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.
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med. 1999;61:154–62.
Stroud LR, Salovey P, Epel ES. Sex differences in stress responses: social rejection versus achievement stress. Biol Psychiatry. 2002;52:318–27.
Altemus M. Sex differences in depression and anxiety disorders: potential biological determinants. Horm Behav. 2006;50:534–8.
Nolen-Hoeksema S. Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol. 2012;8:161–87.
Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry. 2002;7:254–75.
Nater UM, Rohleder N, Gaab J, Berger S, Jud A, Kirschbaum C, et al. Human salivary alpha-amylase reactivity in a psychosocial stress paradigm. Int J Psychophysiol. 2005;55:333–42.
Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10:397–409.
de Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–75.
Kajantie E, Phillips DIW. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology. 2006;31:151–78.
Kudielka BM, Hellhammer J. Sex differences in endocrine and psychological responses to psychosocial stress in healthy elderly subjects and the impact of a 2-week dehydroepiandrosterone treatment. J Clin Endocrinol Metab. 1998;83:1756–61.
Gallucci WT, Baum A, Laue L, Rabin DS, Chrousos GP, Gold PW, et al. Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis. Health Psychol. 1993;12:420–5.
Kudielka BM, Buske-Kirschbaum A, Hellhammer DH, Kirschbaum C. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology. 2004;29:83–98.
Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005;69:113–32.
Carr AR, Scully A, Webb M, Felmingham KL. Gender differences in salivary alpha-amylase and attentional bias towards negative facial expressions following acute stress induction. Cogn Emot. 2016;30:315–24.
Childs E, Dlugos A, De Wit H. Cardiovascular, hormonal, and emotional responses to the TSST in relation to sex and menstrual cycle phase. Psychophysiology. 2010;47:550–9.
Takai N, Yamaguchi M, Aragaki T, Eto K, Uchihashi K, Nishikawa Y. Gender-specific differences in salivary biomarker responses to acute psychological stress. Ann N Y Acad Sci. 2007;1098:510–5.
van Stegeren AH, Wolf OT, Kindt M. Salivary alpha amylase and cortisol responses to different stress tasks: impact of sex. Int J Psychophysiol. 2008;69:33–40.
Taylor SE, Klein LC, Lewis BP, Gruenewald TL, Gurung RA, Updegraff JA. Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight. Psychol Rev. 2000;107:411–29.
Tamres LK, Janicki D, Helgeson VS. Sex differences in coping behavior: a meta-analytic review and an examination of relative coping. Pers Soc Psychol Rev. 2002;6:2–30.
Engert V, Vogel S, Efanov SI, Duchesne A, Corbo V, Ali N, et al. Investigation into the cross-correlation of salivary cortisol and alpha-amylase responses to psychological stress. Psychoneuroendocrinology. 2011;36:1294–302.
Andrews J, D’Aguiar C, Pruessner JC. The combined dexamethasone/TSST paradigm–a new method for psychoneuroendocrinology. PLoS ONE. 2012;7:e38994.
Andrews J, Pruessner JC. The combined propranolol/TSST paradigm–a new method for psychoneuroendocrinology. PLoS ONE. 2013;8:e57567.
Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374–81.
de Kloet ER, van der Vies J, de Wied D. The site of the suppressive action of dexamethasone on pituitary-adrenal activity. Endocrinology. 1974;94:61–73.
Winzer A, Ring C, Carroll D, Willemsen G, Drayson M, Kendall M. Secretory immunoglobulin A and cardiovascular reactions to mental arithmetic, cold pressor, and exercise: effects of beta-adrenergic blockade. Psychophysiology. 1999;36:591–601.
Ali N, Pruessner JC. The salivary alpha amylase over cortisol ratio as a marker to assess dysregulations of the stress systems. Physiol Behav. 2012;106:65–72.
Vreeburg SA, Zitman FG, van Pelt J, Derijk RH, Verhagen JCM, van Dyck R, et al. Salivary cortisol levels in persons with and without different anxiety disorders. Psychosom Med. 2010;72:340–7.
Bale TL, Epperson CN. Sex differences and stress across the lifespan. Nat Neurosci. 2015;18:1413–20.
Ali N, Nitschke JP, Cooperman C, Pruessner JC. Suppressing the endocrine and autonomic stress systems does not impact the emotional stress experience after psychosocial stress. Psychoneuroendocrinology. 2017;78:125–30.
Cohen, J. Statistical Power Analysis for the Behavioral Sciences–Second Edition. Lawrence Erlbaum Associates Inc. Hillsdale, New Jersey, 1998;13.
Buchner A, Faul F, Erdfelder E. G*power. 1997. http://www.Psycho.Uni-duesseldorf.De/aap/projects/gpower/how_to_use_gpower.html.
Kirschbaum C, Pirke K-M, Hellhammer DH. The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81.
Dressendörfer RA, Kirschbaum C, Rohde W, Stahl F, Strasburger CJ. Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol. 1992;43:683–92.
Gift AG. Visual analogue scales: measurement of subjective phenomena. Nurs Res. 1989;38:286–8.
Lorr M, McNair DM, Fisher SU. Evidence for bipolar mood states. J Pers Assess. 1982;46:432–6.
Gueorguieva R, Krystal JH. Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the archives of general psychiatry. Arch Gen Psychiatry. 2004;61:310–7.
Barr DJ, Levy R, Scheepers C, Tily HJ. Random effects structure for confirmatory hypothesis testing: keep it maximal. J Mem Lang. 2013;68:255–78.
Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 2003;28:916–31.
van Buuren S, Groothuis-Oudshoorn K. Mice: multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1–67.
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2013. http://www.R-project.org/.
Bates D, Mächler M, Bolker B, Walker S. Fitting Linear Mixed-Effects Models Using lme4. J Stat Softw. 2015;67:1–48. https://doi.org/10.18637/jss.v067.i01.
Preacher KJ, Curran PJ, Bauer DJ. Computational tools for probing interactions in multiple linear regression, multilevel modeling, and latent curve analysis. J Educ Behav Stat. 2006;31:437–48.
Miller R, Plessow F, Kirschbaum C, Stalder T. Classification criteria for distinguishing cortisol responders from nonresponders to psychosocial stress: evaluation of salivary cortisol pulse detection in panel designs. Psychosom Med. 2013;75:832–40.
Wilder J. Basimetric approach (law of initial value) to biological rhythms. Ann N Y Acad Sci. 1962;98:1211–20.
Young E, Korszun A. Women, stress, and depression: Sex differences in hypothalamic-pituitary-adrenal axis regulation. In Leibenluft, E (Ed.), Gender differences in mood and anxiety disorders: From bench to bedside (pp. 31–52). Washington, DC: American Psychiatric Press. 1999.
Heck AL, Handa RJ. Sex differences in the hypothalamic-pituitary-adrenal axis’ response to stress: an important role for gonadal hormones. Neuropsychopharmacology. 2019;44:45–58.
Douma SL, Husband C, OʼDonnell ME, Barwin BN, Woodend AK. Estrogen-related mood disorders: reproductive life cycle factors. ANS Adv Nurs Sci. 2005;28:364–75.
Troisi A. Gender differences in vulnerability to social stress: a Darwinian perspective. Physiol Behav. 2001;73:443–9.
Galea LA, McEwen BS, Tanapat P, Deak T, Spencer RL, Dhabhar FS. Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience. 1997;81:689–97.
Spear LP. Heightened stress responsivity and emotional reactivity during pubertal maturation: Implications for psychopathology. Dev Psychopathol. 2009;21:87–97.
Lazarus RS, Folkman S. Coping and Adaptation. In Gentry, WD (Ed.), The Handbook of Behavioral Medicine (pp. 282–325). New York: Guilford. 1984.
Het S, Wolf OT. Mood changes in response to psychosocial stress in healthy young women: effects of pretreatment with cortisol. Behav Neurosci 2007;121:11–20.
Het S, Schoofs D, Rohleder N, Wolf OT. Stress-induced cortisol level elevations are associated with reduced negative affect after stress: indications for a mood-buffering cortisol effect. Psychosom Med. 2012;74:23–32.
Luecken LJ, Appelhans BM. Early parental loss and salivary cortisol in young adulthood: the moderating role of family environment. Dev Psychopathol. 2006;18:295–308.
Ehlert U, Gaab J, Heinrichs M. Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus–pituitary–adrenal axis. Biol Psychol. 2001;57:141–52.
Tuross N, Patrick RL. Effects of propranolol on catecholamine synthesis and uptake in the central nervous system of the rat. J Pharm Exp Ther. 1986;237:739–45.
Andreano JM, Arjomandi H, Cahill L. Menstrual cycle modulation of the relationship between cortisol and long-term memory. Psychoneuroendocrinology. 2008;33:874–82.
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.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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). https://doi.org/10.1038/s41386-020-0726-8