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Review
. 2019 Jan;44(1):45-58.
doi: 10.1038/s41386-018-0167-9. Epub 2018 Aug 1.

Sex differences in the hypothalamic-pituitary-adrenal axis' response to stress: an important role for gonadal hormones

Ashley L Heck  1 , Robert J Handa  2
Affiliations
Review

Sex differences in the hypothalamic-pituitary-adrenal axis' response to stress: an important role for gonadal hormones

Ashley L Heck et al. Neuropsychopharmacology. 2019 Jan.

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine network that controls hormonal responses to internal and external challenges in an organism's environment, exhibits strikingly sex-biased activity. In adult female rodents, acute HPA function following a stressor is markedly greater than it is in males, and this difference has largely been attributed to modulation by the gonadal hormones testosterone and estradiol. These gonadal hormones are produced by the hypothalamic-pituitary-gonadal (HPG) axis and have been shown to determine sex differences in adult HPA function after acute stress via their activational and organizational effects. Although these actions of gonadal hormones are well supported, the possibility that sex chromosomes similarly influence HPA activity is unexplored. Moreover, questions remain regarding sex differences in the activity of the HPA axis following chronic stress and the underlying contributions of gonadal hormones and sex chromosomes. The present review examines what is currently known about sex differences in the neuroendocrine response to stress, as well as outstanding questions regarding this sex bias. Although it primarily focuses on the rodent literature, a brief discussion of sex differences in the human HPA axis is also included.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Stress-related neuronal inputs to the PVN are candidates for gonadal hormone influence on the HPA activity. A diagrammatic representation of the major limbic and brainstem structures that send projections to the PVN to either enhance or inhibit the activity of the HPA axis in response to stressors is shown. Projections either directly contact PVN neurosecretory neurons or are indirect in nature and first synapse in the peri-PVN or limbic relay nuclei, such as the BNST. Excitatory and inhibitory projections are indicated by blue plus and red minus signs, respectively. Because their limbic and brainstem origins express androgen and/or estrogen receptors, these projections are potential targets for gonadal hormone modulation of HPA activity. PVN paraventricular nucleus, PFC prefrontal cortex, LS lateral septum, BNST bed nucleus of the stria terminalis, MPOA medial preoptic area, AMY amygdala, LC locus coeruleus, NTS nucleus of the solitary tract, Raphe represents both dorsal and medial raphe nuclei
Fig. 2
Fig. 2
Organizational actions of gonadal hormones program lasting changes in the adult male HPA axis response to stress. Testosterone surges that occur during the perinatal period and puberty play important roles in masculinizing the HPA axis response to stress in adult male rodents. During the perinatal period, testosterone, largely via its conversion to estradiol by the aromatase enzyme, is involved in establishing a blueprint for a male typical pattern of HPA axis activity in adulthood. Pubertal testosterone then acts on this blueprint to complete the development of the masculinized HPA axis. Thus, in adulthood, males have decreased HPA axis responses to acute stressors characterized by decreased PVN neuronal activation and gene expression, decreased pituitary expression of POMC, and decreased ACTH and CORT responses to acute stressors. Adult males also have enhanced negative feedback resulting from their relatively reduced CBG levels, their increased PVN and pituitary GR gene expression, and their increased neuronal activation in limbic regions that inhibit the HPA axis. Organizational effects of testosterone, therefore, are important contributors to sex differences in the adult HPA axis in which females have relatively enhanced activity. Triangles indicate neuronal activation
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