Systematic manipulations of the biological stress systems result in sex-specific compensatory stress responses and negative mood outcomes


Women are twice as likely as men to be diagnosed with anxiety and mood disorders. One potential underlying mechanism is sex differences in physiological and psychological responses to stress; however, no studies to date have investigated this proposed mechanism experimentally. In a double-blind, placebo-controlled design, pharmacological challenges were administered to individually suppress the hypothalamic–pituitary–adrenal (HPA) axis, or the sympathetic nervous system (SNS) prior to stress exposure, to investigate sex differences in the resulting cross talk among the physiological and psychological stress responses. Sex-specific compensatory patterns and psychological effects emerged when the stress systems were manipulated. Men demonstrated heightened SNS reactivity to stress when the HPA axis was suppressed, and greater HPA reactivity after SNS suppression. This ability to react appropriately to the stressor, even with one system, did not lead to significant negative mood effects. In women, higher baseline activation (but dampened reactivity to stress) of SNS or HPA was observed when the other system was suppressed. This was coupled with worsened mood in response to stress when either stress system was compromised. Our results indicate that men and women may be differentially sensitive to fluctuations of their stress systems. This might be a potential link that underlies the sexual dimorphism in vulnerability for psychopathology.

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Fig. 1: Physiological stress responses in each drug condition.
Fig. 2: Physiological stress responses in men and women.
Fig. 3: Effect of TSST on mood and subjective stress.
Fig. 4: Effect of TSST on mood and subjective stress.


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This study was supported by research grants awarded by the Canadian Institutes of Health Research to JCP (grants no. 125881 and 148728). NA was awarded the doctoral research award by the Fonds de Recherche du Québec—Santé.

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NA and JCP conceived and designed the study. NA and CC collected the data. NA and JPN conducted statistical analyses. NA, JPN, MWB, and JCP interpreted the findings. NA, MWB, and JCP wrote and edited the manuscript. CC and JPN reviewed and edited the manuscript.

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Correspondence to Nida Ali.

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Ali, N., Nitschke, J.P., Cooperman, C. et al. Systematic manipulations of the biological stress systems result in sex-specific compensatory stress responses and negative mood outcomes. Neuropsychopharmacol. (2020).

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