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Sex Differences in the HPA Axis

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Abstract

The hypothalamic‐pituitary‐adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper‐ and hypo‐activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons.

The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex‐specific. © 2014 American Physiological Society. Compr Physiol 4:1121‐1155, 2014.

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Figure 1. Figure 1. Schematic diagram of the hypothalamic‐pituitary‐adrenal (HPA) axis. When a stressor is perceived, the paraventricular nucleus of the hypothalamus (PVN) releases corticotropin‐releasing hormone (CRH) and arginine vasopressin (AVP), which is transported to the anterior pituitary, leading to the release of adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH stimulates the adrenal cortex to release glucocorticoids (CORT), which have numerous physiological effects. Glucocorticoids also exert negative feedback at the level of the brain and pituitary to dampen excess activation of the HPA axis.
Figure 2. Figure 2. Female rats release greater levels of corticosterone basally and following a 30 min restraint stress. *, P < 0.001 versus males.
Figure 3. Figure 3. Basal plasma corticosterone levels (ng/mL) measured every 10 min over 24 h (07.00‐19.00 h) under basal conditions for a female rat (A) and a male rat (B). Dark phase (19.00‐05.00 h) is indicated by the hatched bar. Females have a significantly higher number of pulses (P < 0.001) and pulse amplitude (P < 0.001) compared to males. Adapted from () with permission.
Figure 4. Figure 4. Plasma corticosterone levels after infusion of adrenocorticotropic hormone (ACTH; 0 [saline]‐0.10 mg/rat) in male and female rats. Females secrete significantly higher levels of corticosterone than males (P < 0.001). Reprinted from () with permission.
Figure 5. Figure 5. Plasma corticosterone (CORT) responses to acute restraint exposure in sham‐gonadectomized (intact) and gonadectomized (GDX) male rats. CORT was measured under basal conditions or at different intervals following a 30 min restraint stress. **, P < 0.01 versus basal; †, P < 0.01 versus intact counterpart. Adapted from () with permission.
Figure 6. Figure 6. Restraint‐induced Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in sham‐gonadectomized (intact) and gonadectomized (GDX) male rats. (A) Representative bright‐field photomicrographs through the PVN under basal conditions (left panels) and at 30 min of restraint exposure (right panels) in intact and GDX male rats. (B) Quantitative assessment of Fos‐immunoreactivity (Fos‐ir) through the medial parvocellular division of the PVN under basal conditions or at different intervals following a 30 min restraint stress. **, P < 0.01 versus basal; †, P < 0.01 versus intact counterpart. Adapted from () with permission.
Figure 7. Figure 7. Diagram depicting synthetic pathway for androgens from its cholesterol precursor. Arrows indicate the direction in which the reaction proceeds. 3α/3β/17β‐HSD, hydroxysteroid dehydrogenase. Reprinted from () with permission.
Figure 8. Figure 8. In situ hybridization was used to detect paraventricular nucleus of the hypothalamus c‐fos mRNA levels in gonadectomized male rats. Rats were treated subcutaneously (once/day for 4 days) with dihydrotestosterone (DHT) (1 mg/kg) before restraint stress. c‐fos mRNA was measured at 10 and 30 min during stress and during recovery 20 min following the 30 min stress. (A) c‐fos mRNA expression is significantly decreased in stressed DHT‐treated rats compared to controls (P < 0.05). (B) Representative film autoradiograms demonstrating the relative level of hybridization in nonstressed and poststressed rats. 3V, third ventricle. Adapted from () with permission.
Figure 9. Figure 9. Schematic summarizing the organization of cell groups identified as projecting to the paraventricular nucleus of the hypothalamus (PVN) region and displaying androgen receptor (AR) immunoreactivity. The number of dots provides an index of AR containment, where each dot represents a 5% unit of colocalization within a cell group of interest (e.g., 65% in the MPN). Brain regions in italics represent AR‐rich structures providing indirect input to the PVN. AHA, Anterior hypothalamic nucleus; AVPV, Anteroventral periventricular nucleus; BST, Bed nucleus of the stria terminalis; CG, Central gray; HIP, hippocampus; LS, Lateral septum; MeA, Medial amygdala; MPN, Medial preoptic nucleus; NTS, Nucleus of the solitary tract; PAG, Periaqueductal gray; PB, Parabrachial nucleus; PFC, Prefrontal cortex; PoT, Posterior thalamamic complex; RMg, Raphe magnus; VLM, Ventrolateral medulla; VMH, Ventromedial nucleus of the hypothalamus. Reprinted from () with permission.
Figure 10. Figure 10. Fluorescent immunohistochemistry was used to detect tryptophan hydroxylase (green fibers), the rate‐limiting enzyme for serotonin (5‐HT) synthesis, and c‐Fos (red nuclei) induced by a 30 min restraint stress. White outline defines the borders of the paraventricular nucleus of the hypothalamus (PVN). The majority of stress‐activated cells lie within the dorsal medial parvocellular (mpd) division, where there is relatively lower expression of serotonergic fibers. Serotonergic fibers are densest in periventricular (pv) division and the outside of the PVN. pm, posterior magnocellular part; 3V, third ventricle.
Figure 11. Figure 11. Sex differences in corticosterone levels in response to citalopram (15 mg/kg) were masculinized by testosterone. Intact females exhibited greater corticosterone than males after ip injection of vehicle (A) and citalopram (B). *, P < 0.05. Corticosterone was not altered in the ovariectomized plus vehicle group (OVX+V) but was masculinized in the ovariectomized plus testosterone propionate group (OVX+TP). #, P < 0.05, compared with intact and OVX+V females. Citalopram delayed recovery at time 120 in OVX+V females. §, P < 0.05, compared with vehicle. The ip injection occurred immediately after time 0. (C) Analysis of area under the curve (AUC) revealed overall sex difference in corticosterone that was masculinized by TP in response to vehicle or citalopram injections. *, P < 0.05, different from males and OVX+TP females. Citalopram significantly increased overall levels of corticosterone. #, P < 0.05, main effect of drug. (D) The rise of corticosterone from 0 to 30 min in response to vehicle or citalopram injections was greater in intact females than males. *, P < 0.05. Citalopram caused a greater rise than vehicle. #, P < 0.0001. (E) The rate of recovery from 30 to 120 min was higher with citalopram treatment than vehicle. #, P < 0.05. Reprinted from () with permission.


Figure 1. Schematic diagram of the hypothalamic‐pituitary‐adrenal (HPA) axis. When a stressor is perceived, the paraventricular nucleus of the hypothalamus (PVN) releases corticotropin‐releasing hormone (CRH) and arginine vasopressin (AVP), which is transported to the anterior pituitary, leading to the release of adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH stimulates the adrenal cortex to release glucocorticoids (CORT), which have numerous physiological effects. Glucocorticoids also exert negative feedback at the level of the brain and pituitary to dampen excess activation of the HPA axis.


Figure 2. Female rats release greater levels of corticosterone basally and following a 30 min restraint stress. *, P < 0.001 versus males.


Figure 3. Basal plasma corticosterone levels (ng/mL) measured every 10 min over 24 h (07.00‐19.00 h) under basal conditions for a female rat (A) and a male rat (B). Dark phase (19.00‐05.00 h) is indicated by the hatched bar. Females have a significantly higher number of pulses (P < 0.001) and pulse amplitude (P < 0.001) compared to males. Adapted from () with permission.


Figure 4. Plasma corticosterone levels after infusion of adrenocorticotropic hormone (ACTH; 0 [saline]‐0.10 mg/rat) in male and female rats. Females secrete significantly higher levels of corticosterone than males (P < 0.001). Reprinted from () with permission.


Figure 5. Plasma corticosterone (CORT) responses to acute restraint exposure in sham‐gonadectomized (intact) and gonadectomized (GDX) male rats. CORT was measured under basal conditions or at different intervals following a 30 min restraint stress. **, P < 0.01 versus basal; †, P < 0.01 versus intact counterpart. Adapted from () with permission.


Figure 6. Restraint‐induced Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in sham‐gonadectomized (intact) and gonadectomized (GDX) male rats. (A) Representative bright‐field photomicrographs through the PVN under basal conditions (left panels) and at 30 min of restraint exposure (right panels) in intact and GDX male rats. (B) Quantitative assessment of Fos‐immunoreactivity (Fos‐ir) through the medial parvocellular division of the PVN under basal conditions or at different intervals following a 30 min restraint stress. **, P < 0.01 versus basal; †, P < 0.01 versus intact counterpart. Adapted from () with permission.


Figure 7. Diagram depicting synthetic pathway for androgens from its cholesterol precursor. Arrows indicate the direction in which the reaction proceeds. 3α/3β/17β‐HSD, hydroxysteroid dehydrogenase. Reprinted from () with permission.


Figure 8. In situ hybridization was used to detect paraventricular nucleus of the hypothalamus c‐fos mRNA levels in gonadectomized male rats. Rats were treated subcutaneously (once/day for 4 days) with dihydrotestosterone (DHT) (1 mg/kg) before restraint stress. c‐fos mRNA was measured at 10 and 30 min during stress and during recovery 20 min following the 30 min stress. (A) c‐fos mRNA expression is significantly decreased in stressed DHT‐treated rats compared to controls (P < 0.05). (B) Representative film autoradiograms demonstrating the relative level of hybridization in nonstressed and poststressed rats. 3V, third ventricle. Adapted from () with permission.


Figure 9. Schematic summarizing the organization of cell groups identified as projecting to the paraventricular nucleus of the hypothalamus (PVN) region and displaying androgen receptor (AR) immunoreactivity. The number of dots provides an index of AR containment, where each dot represents a 5% unit of colocalization within a cell group of interest (e.g., 65% in the MPN). Brain regions in italics represent AR‐rich structures providing indirect input to the PVN. AHA, Anterior hypothalamic nucleus; AVPV, Anteroventral periventricular nucleus; BST, Bed nucleus of the stria terminalis; CG, Central gray; HIP, hippocampus; LS, Lateral septum; MeA, Medial amygdala; MPN, Medial preoptic nucleus; NTS, Nucleus of the solitary tract; PAG, Periaqueductal gray; PB, Parabrachial nucleus; PFC, Prefrontal cortex; PoT, Posterior thalamamic complex; RMg, Raphe magnus; VLM, Ventrolateral medulla; VMH, Ventromedial nucleus of the hypothalamus. Reprinted from () with permission.


Figure 10. Fluorescent immunohistochemistry was used to detect tryptophan hydroxylase (green fibers), the rate‐limiting enzyme for serotonin (5‐HT) synthesis, and c‐Fos (red nuclei) induced by a 30 min restraint stress. White outline defines the borders of the paraventricular nucleus of the hypothalamus (PVN). The majority of stress‐activated cells lie within the dorsal medial parvocellular (mpd) division, where there is relatively lower expression of serotonergic fibers. Serotonergic fibers are densest in periventricular (pv) division and the outside of the PVN. pm, posterior magnocellular part; 3V, third ventricle.


Figure 11. Sex differences in corticosterone levels in response to citalopram (15 mg/kg) were masculinized by testosterone. Intact females exhibited greater corticosterone than males after ip injection of vehicle (A) and citalopram (B). *, P < 0.05. Corticosterone was not altered in the ovariectomized plus vehicle group (OVX+V) but was masculinized in the ovariectomized plus testosterone propionate group (OVX+TP). #, P < 0.05, compared with intact and OVX+V females. Citalopram delayed recovery at time 120 in OVX+V females. §, P < 0.05, compared with vehicle. The ip injection occurred immediately after time 0. (C) Analysis of area under the curve (AUC) revealed overall sex difference in corticosterone that was masculinized by TP in response to vehicle or citalopram injections. *, P < 0.05, different from males and OVX+TP females. Citalopram significantly increased overall levels of corticosterone. #, P < 0.05, main effect of drug. (D) The rise of corticosterone from 0 to 30 min in response to vehicle or citalopram injections was greater in intact females than males. *, P < 0.05. Citalopram caused a greater rise than vehicle. #, P < 0.0001. (E) The rate of recovery from 30 to 120 min was higher with citalopram treatment than vehicle. #, P < 0.05. Reprinted from () with permission.
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Nirupa Goel, Joanna L. Workman, Tiffany T. Lee, Leyla Innala, Victor Viau. Sex Differences in the HPA Axis. Compr Physiol 2014, 4: 1121-1155. doi: 10.1002/cphy.c130054