Elsevier

Biological Psychiatry

Volume 86, Issue 6, 15 September 2019, Pages 421-432
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2019.04.028Get rights and content

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.

Section snippets

Prenatal Stress Shapes an Individual’s Response to the Environment

The prenatal experience shapes an individual’s brain, body, and behavior for their lifetime and potentially even affects the response of subsequent generations through transgenerational mechanisms. Human offspring exposed to extreme gestational stress in the form of maternal starvation during the Dutch Hunger Winter had increased risk of psychiatric disorders, including affective disorders (15), addiction (16), and schizophrenia (17). Effects of famine were also associated with increased risk

Potential Mechanisms for Intergenerational Transmission of Stress: Consideration of In Utero Adaptation by Sex

Initially, female development was characterized as a passive default. However, preclinical research suggests that female brain development is an active process regulated by DNA methylation (43), an epigenetic process through which genetic transcription is silenced (44). Female fetuses have higher placental levels of DNA methyltransferase 1 (DNMT1) involved in maintenance methylation and respond to maternal variable stress with further increases, supporting the likelihood of continued recreation

Early Life Stress

Studies of children isolated in orphanages in accordance with former policies of the Romanian government have provided insight into the lasting damage of neglect and early life stress even when basic needs such as food and shelter are met. Caregiver deprivation is associated with an accentuation of the female bias toward anxiety and depressive disorders and the male bias toward impulsivity and conduct disorders 56, 57. Neuroimaging studies show abnormalities in amygdala development and

Conclusions

Male offspring are at greater risk of adverse proximal and some distal behavioral effects of gestational and early life stress owing to a lack of compensatory mechanisms and alterations in epigenetic regulation and organizational effects of hormones. The greatest distal impact of stress in male offspring at all life span epochs seems to be on cognitive ability, particularly spatial learning, and may contribute symptoms associated with autism spectrum disorder, attention-deficit/hyperactivity

Acknowledgments and Disclosures

This work was supported by the National Cancer Institute (Grant No. R01CA201295 [to CNE]), National Institute on Drug Abuse (Grant No. R01DA037289 [to CNE]), and Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression Young Investigator Grant [to GEH]).

CNE serves as a consultant for Sage Therapeutics and on the advisory board for Asarina Pharma. CNE or her spouse has personal investments in Merck & Co., Inc., Abbott Laboratories, AbbVie Inc.,

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