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date: 18 October 2019

Neuroendocrine Mechanisms of Psychological Stress: Age and Sex Differences in Adults

Summary and Keywords

There are two main branches of the human stress response. The autonomic nervous system acts rapidly and is often referred to as our fight or flight response. The slow-acting arm of the stress response refers to the hypothalamic-pituitary-adrenal (HPA) axis, which triggers a hormone cascade resulting in the release of various hormones including cortisol. Healthy functioning of the HPA axis is tightly regulated by negative feedback, the endogenous self-regulatory mechanism of the system that terminates cortisol production. Alterations in HPA axis functioning are characterized by both hypo- and hypersecretion of cortisol in response to psychological stress and are typically associated with negative physical health outcomes as well as clinical pathology. What remains poorly understood is how HPA activity changes with age and the pathways through which these changes occur.

In addition to changes associated with the normative aging process, age-related changes in cortisol may also be driven by the cumulative effects of stress experienced across the life span (e.g., traumatic stress); stressors unique to later life (e.g., caring for an ailing loved one); or health problems. Although research examining how the HPA axis might change with age is inconsistent, there appears to be reasonable evidence to suggest that: (1) both stress-induced and diurnal cortisol output may increase with age, potentially beginning with changes in the cortisol awakening response, (2) variability in cortisol production increases with age, (3) diurnal (i.e., daily) cortisol rhythms are preserved in later life, and (4) age-related differences in cortisol may be more distinct in men than in women. However, it remains unknown whether these changes in older adults’ physiology reflect maladaptive functioning of the HPA axis or interact with other health concerns to negatively affect overall psychophysiological health. Further research is needed to disentangle the interplay between aging and HPA axis functioning to better understand what alterations are associated with the normative aging process, when they occur, and how they influence longevity.

Keywords: human, stress, hypothalamic-pituitary-adrenal axis, HPA axis, cortisol, age differences, aging, older adult, life span

Introduction: Psychological Stress in Adulthood

Stress can be broadly construed as a complex psychosocial and psychophysiological experience (Dickerson & Kemeny, 2004). In relevant literature, the umbrella term stress includes daily hassles, subjective or perceived stress, and major life events (Almeida & Wong, 2009; Scott et al., 2015). Altogether, psychological stress may be classified as either acute or chronic in nature, depending on the duration of the event and the subsequent psychophysiological impact (Lupien, McEwen, Gunnar, & Heim, 2009). The natural aging process may alter how stress is experienced psychologically and the concomitant physiological response (Gaffey, Bergeman, Clark, & Wirth, 2016). For example, aging populations are characterized by physical and cognitive health deterioration typical of the normative aging process. These changes may contribute to the experience of daily and acute stressors (e.g., affecting the ability to perform everyday cognitive abilities such as remembering where the car is parked or if a medication has been taken) such that they can become a source of chronic stress over time. The older adult population is also at a significantly greater risk for experiencing more severe psychosocial stressors, such as major life events like loved ones passing away, and unique chronic stressors, such as caregiving for aging partners (Moss, Moss, & Hansson, 2001; Ong, Bergeman, Bisconti, & Wallace, 2006).

Cumulative psychological stress experienced earlier in life shapes the activity of stress-responsive central and peripheral systems during adulthood (Heim & Binder, 2012; Pechtel & Pizzagalli, 2011). Early life stress may accelerate physiological aging processes and increase accompanying risks for psychopathology and disease. Such hypotheses have been discussed in theories related to allostatic load (Glei, Goldman, Chuang, & Weinstein, 2007; McEwen, 1998). Allostatic load refers to the idea that chronic stressful life experiences deleteriously affect physiological functioning. Effects include alterations in the biological systems inherent in the stress response as well as processes central to maintaining homeostasis (i.e., immunity). For example, repeated activation of the hypothalamic-pituitary-adrenal (HPA) axis, a primary and dynamic physiological stress response system (Gaffey & Wirth, 2014), may result in the inability to turn off the sequence of biomediators that help an individual adequately recover from stress (McEwen, 1998; McEwen & Stellar, 1993). Within this theoretical framework, it follows then that older adults who experience multiple major life stressors or long-term (i.e., chronic) challenges may develop an altered (i.e., maladaptive) physiological reaction to stress and place them at a greater risk for negative health outcomes. Thus, a sound grasp of the potential bidirectional effects of stress and aging on HPA axis activity in adults is central to understanding how those interactions promote health or beget disease.

The Hypothalamic-Pituitary-Adrenal Axis

The timing and type of a given stressor determines the magnitude of the resulting physiological stress response. Immediate (e.g., physical or psychological) threats activate the sympathetic nervous system (SNS), a branch of the autonomic nervous system (ANS) more generally referred to as the so-called fight or flight response (Gaffey & Wirth, 2014). As a stressor becomes prolonged, the HPA axis is also stimulated. In contrast to the SNS response, which is initiated within seconds of a stressor, triggering the HPA axis requires longer stress exposure (i.e., minutes) to stimulate a physiological response (Herman et al., 2016). More generally, the HPA axis responds to psychological threats distinguished by novelty, unpredictability, a lack of control (Mason, 1975), and social evaluation (Dickerson & Kemeny, 2004). The Trier Social Stress Test (Kirschbaum, Pirke, & Hellhammer, 1993), a standardized laboratory stressor involving an impromptu speech and mental arithmetic task, is an exemplar of the type of psychological stress that can elicit a robust HPA response.

When an individual encounters a psychological or environmental challenge, excitatory sensory inputs signal the hypothalamus and thereby the HPA axis. Activation of the HPA axis initiates a hormone cascade beginning with the release of corticotrophin releasing hormone (CRH) from the hypothalamus. The release of CRH stimulates the anterior pituitary to secrete adrenocorticotrophic hormone (ACTH). In response to increases in ACTH, the adrenal cortex releases cortisol, the primary glucocorticoid (GC) in humans, into the bloodstream and the brain.

As GC levels rise, the hormones signal the HPA axis to terminate CRH production. Without continued CRH release, the anterior pituitary discontinues the release of ACTH and terminates the production of GCs, which reduces GC levels back to a prestress baseline. This endogenous self-regulating mechanism of the HPA axis is referred to as negative feedback. The rate of one’s negative feedback is determined by an individuals’ sensitivity to GCs, which is influenced by the central (i.e., within the brain) accessibility of glucocorticoid receptors (GR; Wirth & Gaffey, 2013).

Cortisol Indices Used in Research

Cortisol levels are assessed using several different indices to capture fluctuations in secretion of the hormone. Investigators may use multiple time points to calculate area under the curve (AUC), total output, or net change over time (Pruessner, Kirschbaum, Meinlschmid, & Hellhammer, 2003). Researchers have also examined average cortisol levels across multiple samples; difference scores calculated using levels before and after an event or task; diurnal cortisol slope or decline (across the day from waking to evening); the daily peak and nadir; and the cortisol awakening response (CAR; see Ross, Murphy, Adam, Chen, & Miller, 2014; Saxbe, 2008).

Typical and Atypical Functioning of Hypothalamic-Pituitary-Adrenal Axis

More generally, the HPA axis is a key mechanism for managing homeostasis in humans (Nelson, 2005). A healthy HPA system is sensitive to acute and chronic stress. Typical HPA axis activity is also characterized by diurnal variations. That is, HPA hormone secretion patterns are subject to endogenous circadian or ultradian rhythms in the absence of a specific stressor (Otte et al., 2005; Van Cauter, 1990). The HPA system is also intimately linked with other systems that regulate immunological and endocrinological functioning (Maier & Watkins, 1998; Stratakis & Chrousos, 1995; Toufexis, Rivarola, Lara, & Viau, 2014). Consequently, HPA axis activity affects multiple systems throughout the human body.

Levels of cortisol fluctuate naturally throughout the day, with the highest levels in the morning and a natural nadir at night. In a typical adult, there is a reliable 50% to 150% daily increase in cortisol output, which occurs for approximately 30 to 45 minutes after morning awakening (i.e., CAR; Clow, Thorn, Evans, & Hucklebridge, 2004; Fries, Dettenborn, & Kirschbaum, 2009). Although researchers are unclear regarding the CAR’s physiological purpose, it is hypothesized that it may help people attain consciousness, access stored cognitive information, or mobilize energy in preparation for the day ahead (Clow, Hucklebridge, Stalder, Evans, & Thorn, 2010; Fries et al., 2009). The CAR can also become dysregulated as a consequence of extreme acute or chronic stress (e.g., Schlotz, Hellhammer, Schulz, & Stone, 2004; Wust et al., 2000) and such alterations have been linked to serious health risks (e.g., Fries et al., 2009). Thus, the CAR is an important variable for assessing age-related changes in cortisol output.

Because of significant acute or chronic stress, the HPA axis may become dysregulated, leading to long-term, irregular elevations in GCs (Wirth & Gaffey, 2013). Such circumstances can reduce GR sensitivity in the brain and impair the HPA system’s capacity to appropriately self-regulate via negative feedback (Becker, Breedlove, Crews, & McCarthy, 2002; Nelson, 2005). Consequently, individuals may be unable to mount an appropriate neuroendocrinological response to acute stress, which may result in either chronically flattened or elevated levels of cortisol (i.e., hypocortisolism or hypercortisolism), both of which may serve as indicators of altered (i.e., maladaptive) negative feedback functioning.

HPA dysregulation could also present as dysregulated cortisol levels after an individuals’ morning awakening (i.e., CAR; Chida & Steptoe, 2009; Fries, et al., 2009) or a flatter morning-to-evening curve (i.e., diurnal slope; Gunnar & Vazquez, 2001). It is often unclear whether disruptions in negative feedback precede, follow, or coincide with the development of negative health consequences. However, it is evident that the HPA axis must be precisely regulated to maintain optimal neuroendocrinological fitness.

Health Conditions Associated With HPA Axis Dysregulation

Of direct relevance to normative aging, HPA axis dysregulation and altered cortisol levels have been associated with impaired cognition, more rapid cognitive decline, and the advancement of dementia (Aguilera, 2011; Csernansky et al., 2006; Lupien et al., 1999; MacLullich et al., 2005). When examining general adult samples, alterations in HPA axis secretion of cortisol are tied to a variety of physical health diagnoses including sleep disturbances, atherosclerosis, hypertension, heart failure, cardiovascular disease, type 2 diabetes, stroke, poor immunity, faster progression of cancer, and HIV/AIDS, as well as a greater number of hospitalizations (Antoni et al., 2006; Clark et al., 2015; Epel et al., 2004; Go et al., 2013; Gouin, Hantsoo, & Kiecolt-Glaser, 2008; Kivimaki et al., 2006; Krantz & McCeney, 2002; Leserman, 2000; Matthews, Schwartz, Cohen, & Seeman, 2006; Rosmond & Björntorp, 2000; Schoorlemmer, Peeters, Van Schoor, & Lips, 2009; Seeman et al., 2004; Vgontzas & Chrousos, 2002). Similarly, in cohorts of older adults specifically, higher diurnal cortisol is associated with frailty and a higher risk of mortality (Johar et al., 2014; Noordam et al., 2012; Varadhan et al., 2008).

As humans approach the later years of life, normative as well as stress-related changes to typical HPA axis activity are correlated with a greater vulnerability to mental health conditions (Conrad & Bimonte-Nelson, 2010; Murri et al., 2014). Robust evidence associates dysregulated cortisol secretion with many mood, anxiety, and stress-related psychiatric conditions (e.g., Cowen, 2010; De Kloet et al., 2006; Djernes, 2006; Hammen, 2005; Pariante & Lightman, 2008; Slavich & Irwin, 2014; Vreeburg et al., 2010; Yehuda, 2006). For example, a dampened cortisol awakening response (CAR) but elevated diurnal cortisol output was found in older patients with generalized anxiety disorder (Hek et al., 2013). Research has demonstrated that in some older populations, cortisol hypersecretion is rectified by psychotropic treatment (Lenze et al., 2011). In contrast, elderly individuals reporting a history of major depression showed a sustained increase in basal cortisol secretion following treatment (Beluche et al., 2009). These contradictory research findings suggest that cortisol hypersecretion or hyposecretion occurring later in life may be more challenging to address compared to HPA axis alterations in younger adults.

Potential Age Differences in Cortisol

Cortisol levels secreted by the HPA axis may become altered due to (1) mechanisms of normative aging, (2) the influence of stressors earlier in the life span, (3) stressors unique to later life, and (4) health problems (Gaffey et al., 2016). For adults who are healthy, as well as their unhealthy counterparts who have been diagnosed with adverse conditions (i.e., the more normative older adult population), the aging process of the HPA axis may be vulnerable to each of these pathways, resulting in altered negative feedback and cortisol secretion. To examine interactions among aging, stress, and HPA axis activity, researchers have assessed changes in adults’ levels of cortisol in response to acute psychological or cognitive challenges as a proxy for their acute physiological stress responsivity, and measured diurnal cortisol as a proximal indicator of the effects of chronic psychological stress.

Cortisol Responses to Acute Stressors

In addition to physical challenge, acute stress experienced in vivo may consist of a psychological or cognitive challenge. There is an expansive literature examining the influence of acute stress on cortisol, additional indices of HPA activity, and a multitude of other psychophysiological outcomes in young adults (Dickerson & Kemeny, 2004). Disappointingly, few studies have specifically examined age-related changes in acute stress-induced cortisol across a broader range of the population or in middle-aged and older adult cohorts specifically. The paucity of research in this area has yielded inconsistent findings. It suggests that cortisol released in response to acute stress increases with age and more significantly for women (Otte et al., 2005), decreases (Ice, 2005), or is unchanged compared to observations in younger individuals (Lai, 2014). In one study, a cognitive challenge produced higher cortisol in older adults compared with younger adults (Gotthardt et al., 1995). In response to the Trier Social Stress Test, elderly men produced a greater cortisol response as compared with younger men (Kudielka, Buske-Kirschbaum, Hellhammer, & Kirschbaum, 2004). Using a stress test battery, older women exhibited greater total cortisol output compared to their younger female counterparts (Aguilera, 2011). Other investigators did not find significantly higher cortisol responses to psychosocial stress based on age (Kudielka, Schmidt-Reinwald, Hellhammer, & Kirschbaum, 1999; Nicolson, Storms, Ponds, & Sulon, 1997; Rohleder, Kudielka, Hellhammer, Wolf, & Kirschbaum, 2002).

Drawing conclusions about acute stress and cortisol is complicated by the moderating role of biological sex in psychophysiological responses. Compared to young adult women, young men often demonstrate a more robust cortisol response (Kudielka & Kirschbaum, 2005), warranting further study of age-by-sex interactions in predicting acute-induced cortisol. Extant work suggests that acute psychological stress may stimulate higher cortisol and a dampened negative feedback response to acute stress and recovery to prestress baselines is effectively blunted with advancing age (Gotthardt et al., 1995; Kudielka et al., 2004; Neupert et al., 2006; Otte et al., 2005; Seeman & Robbins, 1994; Wright & Steptoe, 2005).

Cortisol Responses to Chronic Stressors

Diurnal cortisol is a valuable index of the lasting physiological impact of repeated acute stressors or more pervasive, chronic stressors. When assessing diurnal cortisol, due to the various influences on HPA hormones it is recommended to sample cortisol levels over at least three days to gain a reliable composite of hormonal activity (Kraemer et al., 2006). Recent research examining diurnal rhythms in aging populations suggests that total diurnal cortisol output increases with age (Karlamangla, Friedman, Seeman, Stawksi, & Almeida, 2013; Nater, Hoppmann, & Scott, 2013), potentially beginning with the CAR (Almeida, Piazza, & Stawski, 2009). The diurnal rhythm of cortisol also appears to be preserved in older age (Van Cauter, Leproult, & Kupfer, 1996). Finally, increased age has been associated with a flatter diurnal cortisol slope, which may arise from changes to morning or evening levels (Adam, Hawkley, Kudielka, & Cacioppo, 2006; Dmitrieva, Almeida, Dmitrieva, Loken, & Pieper, 2013; Karlamangla et al., 2013; Nater et al., 2013). In aggregate, aging appears to correspond with greater levels of diurnal cortisol, which are possibly due to normal aging and the exposure to chronic stressors, although it remains uncertain which aspect of the diurnal cycle changes first.

Additionally, comparable to observed HPA reactivity to acute stressors, it is likely that sex differences play a key role in relation to aging and cortisol secretion (Laughlin & Barrett-Connor, 2000; Seeman, Singer, & Charpentier, 1995). With increasing age, men might exhibit a greater CAR, peak, nadir, and overall output as well as a flatter diurnal slope (Adam et al., 2006; Almeida et al., 2009; Dmitrieva et al., 2013; Karlamangla et al., 2013). A sex difference in cumulative lifetime stress or experiencing different types of psychosocial stress are two of many potential explanations for greater diurnal cortisol observed in older men compared to women. Alternate explanatory mechanisms underlying age differences in HPA activity include age-related differences in other hormonal systems, such as the hypothalamic-pituitary-gonadal (HPG) axis (Wirth & Gaffey, 2013). The HPG system is responsible for producing estrogen and testosterone, hormones that decrease appreciably with age.

Mechanisms of Aging and Glucocorticoid Sensitivity

Age-related changes in the HPA axis may include greater stress-induced and diurnal cortisol as well as a flatter diurnal cortisol rhythm (Gaffey et al., 2016). A variety of neuroendocrine mechanisms are vulnerable to stress, aging, and pharmacological treatments, and therefore may be involved in age-related differences in cortisol. One potential explanation pertains to variations in GC sensitivity over time (Kudielka et al., 2009). With repeated activation and occupation, GRs become less capable of reducing the typical negative feedback response (Pariante, Thomas, Lovestone, Makoff, & Kerwin, 2004; Rohleder, Wolf, & Kirschbaum, 2003). Individuals with reduced GC sensitivity may show alterations in the integrated biological mechanisms regulating diurnal GC release (Chahal & Drake, 2007). Chronic activation of the HPA axis may also blunt GR sensitivity throughout central and peripheral tissues, as well as lead to a reduced number of GRs across the body, and each effect could alter GC sensitivity (Ferrari et al., 1995). In turn, lower GC sensitivity would effectively prevent the HPA axis from exerting negative feedback in a timely manner, leading to greater cortisol levels and prolonging the physiological response to stress (Hibberd, Yau, & Seckl, 2000; Sapolsky, Krey, & McEwen, 1986).

HPA dysregulation arising from age-induced decreases in GC sensitivity may result in greater diurnal cortisol, higher stress-induced cortisol levels, and a longer latency before HPA activation is terminated and the system returns to homeostasis (Gaffey et al., 2016). When interpreting these findings it is notable that cortisol secreted in response to an acute stressor appears to correlate with diurnal cortisol output in older adults (Kidd, Carvalho, & Steptoe, 2014). During the aging process, higher diurnal cortisol may arise from the same mechanisms as changes in stress-induced cortisol. As diurnal and stress-induced cortisol appear to be correlated in older adults, dysregulation in one domain could affect cortisol levels in another. Depending on the population, there may also be subtypes of individuals who exhibit different age-cortisol associations. As observed in animal models, one group of adults could demonstrate significant changes in cortisol levels in response to acute stressors as well as diurnally, while other adults might show only minimal or moderate changes (Aguilera, 2011).

Conclusions and Future Directions

Across the life span, cortisol levels appear to increase, although the diurnal curve becomes depressed. Such changes are likely contingent on the types of stressors endured earlier in life as well as an individual’s biological sex (Gaffey et al., 2016). The complex interplay between stress, aging, and HPA axis activity calls for more elegant scientific inquiries. The intricacies of this system as well as the number of factors that affect HPA functioning substantiate the need to examine multiple HPA axis hormones within single studies and to assess not only cohort differences but changes in those systems across time. Longitudinal studies assessing intra- and interindividual changes as well as cohort differences are required to obtain a more complete understanding of the interactions between adults’ psychological stress, age, and cortisol as an index of HPA axis activity. This research is particularly challenging due to the expense, but will dramatically improve existing knowledge of the normative changes in the HPA system compared to those accelerated by early life adversity, exposure to cumulative acute or chronic stressors, or disease processes. Conducting such investigations will help elucidate bidirectional signatures of stress and developmental changes in human health across multiple neuroendocrine systems.

Acknowledgments

The authors would like to thank research assistants from the Notre Dame Emotion and Stress Physiology Laboratory for assistance with the literature search and Michelle Wirth for her support of this manuscript.

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