The HPA (hypothalamic–pituitary–adrenal) Axis

As widely reviewed, the HPA axis is a tightly regulated system that represents one of the body’s mechanisms for responding to acute and chronic stress. In response to physiological or psychological stressors, the HPA axis is activated, resulting in secretion of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates the anterior pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then stimulates release of cortisol from the adrenal gland, resulting in a cascade of physiological events. Once the stressor has resolved, the response is terminated through a negative feedback loop, in which cortisol suppresses further release of ACTH and CRH.

What is Cortisol?

Overview

The glucocorticoid hormone cortisol is a primary product of the hypothalamic-pituitary adrenal (HPA) axis, a key biological stress response system. Cortisol is one of the most frequently employed biomarkers in psychobiological research for several reasons.

1. Cortisol levels are responsive to social and psychological stress. Cortisol levels respond to both acute stress (e.g., acute loneliness or negative social evaluation) and chronic stress (e.g., the stress of poverty or ongoing family conflict).

2. The development and adult functioning of the HPA axis is profoundly influenced by prior developmental experience.

3. Cortisol has pervasive effects throughout the body and brain, and is thought to play important roles in daily cognitive and behavioural functioning.

4. Cortisol has also been implicated in the aetiology of a wide range of mental and physical health outcomes.

As a result, researchers have suggested that stress-related alterations in cortisol regulation may play a role in mediating associations between stress exposure and later developmental and health outcomes, including both the onset and progression of mental and physical health disorders.

Cortisol and Stress

Past research on cortisol and health has focused on cortisol reactivity to acute stress as well as variations in average basal cortisol levels. More recently, researchers have appreciated the importance of circadian variability in cortisol levels, by examining influences on, and consequences of, individual differences in the diurnal (daytime) cortisol rhythm.

A recent meta-analysis, Diurnal Cortisol Slopes and Health 4 examined associations between one aspect of the diurnal cortisol rhythm – the diurnal cortisol slope (DCS) - and mental and physical health outcomes.

Diurnal Cortisol Rhythms: Description and Background Research

Cortisol levels typically follow a strong diurnal rhythm: levels are high on waking, surge an average of 50-60% in the 30-40 minutes after waking, drop rapidly in subsequent few hours after the awakening surge and then drop more slowly until reaching a nadir around bedtime. Variation in cortisol levels as a function of time of day is substantial. In one study, time of day accounted for 72% of the variance in salivary cortisol levels. Early research often considered this time-of-day variation to be “nuisance” variation. Over the past 15 years, however, individual differences in the diurnal cortisol rhythm have emerged as a construct of interest.

Researchers have examined the genetic, developmental, and psychosocial determinants of individual differences in the diurnal cortisol rhythm, as well as the potential health consequences of variation in the diurnal cortisol rhythm. The diurnal cortisol rhythm has been divided into several key components which provide complementary information. Most often examined are: the average level of cortisol across the day (daily average cortisol or DAC); the size of the post-awakening surge, called the cortisol awakening response (CAR); and the diurnal cortisol slope (DCS), the degree of change in cortisol from morning to evening over the waking day.

Flat cortisol levels are bad.

An accumulating body of research focusing on the DCS suggests that it is sensitive to emotional and psychosocial stress and related to health outcomes, with both adverse experience and worse health being associated with a flatter DCS across the waking day. It has therefore been proposed that a flattened DCS may be one mechanism by which stress influences negative health outcomes.

For example, prior studies have found associations between flatter cortisol rhythms and depression, fatigue, cardiovascular disease, and mortality among both breast cancer patients and in community samples

The physiological role of cortisol

Cortisol has important regulatory effects throughout the body and brain, impacting arousal, energy and metabolic processes, immune and inflammatory system functioning, and mood and sexual behaviour. Cortisol’s diurnal variation may be an important element of its regulatory actions; indeed, cortisol is one pathway by which central circadian rhythms are signalled to multiple peripheral biological systems. We argue here that disruption of cortisol’s circadian pattern and signalling may affect the functioning of a diverse set of central and peripheral systems, with these effects cascading over time to contribute to a wide variety of negative health outcomes.

Why is cortisol high in the morning – the cortisol awakening response (CAR) effect?

First, we observed that the CAR is only mounted in the morning following the individual getting out of bed and starting the daily routine. Waking up the same individuals in the middle of the night, no CAR occurred. Consistently, it was described that there was no CAR after a short nap (duration 1–2 h) in the early evening hours. We interpret these results such that the CAR only emerges when the organism is confronted with a series of upcoming demands as is the case after awakening in the morning, but not after awakening during the night or in the early evening. Second, an increased CAR was observed in subjects facing elevated burden, again, supporting the hypothesis on the special importance of daily demands for the cortisol secretion after awakening. For example, an increased CAR was described for workdays in comparison to work free weekend days or in subjects reporting chronic stress and worrying, work overload, social stress and lack of social recognition, or increased stress early in the day. Whereas these studies do not clearly disentangle whether alterations of the CAR are a consequence of chronic stressor occur in anticipation of upcoming demands.

In a study, participants of a competitive ballroom dance tournament showed an increased CAR on the day of the competition, whereas the CAR on a regular, non-competition day was within the normal range. These results clearly demonstrate a modulation of the CAR in dependence of demands of the upcoming day.

Third, the assumption of an adaptation of the CAR depending on daily burden is supported by analyses applying structural equation models to disentangle state and trait components of the CAR. These analyses revealed that the area under the curve for the CAR on a single day is determined to a great extent by situational factors (occasion specificity between 40% and 63%) and to a lesser extent by trait factors. This supports the assumption on the situation-dependent adaptation of the CAR depending on daily hassles and stress load.

Cortisol’s effect on immunity

The central and peripheral effects of cortisol during stress, predominantly mediated via its binding to glucocorticoid receptors (GR), include immunosuppression, increased energy metabolism, and negative feedback inhibition of the HPA axis. How strongly GRs respond to available cortisol is determined by a complex process, but the net activity of GRs can be measured in several ways, e.g., by investigating effects of synthetic forms of cortisol such as dexamethasone on salivary cortisol levels or immune activation.

The immune system is the body’s defence system against outside pathogens. Proinflammatory cytokines are signalling molecules with an important role in orchestrating the immune response. Upon immune system activation, cytokines are released by immune cells and various peripheral organs; the HPA axis is activated by the pro-inflammatory cytokines. In turn, cortisol released upon HPA axis activation, regulates immune system function, e.g., by inhibiting immune cell proliferation and pro-inflammatory cytokine production.

Chronic psychological stress is a state of mental or emotional strain where an individual perceives that environmental demands tax or exceed his/her adaptive capacity. Stress can be measured as the interpretation and perception of stressors or the actual exposure to events assumed to be stressful. To this point, most of the work on stress and incident diabetes has been concentrated on work-related stress, and the results have been mixed, with reports of both positive and negative associations, depending on sex, length of follow-up, diabetes ascertainment method, and stress measurement instrument.

In 2008, a meta-analysis attempted to examine the association of general chronic psychological stress with diabetes risk but was unable to determine an etiological association because of a lack of published longitudinal cohorts. Since that time, six prospective longitudinal studies with follow-up durations ranging from 10 to 35 years have been published,30–32 using different methods to assess stress and revealing divergent findings. Two of these studies found a positive association in women only; three studies found a positive association in men but not in women; one study of only men showed a positive association at 35 years; and one study found a positive association in prediabetic men and women. Another study of men and women revealed a hazard ratio of 1.33 for incident diabetes at 18 years for those with chronic psychological stress versus none (adjusted for age, sex, education level, and household income), but when further adjusted for level of energy, health status, health problems, and activity level, the results were not significant. Among African Americans in the Jackson Heart Study, higher global perceived stress scores (GPSSs) were weakly associated with a higher prevalence of diabetes in women, and higher GPSSs and major life events scores were cross-sectionally associated with obesity in men and women.

Collectively, these studies support a positive association between chronic psychological stress and incident diabetes, but the link is difficult to assess owing to the aforementioned differences in study design and methods. Moreover, there remains a lack of published studies assessing the association of chronic psychological stress with incident diabetes specifically in U.S. racial/ethnic minorities, who have a higher prevalence of diabetes and associated complications.

Cortisol and Stroke

A comprehensive study demonstrated a positive correlation between Blood Pressure (BP) and the selected biological marker of stress, salivary cortisol. How reliable is this biological marker as an indicator of stress? Salivary cortisol was chosen as a biological index of stress since the procedure for its measurement is non-invasive and to date a widely accepted and frequently employed method in psychoneuroendocrinology.

Acute stress elicits a cascade of neuroendocrinological events, including secretion of noradrenaline and adrenaline, together with stimulation of the hypothalamic-pituitary-adrenal axis with the result of increased cortisol secretion. Measurement of cortisol levels appears to produce the most reliable biological index of stress since measurement of catecholamines presents a methodological difficulty in a clinical setting and the blood level of glucose may merely represent the glycogenic effect of adrenaline in interaction with cortisol during acute stress. Normally, cortisol levels in blood and saliva exhibit a circadian rhythm with highest levels in the morning, associated with sympatho-adrenergic arousal (stress), and lowest levels in the evening, which may indicate low stress activity.

The circadian rhythm of cortisol may be altered by episodic spikes, which are believed to reflect the individual responses to different physical and psychological stress situations. Abnormalities in various hormonal systems, particularly in the hypothalamic-pituitary-adrenal axis with increased activity, are described after early stroke. A high level of cortisol is found in patients with acute stroke compared to age- and sex-matched healthy normal controls.

About 70% of patients in this study had high and/or abnormal cortisol levels, and these patients had a statistically significantly higher SBP than patients with normal cortisol levels. This finding was consistent in the correlation and multiple regression analyses of BP and cortisol.

The positive correlations between BP and salivary cortisol support the hypothesis that stress is one of the contributing factors for high BP in acute stroke.

Cortisol and Obesity

Over the past decades, the number of people with obesity has increased dramatically worldwide. In particular, abdominal obesity is often complicated by metabolic disturbances such as insulin resistance, dyslipidemia, and hypertension, collectively grouped into the term metabolic syndrome (MetS).

MetS ultimately leads to cardiovascular disease (CVD), the leading cause of death worldwide (World Health Organization, 2012). An imbalance between energy (food) intake and energy expenditure is currently regarded as the major cause of obesity, with multiple contributing environmental and genetic factors. However, evidence is now mounting that cortisol is a key player in this pandemic.

In pathological conditions such as Cushing’s disease or use of high doses of exogenous glucocorticoids, increased glucocorticoid exposure can cause all components of MetS and ultimately CVD. It is known that glucocorticoids can

(1) increase appetite with a preference for energy-dense food (“comfort food”),

(2) cause a redistribution of white adipose tissue to the abdominal region, and

(3) suppress the activity of brown adipose tissue, resulting in abdominal obesity and its adverse metabolic sequelae.

Interestingly, coinciding with the rise in obesity, MetS, and CVD, the intake of food with a high glycemic index and levels of stress have increased, while the average hours of sleep has decreased. These are all factors known to induce an increase in daily cortisol production. So, from this perspective, it could be hypothesized that a continuous loop may exist between obesity, an unhealthy lifestyle, and increased cortisol, which maintains or worsens obesity and may counteract weight loss.

 

Higher Waist to Hip Ratios = Higher Cortisol Secretion

Excessive central fat puts one at greater risk of disease. In animal studies, stress-induced cortisol secretion has been shown to increase central fat. The objective of an older study was to assess whether women with central fat distribution (as indicated by a high waist-to-hip ratio ), across a range of body mass indexes, display consistently heightened cortisol reactivity to repeated laboratory stressors.

Fifty-nine healthy premenopausal women, 30 with a high WHR and 29 with a low WHR, were exposed to consecutive laboratory sessions over 4 days (three stress sessions and one rest session). During these sessions, cortisol and psychological responses were assessed.

Women with a high WHR evaluated the laboratory challenges as more threatening, performed more poorly on them, and reported more chronic stress. These women secreted significantly more cortisol during the first stress session than women with a low WHR. Furthermore, lean women with a high WHR lacked habituation to stress in that they continued to secrete significantly more cortisol in response to now familiar challenges (days 2 and 3) than lean women with a low WHR.

The researchers found that central fat distribution is related to greater psychological vulnerability to stress and cortisol reactivity. This may be especially true among lean women, who did not habituate to repeated stress. Stress-induced cortisol secretion may contribute to central fat and demonstrate a link between psychological stress and risk for disease.

11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2 in fat cells

Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features of the metabolic syndrome. Researches compared 11beta-HSD1 gene expression in different fat depots (visceral, subcutaneous abdominal, and subcutaneous gluteal) in lean and obese men and women.

A cross-sectional study design was used for healthy patients undergoing minor abdominal surgery (lean men, 10), minor gynecological surgery (lean woman, 10), or gastric banding operations (obese men, 10; and obese women, 10). Gene expressions of 11beta-HSD1 in adipose tissue samples were determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR).

Lean women had lower 11beta-HSD1 gene expression in subcutaneous adipose tissue compared with men (62% lower, p < 0.01), whereas no significant difference was found between obese men and women.

11Beta-HSD1 mRNA in human adipose tissue was higher in obese subjects compared with lean subjects in both women and men and in both subcutaneous and visceral adipose tissue. No difference in mRNA expression of 11beta-HSD1 between visceral and subcutaneous adipose tissue or between subcutaneous adipose tissue from different depots was found.

The bottom line is that 11Beta-HSD1 in adipose tissue is increased in obesity in both women and men, and may contribute to the associated metabolic syndrome. As 11beta-HSD1 expression in lean women was found to be significantly lower than in lean males, the up-regulation associated with obesity may be relatively more devastating in women than in men, and may help explain the higher relative risk of cardiovascular disease in women suffering from the metabolic syndrome.

Hair Cortisol as an Innovative Parameter of Long-Term Cortisol Exposure

In the past decade, a novel, noninvasive parameter to measure cortisol using scalp hair has been developed, providing the unique opportunity to measure long-term cortisol levels (reflecting mean levels of several months, as hair grows an average of 1 cm per month). In recent years, it has been shown that hair cortisol is an excellent proxy to measure average systemic cortisol levels, thereby overcoming the limitations of measuring highly fluctuating cortisol levels in serum, saliva, or urine. These advantages now enable studying cortisol levels over time in large cohorts.

High Cortisol = High Fat Levels

Recent case-control studies have shown that, on average, hair cortisol levels are increased in people with obesity compared to normal weight individuals. A cross-sectional study that showed in a large, population-based sample of 2,527 middle-aged and elderly men and women that hair cortisol levels were positively associated with body weight, body mass index, and waist circumference and were increased in persons with (abdominal) obesity.

Interestingly, they also showed that long-term cortisol exposure was associated with more persistent obesity over time. This supports the notion that elevated cortisol is a factor in the maintenance of obesity.

Another recent study in a large cohort of 3,019 children showed that even at the age of 6 years, the highest hair cortisol concentrations were associated with an almost 10-fold increased risk of obesity.

Also in this population-based sample, hair cortisol concentrations strongly correlated with abdominal fat mass, one of the typical signs of cortisol excess.

Women and Cortisol – Oestrogen Connection

Women have a higher percentage of body fat than men, and there is a gender-specific difference in fat distribution: Females tend to accumulate fat around the hips, buttocks, and thighs while men have a larger intra-abdominal (visceral) fat mass. After menopause, there is a redistribution of fat depots, and post-menopausal women develop increased amounts of visceral fat.

The risk of developing obesity-related diseases is significantly lower in pre-menopausal women compared to men, a difference that is abolished after menopause, suggesting that the female sex steroid estrogen influences adipogenesis and adipose metabolism. Experimentally, estrogen increases the size and number of subcutaneous adipocytes and reduces lipolysis.

Post-menopausal women also develop a more atherogenic lipid pattern and decreased levels of the prothrombotic protein plasminogen activator inhibitor-1, which attenuates fibrinolysis. Pathologically increased circulating cortisol concentration is associated with dysmetabolic features e.g., central obesity, elevated blood pressure, insulin resistance, and dyslipidemia. In "simple obesity," glucocorticoid production is elevated. Peak levels of circulating cortisol are however low or normal, possibly because of increased clearance and/or tissue-specific changes in cortisol production.

In addition to the adrenal production of cortisol, cortisol is also generated in adipose tissue by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inactive cortisone to active cortisol. The enzyme activity in subcutaneous fat increases with increasing body weight. Estrogen seems to have a tissue-specific influence on 11betaHSD1 enzyme activity, attenuating it in liver, kidney, and testis but upregulating 11betaHSD1 mRNA expression in preadipocytes from women.

This is pathway demonstrated above shows that there is a potential for a positive feed-forward cycle for women.  An excess oestrogen level drives 11BHSD1, which increases cortisol, which in turn upregulates aromatase which further drives oestrogen levels.

Low Cortisol – The PTSD Example

A classic example of lowered cortisol is Post Traumatic Stress Disorder (PTSD). After a traumatic event, individuals show a cascade of stress responses that can lead to development of posttraumatic stress disorder (PTSD). In the DSM-5, PTSD is now categorized as a trauma- and stressor-related disorder, characterized by intrusive symptoms, active avoidance, disturbed mood and cognition, and alterations in arousal and reactivity.

Fitting with this complexity and variability in findings, researchers found that age, sex, time since trauma, developmental timing of trauma, and comorbid depression influenced basal cortisol output and Glucocorticoid Receptor (GR) function. Additionally, differences in study design, participants’ health behaviours and substance use may partially explain this variability.

GR gene single nucleotide polymorphisms

There is also increasing evidence for biologically distinct PTSD subtypes with regard to GR function in association with common single nucleotide polymorphisms (SNPs) in genes associated with GR function. Several candidate-gene studies have reported associations between SNPs influencing GR function, measures of GR function, and PTSD, either directly or in interaction with childhood trauma. Lastly, several studies indicate a direct dose response relationship between HPA axis function and increasing trauma load, which is interesting in light of a similar dose-response relationship observed between increasing trauma load and PTSD risk.

PTSD may be driven by inflammation

A recent meta-analysis found increased levels of several pro-inflammatory cytokines in PTSD. Additionally, a systematic review reported increased CRP levels in PTSD. Stimulated proinflammatory cytokine production has been found to be increased in female and mixed-gender samples, but not male samples with PTSD, compared to healthy traumatized and non-traumatized controls. Furthermore, several hypothesis-driven and hypothesis-free studies observed dysregulation in other upstream mediators of pro-inflammatory cytokine production, consistent with an activated immune system in PTSD.

Long term risks for low cortisol/elevated inflammation

As for cortisol and GR function, clear variability in immune system functioning is present among studies and participants. Important factors potentially explaining this variability include health behaviours and substance use, which may in turn also partially mediate the association between PTSD and inflammation.

Furthermore, regarding biologically distinct subtypes in PTSD, a recent study observed that increased CRP levels in PTSD were associated with the presence of a SNP in the CRP gene. As individuals with PTSD are at increased risk for serious medical conditions, including cardiovascular disease, rheumatoid arthritis, asthma, and dementia (thought to reflect early senescence), the potential role of low-grade inflammation in the risk for these comorbidities needs to be investigated further.

The take home message

Without cortisol, you die. Too much cortisol will kill you also, just more slowly. You will gain fat, become depressed, forgetful and have your immune system depleted. If you are cortisol depleted, you will feel pretty crappy having aches and pains all over. Cortisol must be balanced. There is no other way of putting it.

 

References:

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Curr Opin Psychol. 2017 Apr;14:132-137. Neuroendocrine and neuroimmune markers in PTSD: pre-, peri- and post-trauma glucocorticoid and inflammatory dysregulation. Olff M1, van Zuiden M2.

Curr Opin Psychol. 2017 Apr;14:132-137. Neuroendocrine and neuroimmune markers in PTSD: pre-, peri- and post-trauma glucocorticoid and inflammatory dysregulation. Olff M1, van Zuiden M2.

Ann N Y Acad Sci. 2017 Mar;1391(1):20-34. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Joseph JJ1, Golden SH1.

Psychoneuroendocrinology. 2017 Sep;83:25-41. Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis. Adam EK1, Quinn ME2, Tavernier R3, McQuillan MT4, Dahlke KA5, Gilbert KE6.

Psychoneuroendocrinology. 2017 Sep;83:25-41. Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis. Adam EK1, Quinn ME2, Tavernier R3, McQuillan MT4, Dahlke KA5, Gilbert KE6.

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Curr Opin Psychol. 2017 Apr;14:132-137. Neuroendocrine and neuroimmune markers in PTSD: pre-, peri- and post-trauma glucocorticoid and inflammatory dysregulation. Olff M1, van Zuiden M2.

Ann N Y Acad Sci. 2017 Mar;1391(1):20-34. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Joseph JJ1, Golden SH1.