2005).

    Article  PubMed  Google Scholar 

  137. Kudielka, B.M., Buske-Kirschbaum, A., Hellhammer, D.H. & Kirschbaum, C. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology 29, 83–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Otte, C. et al. A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology 30, 80–91 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Kessler, R.C. et al. Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. Epidemiol Psychiatr Sci 1–17 (2015).

  140. Freeman, E.W., Sammel, M.D., Lin, H. & Nelson, D.B. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch. Gen. Psychiatry 63, 375–382 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Freeman, E.W. et al. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch. Gen. Psychiatry 61, 62–70 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Bowman, R.E., Maclusky, N.J., Diaz, S.E., Zrull, M.C. & Luine, V.N. Aged rats: sex differences and responses to chronic stress. Brain Res. 1126, 156–166 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Roca, C.A. et al. Sex-related differences in stimulated hypothalamic-pituitary-adrenal axis during induced gonadal suppression. J. Clin. Endocrinol. Metab. 90, 4224–4231 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Rubinow, D.R. et al. Testosterone suppression of CRH-stimulated cortisol in men. Neuropsychopharmacology 30, 1906–1912 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Woolley, C.S. Acute effects of estrogen on neuronal physiology. Annu. Rev. Pharmacol. Toxicol. 47, 657–680 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Bloss, E.B. et al. Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. Neurobiol. Aging 34, 200–210 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work discussed in this Review was funded in part by US National Institutes of Health grants MH073030 (T.L.B.), MH091258 (T.L.B.), MH087597 (T.L.B.), MH104184 (T.L.B.), MH108286 (T.L.B.), MH099910 (C.N.E. and T.L.B.), AG048839 (C.N.E.), DA030301 (C.N.E.). We thank T. Tiliakos for editorial assistance with the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tracy L Bale.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bale, T., Epperson, C. Sex differences and stress across the lifespan. Nat Neurosci 18, 1413–1420 (2015). https://doi.org/10.1038/nn.4112

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4112

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing