Sex differences in autonomic responses to stress: implications for cardiometabolic physiology

Abstract

Chronic stress is a significant risk factor for negative health outcomes. Furthermore, imbalance of autonomic nervous system control leads to dysregulation of physiological responses to stress and contributes to the pathogenesis of cardiometabolic and psychiatric disorders. However, research on autonomic stress responses has historically focused on males, despite evidence that females are disproportionality affected by stress-related disorders. Accordingly, this mini-review focuses on the influence of biological sex on autonomic responses to stress in humans and rodent models. The reviewed literature points to sex differences in the consequences of chronic stress, including cardiovascular and metabolic disease. We also explore basic rodent studies of sex-specific autonomic responses to stress with a focus on sex hormones and hypothalamic-pituitary-adrenal axis regulation of cardiovascular and metabolic physiology. Ultimately, emerging evidence of sex differences in autonomic-endocrine integration highlights the importance of sex-specific studies to understand and treat cardiometabolic dysfunction.

INTRODUCTION

Chronic stress exposure is increasingly prevalent in modern society. Whether interpersonal, economic/occupational, sociocultural, environmental, or a combination of these, stress is a fundamental part of daily life for many people. Subsequently, chronic stress is a significant contributor to cardiometabolic and psychiatric disorders including the global leading causes of death, cardiovascular disease (1, 2), and years lived with disability, depression (3). Although the detrimental effects of stress are well documented, the majority of physiological studies have been conducted in males. Emerging evidence indicates that females respond to stress differently (4); therefore, this review focuses on the current understanding of how sex impacts stress-related physiological outcomes.

Stress can be operationally defined as a stimulus that signals real or perceived challenges to homeostasis or well-being (5), resulting in both neural and physiological responses (6). Exposure to acute stress initiates a homeostatic response that promotes adaptation (5, 7). However, chronic stress, defined as long-term exposure to real or perceived threats leading to repeated activation of physiological systems, can tax adaptive capacity (8, 9). Although chronic exposure to stressors and subsequent allostatic load have increased in society (10), certain populations are impacted to a greater extent than others. In particular, socioeconomic disadvantage associates with increased perceived stress (11, 12), higher allostatic load (13), flattened diurnal cortisol profiles (14), inflammation (15), changes in DNA methylation (16), and, consequently, increased risk of psychiatric (17), cardiovascular (18, 19), and metabolic disease (20).

Metabolic syndrome is characterized by a set of clinical signs including insulin resistance, hyperlipidemia, abdominal obesity, and hypertension that creates predispositions for type two diabetes mellitus and cardiovascular disease (21). Although the development of metabolic disease is multifactorial, stress is widely recognized as a causative agent (22). Specifically, chronic stress positively correlates with the development of metabolic syndrome in both children (20, 23) and adults (24). Similarly, chronic stress worsens the progression of cardiovascular disease (25).

Cardiometabolic disorders are frequently comorbid with mood disorders (3). In addition, the reciprocal relationship between cardiometabolic and depressive disorders further contributes to years lived with disability (3, 26). Although depressive disorders are also complex and multifactorial, chronic stress commonly exacerbates mood symptoms (27). In addition, depression has inflammatory and immunomodulatory components related to increased cortisol (28, 29). Importantly, mood and cardiometabolic comorbidity disproportionately affect females (30). However, basic physiological investigations into the consequences of chronic stress have only recently taken female subjects into account.

AUTONOMIC AND ENDOCRINE STRESS RESPONSES

The autonomic nervous system (ANS) modulates the physiology of organ systems to maintain homeostasis through the integration of sympathetic norepinephrine and vagal parasympathetic acetylcholine signaling (31). In response to stressors, the ANS prepares the body to respond to real or perceived threats. The prototypical acute stress response is characterized by rapid activation of the sympathetic nervous system to prime the body for action, resulting in a wide range of physiological changes including epinephrine and norepinephrine release, increased heart rate and respiration, glucose mobilization, peripheral vasodilation, and visceral vasoconstriction (32).

The hypothalamic-pituitary-adrenal (HPA) axis aids in homeostatic regulation of stress responses over a longer timeframe through the release of glucocorticoids (cortisol in humans, corticosterone in rats and mice) from the adrenal cortex (9). Broadly, glucocorticoids increase gluconeogenesis and lipolysis, promoting catabolic energy mobilization (5). The HPA axis response is initiated by corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamus. CRH then acts on the anterior pituitary to cause the release of adrenocorticotropic hormone (ACTH), which stimulates synthesis and release of glucocorticoids from the adrenal cortex into systemic circulation. Glucocorticoids then bind mineralocorticoid (MR) and glucocorticoid receptors (GR) to inhibit further release of CRH via negative feedback. Furthermore, HPA axis activity is regulated through multiple mechanisms including descending neural inputs (33), the recruitment and synchronicity of CRH neurons during acute stress (34), and rhythmicity on both ultradian and circadian timescales (35). Importantly, acute autonomic and endocrine stress responses dynamically interact to integrate physiological states and promote adaptation.

In contrast to adaptive acute stress responses, chronic stress produces different physiological outcomes, both autonomically and hormonally. Chronic stress leads to prolonged sympathetic stimulation, vagal withdrawal, and subsequent autonomic imbalance. Dysregulation of sympathetic/parasympathetic balance results in cardiovascular changes including baroreflex blunting (36), reduced heart rate variability (37), decreased blood pressure variability (38), and diminished neurovascular coupling (39). Importantly, chronic stress-induced autonomic imbalance is impacted by hormonal signaling. For example, inhibition of CRH receptors 1 and 2 in the limbic bed nucleus of the stria terminalis increases arterial pressure and impairs baroreflex (40). Chronic stress also leads to prolonged HPA axis activation, which can manifest in adrenal hyperplasia and hypertrophy, suggesting greater cumulative exposure to glucocorticoids and epinephrine (41). Although chronic stress disrupts glucocorticoid rhythmicity, multiple studies have reported differing effects on diurnal cortisol profiles. A flattening of diurnal cortisol curves is common (42); however, a study of chronic stress in adolescents found that those with the highest genetic risk for HPA axis-linked disease, such as mood disorders, had a pattern of lower morning cortisol coupled with a flatter diurnal curve. Those with lower genetic risk had elevated morning cortisol and a steep diurnal curve. Ultimately, these variable outcomes indicate a genetic component to the consequences of chronic stress (43).

GONADAL HORMONES: ESTROGENS AND PROGESTERONE

Historically, rodent stress research has focused largely on male subjects or has not considered the effect of sex on physiological outcomes. Therefore, sex-dependent autonomic regulation during chronic stress is an emerging area for understanding sex differences in disease incidence, as well as potential clinical targets. Although the rate of metabolic syndrome is similar in males and females (44), females are at greater risk for depressive disorders and cardiovascular disease has a higher female prevalence after menopause (45, 46). In addition to cardiovascular disease being the primary cause of death in women (47), women are at twice the risk for developing major depressive disorder (48). Underscoring these disease predilections are a number of uniquely female experiences including pregnancy, parturition, and conditions, like polycystic ovarian syndrome, that affect female reproductive physiology (30, 49).

Although female sex hormones, centrally estrogens and progesterone, are not unique to females, they are cyclically variable due to menstrual or estrous cycling and change with age. Evidence suggests that female-specific responses to stress are cycle phase-dependent with greater HPA axis reactivity in early proestrus, a period characterized by high estrogens and low progesterone (50). The effects of estrogens are primarily mediated by three estrogen receptors (ERs): ERα, ERβ, and g-protein-coupled ER (GPER). Although there are several estrogens that bind ERs, estradiol predominates in cycling females and estrone predominates following reproductive senescence (51). The production of estradiol primarily occurs through the aromatization of testosterone. Progesterone effects are mediated by intracellular and membrane-bound progesterone receptors (PRs) and GABA_A receptors. Importantly, ERs and PRs are found throughout the body (Fig. 1) and have wide-reaching effects on most physiological systems (79–83). Generally, estrogens are thought to convey protective cardiometabolic effects in females (84–91), as well as males (92, 93). Although many of these effects are activational and life-stage dependent, there is also evidence of sex-dependent organizational effects of steroid hormones (94). Sex steroid receptors are also found in select cells throughout the brain and gonadal hormone action in the central nervous system is an ongoing field of study.

Figure 1.

Stress and gonadal hormone receptor expression across neuroendocrine and cardiovascular organs. Neurons in the paraventricular nucleus (PVN) of the hypothalamus initiate both autonomic and hypothalamic-pituitary-adrenal (HPA) axis responses to stress. Corticotropin-releasing hormone (CRH) acts on anterior pituitary corticotropes to cause the release of ACTH and the subsequent synthesis and release of glucocorticoids (cortisol in humans, corticosterone in rats and mice) from the adrenal cortex. Glucocorticoids have systemic action on cardiovascular responses and provide negative feedback on the PVN and anterior pituitary. PVN neurons also synapse in the sympathetic intermediolateral nucleus (IML) and the parasympathetic dorsal motor nucleus of the vagus (DMX). Efferents of the DMX innervate both the carotid body and heart to influence cardiac and baroreflex activity but are generally not found in the systemic vasculature. Efferents of the IML act through sympathetic ganglia to stimulate cardiovascular activity and the release of epinephrine from the adrenal medulla, which acts systemically. In addition, stress and gonadal hormone receptors regulate activity in a tissue-dependent manner. It is important to note that receptor distribution has not been completely characterized and further study is warranted. Thus, the absence of reports on expression does not indicate that receptors are not present. CRH neurons express estrogen receptors β (ERβ), G protein-coupled estrogen receptor (GPER) (52), and androgen receptors (AR) (53), as well as glucocorticoid receptors (GR) (54) and mineralocorticoid receptors (MR) (55). Similarly, the anterior pituitary expresses ERα, ERβ (56), GPER (57), AR (58), GR, and MR (59). The adrenal cortex expresses ERα, ERβ, GPER, and AR (60). The IML is known to express ERα (61) and AR (62). The DMX shows ERα, ERβ (63), GPER (64), and AR (62) expression. Sympathetic ganglia express ERα, ERβ (65), and AR (66). Cardiac tissue (67–69) and systemic vasculature (70–74) express ERα, ERβ, GPER, and AR, as well as GR and MR. The carotid body shows ERβ (75), GPER (76), GR (77), and MR expression (78). While many of the mechanistic interactions are yet to be elucidated, the integration of these systems modulates stress responses in sex-, age-, and tissue-dependent manners that impact the physiological outcomes of chronic stress. Created with BioRender.com.

Importantly, neurons that activate autonomic and endocrine stress responses are regulated by a network of cortical and limbic structures, allowing for emotional-regulatory regions to modulate stress responses (95). Ovarian hormones have widespread effects on the activity of these corticolimbic regions, potentially accounting for sex differences in stress physiology (96, 97). In fact, estradiol administration in ovariectomized female rats mediates chronic stress-induced morphological plasticity (98) and brain-derived neurotrophic factor expression in the prefrontal cortex (99), a region that has sexually divergent modulatory effects on HPA axis, cardiovascular, and glucoregulatory stress responses (100). Interestingly, a study of gonadectomized and intact rats found that chronically stressed ovariectomized females had increased plasma estradiol compared with unstressed controls (101), suggesting that extra-ovarian estradiol synthesis may be recruited by chronic stress. Furthermore, aromatase-dependent ERα signaling in the prefrontal cortex of ovariectomized female rodents prevents neurobehavioral changes following repeated stress (102).

The hippocampus, a key limbic structure that moderates stress responding (103), is also a site of estrogen action. Hippocampal ERα agonism is protective against chronic stress-induced depressive behaviors in female rats (104). Thus, potential protective effects of central nervous system ERα signaling against the negative outcomes associated with chronic stress require further exploration. There is also sexual dimorphism in the hypothalamic rostral anteroventral periventricular nucleus which expresses CRH receptor 1 in female but not male mice (105). These cells also coexpress both ERα and GR, indicating the presence of a sex-specific stress hormone-responsive nucleus in female mice that may contribute to sexually-divergent homeostatic responses (105). In addition, injection of estradiol into the nucleus of the solitary tract or rostral ventrolateral medulla, brainstem preautonomic nuclei, of ovariectomized rats enhances baroreflex sensitivity and reduces arterial pressure (106). Furthermore, in both the paraventricular nucleus and rostral ventrolateral medulla, ER β, but not ERα, contributes to protection against aldosterone/salt-induced hypertension in female rats (107). Thus, ovarian hormones act in multiple brain regions in a receptor-specific manner to modulate cardiovascular physiology.

The sexually dimorphic distribution of gonadal steroid receptors and their activation by circulating estrogens impacts the development of hypertension, likely through sympathoinhibitory effects (108). This is supported by the increase in hypertension seen in postmenopausal women compared with premenopausal women which is, in part, due to a loss of the protective effects of estrogens, centrally estradiol (109). These protective effects are also seen following chronic stress. Chronically stressed cycling female rats maintain vasoactive metabolite profiles, higher NO and lower H₂O₂, and vascular reactivity compared with both chronically stressed ovariectomized female and male rats. Thus, ovarian hormones mitigate the proinflammatory and prooxidant effects of chronic stress that mediate vascular dysfunction (110).

Taken together, sex-specific physiological responses to chronic stress are impacted by the organizational and activational actions of sex steroids. These responses are integrated across neuroendocrine, autonomic, and cardiovascular systems. This places additional importance on determining how these interactions are mediated and how they affect long-term health outcomes in both females and males.

GONADAL HORMONES: TESTOSTERONE

Although testosterone is not unique to males, it plays an important role in male-specific responses to chronic stress. The central effects of androgens are mediated by androgen receptors (AR) by binding either testosterone or dihydrotestosterone. Generally, androgens are protective against the development of metabolic syndrome, while male testosterone deficiency associates with signs of metabolic dysfunction such as insulin resistance (111). Furthermore, hypotestosteronemia in rats, via orchidectomy, leads to a progressive rise in systolic and diastolic blood pressure that is reduced by the administration of exogenous androgens (112). The antihypertensive effects of endogenous testosterone in male rats are mediated by estrogen-independent genomic and nongenomic mechanisms that reduce kidney renin-angiotensin expression and subsequently reduce fluid retention and increase systemic vasodilation (113). In addition, androgen deficiency is thought to increase the risk of hypertension through increased visceral adiposity, which promotes chronic inflammation that contributes to endothelial dysfunction and hypertension. This cardiometabolic susceptibility is seen in both men and postmenopausal women, who have a reduction in adrenal and ovarian androgens (114). Similarly, testosterone prevents the development of depressive-like symptoms. For instance, testosterone treatment following chronic variable stress reduces passive coping behaviors as well as basal corticosterone and adrenal mass (115). However, research on the mechanistic consequences of AR signaling during chronic stress is limited with more work needed to determine the basis for cardiometabolic regulation.

Although causal effects of androgens on autonomic stress regulation are not well understood, chronic stress decreases expression of the cytochrome P450 protein CYP11A1, subsequently reducing testosterone (116). The reduction in testosterone may play a role in male neuroendocrine regulation, including glucocorticoid secretion, as testosterone inhibits HPA axis stress responses in male rats. Specifically, implantation of testosterone in the hypothalamic medial preoptic area reduces ACTH responses to acute stress, an effect that may be mediated through AR or ER due to the presence of aromatase. In addition, elevated testosterone increases GR binding in the medial preoptic area, possibly contributing to negative feedback inhibition of the HPA axis (117). Taken together, reduced testosterone following chronic stress likely factors into HPA axis dysregulation. However, it is unclear how cardiovascular outcomes may be impacted.

SEX DIFFERENCES IN AUTONOMIC INTEGRATION

In addition to the acute actions of gonadal hormones, sex differences in stress responding may also arise from organizational and/or chromosomal effects that lead to variations in autonomic signaling. This is particularly evident in cardiovascular physiology. Although blood pressure and muscle sympathetic nerve activity are directly related in males, these two physiological measures are unrelated in actively cycling young women (118). This is attributed to increased β-adrenergic relative to α-adrenergic activity. However, postmenopausal women show a positive relationship between blood pressure and muscle sympathetic nerve activity observed in males. Furthermore, premenopausal women undergoing an acute stress event such as maximal exercise have cardioprotective effects that originate from lower resting sympathetic tone and a more rapid vagal response compared with age-matched males (119). In addition, women have increased parasympathetic activity in response to acute painful stimuli compared with men (120).

Generally, vagal activity increases heart rate variability and lowers both heart rate and blood pressure. However, this regulation varies across sex, cycle, and life stage. In females, cycle phases characterized by low estrogens are associated with increased basal heart rate and arterial pressure, as well as decreased baroreflex sensitivity (121). Conversely, high estrogenic phases are associated with increased cardiovascular autonomic modulation (121). Postmenopausal women also show decreased vagal responses and heart rate variability (122, 123) that are reversed by estrogen replacement therapy (124). Interestingly, vagal activity influences β-adrenergic signaling in the rat hippocampus (125), indicating that interplay of both central and peripheral neural activation may contribute to the cognitive and vascular protective effects of estrogens. It remains to be determined how these protective effects impact responses to chronic stress; although, recent studies found cycling female rats were resilient to cardiac hypertrophic remodeling (100) and baroreflex impairment following chronic stress (126). In addition, cycling female rodents were resistant to chronic stress-induced conduit artery and resistance arteriole endothelial-dependent vascular dysfunction and inflammation (127). It is important to note that not all studies have found beneficial effects for ovary-intact females exposed to chronic stress. In fact, ovarian factors are necessary for the cardiovascular consequences of witnessing social defeat including increased blood pressure, arrhythmias, and reduced heart rate variability (128).

Autonomic imbalance also impacts immune regulation. Importantly, inflammatory cytokines have been proposed to link cardiovascular and mood outcomes (129). Furthermore, the regulation of interleukin-1β during chronic stress, an inflammatory cytokine elevated in depressive disorders (130) and chronic stress (131), is influenced by β-adrenergic signaling in male, but not female rats (132). Moreover, chronic stress enhances immune reactivity in a sex-dependent manner whereby male rats have excessive innate immune signaling and females show excessive hippocampal immune reactivity (133). In addition, intact, but not OVX, female rats that witnessed social defeat also have increased interleukin-1β in the central amygdala (128). These sex-dependent changes, among others, are indicative of broad differences in HPA axis activity and sympathovagal balance, likely accounting for sex differences in behavior and physiology.

Although a large body of literature indicates that chronic stress sensitizes male HPA axis stress responses to promote glucocorticoid hypersecretion (9), recent studies in female rodents have yielded equivocal results. A study focusing on the effects of chronic stress in adolescent rats found that female rats had enhanced HPA axis stress reactivity in adulthood that was attenuated by a GR modulator (134). However, a similar adolescent chronic stress study found decreased HPA axis activation in adult female rats (135). More recently, a longitudinal rodent study found that, compared with male littermates, chronically-stressed female rats have increased HPA axis responses to both psychological and glycemic stressors, as well as impaired glucose tolerance (4). Furthermore, the enhanced glucocorticoid responses to glycemic stress persisted into late adulthood. Taken together, the data to date suggest that chronic stress results in numerous sex-specific physiological changes linked to endocrine and autonomic dysregulation that impact long-term health and disease susceptibility. Conflicting results across studies indicate that our current understanding of female endocrine regulation during and after chronic stress is incomplete. Additional studies to parse organizational, reproductive cycle, and life-stage effects are likely to uncover significant new information about basic stress biology.

IMPLICATIONS

The study of sex-specific autonomic responses to stress is a developing area with many unanswered questions. Determining the underlying mechanisms that promote sex-specific differences in disease occurrence is essential for improving clinical outcomes and may lead to targeted sex-specific preventative care. In addition, these physiological processes have broad implications for aging pre-, peri-, and postmenopausal women, particularly those with higher allostatic loads due to adverse life events. The higher female incidence of comorbid cardiometabolic and mood disorders, coupled with sexually dimorphic responses to stress, are hypothesized to contribute to increased risk of Alzheimer’s disease, which also disproportionately affects women (136). Thus, understanding how the endocrine and autonomic consequences of chronic stress affect health across the lifespan is highly important for improving cardiovascular, metabolic, emotional, and cognitive outcomes.

GRANTS

This study was supported by NIH grants F30 OD032120 (to C.D.), R01 DK105826 (to R.J.H.), and R01 HL150559 (to B.M.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C.D., R.J.H., and B.M. conceived and designed research; C.D. prepared figures; C.D. drafted manuscript; B.M. edited and revised manuscript; C.D. and B.M. approved final version of manuscript.