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The Role of Food Supplements Ingredients in Cortisol Regulation

Cortisol, the body's primary stress hormone, plays a critical role in managing stress and maintaining homeostasis. Chronic stress and dysregulation of the hypothalamus-pituitary-adrenal axis can lead to health issues like inflammation and metabolic dysfunction. Ingredients like adaptogens, omega-3 fatty acids, and hydrolyzed casein in food supplements may help modulate cortisol levels and improve overall stress resilience.

AUTHOR: Daria Šurić, Mpharm, univ.spec.pharm.

Though widely known as the body’s stress hormone, Cortisol affects different bodily functions. It is the main glucocorticoid hormone released from the zona fasciculata layer of the adrenal cortex. The hypothalamus-pituitary-adrenal axis (HPA) regulates both the production and secretion of cortisol. Loss of regulation can lead to cortisol excess disorders, such as Cushing syndrome, or cortical insufficiency, such as Addison disease1,2.

Cortisol is crucial in the body’s stress response, regulating various physiological processes. Activating the HPA axis in response to stressful stimuli leads to increased cortisol secretion, which aims to restore homeostasis. However, prolonged stress and sustained HPA axis activation can lead to cortisol resistance, triggering pro-inflammatory pathways and contributing to various chronic health conditions1,2.

Interestingly, the immune system can also activate the HPA axis, providing a shortcut for rapidly activating the stress response during antigenic challenges. This bidirectional relationship highlights the complex nature of cortisol regulation.

Cortisol secretion

Cortisol, a steroid hormone, is synthesized from cholesterol. Adrenocorticotropic hormone (ACTH), released from the anterior pituitary, functions to increase LDL receptors and increase the activity of cholesterol desmolase, which converts cholesterol to pregnenolone and is the rate-limiting step of cortisol synthesis. The majority of glucocorticoids circulate in an inactive form, bound to either corticosteroid-binding globulin (CBG) or albumin. The inactive form is converted to its active form by 11-beta-hydroxysteroid dehydrogenase 1 (11-beta-HSD1) in most tissues, while 11-beta-HSD2 inactivates cortisol back to cortisone in the kidney and pancreas1.

Normal cortisol curve

Under normal physiological conditions, cortisol secretion exhibits a predictable rhythm:

1. Morning peak: Cortisol levels are highest approximately 30-45 minutes after waking, known as the cortisol awakening response (CAR).

2. Gradual decline: Levels decrease steadily throughout the day.

3. Nocturnal nadir: Cortisol is lowest during the night, supporting restorative processes such as immune function and tissue repair.

The shape of this curve is critical for maintaining homeostasis, influencing metabolism, immune responses, and the central nervous system.

Cortisol secretion follows a natural 24-hour cycle (see Figure 2). In healthy individuals, peak levels are reached about 30 min after waking – this early peak is known as the cortisol awakening response (CAR). Levels decline throughout the day, with the lowest levels occurring during the early sleeping phase. However, prolonged exposure to stressors can lead to the overstimulation of the HPA axis resulting in fluctuating cortisol levels. This dysregulation of the HPA axis and its resultant disruption of the 24-hr cycle have been the subject of several studies which seek to establish a link between cortisol levels and ill-health3.

Impact of stress on cortisol dynamics

Stress disrupts the normal circadian rhythm of cortisol.

Acute stress typically triggers a rapid increase in cortisol levels, as the HPA axis activates to mobilize energy resources and adapt to the stressor. This response is characterized by:

  • Increased cortisol amplitude: A pronounced elevation beyond the normal peak level.
  • Delayed return to baseline: Extended stress can prolong elevated cortisol levels, impairing the resolution phase.

Chronic stress, however, may lead to dysregulation of the HPA axis, resulting in:

  • Flattened diurnal rhythm: Reduced variability between peak and nadir levels, often observed as persistently elevated or suppressed cortisol.
  • Blunted CAR: Diminished morning cortisol increase, associated with stress-related disorders such as burnout and depression.

Such alterations have far-reaching effects on health, including impaired glucose metabolism, immune suppression, cardiovascular strain, and cognitive dysfunction4, 5, 6.

Role of adaptogens in cortisol regulation

Food supplements containing certain ingredients have shown promise in modulating cortisol levels and mitigating the negative effects of chronic stress. One such ingredient is Withania somnifera, also known as ashwagandha, which has been studied for its adaptogenic properties.

Adaptogens like Withania somnifera are believed to exert their activity through a reduction in adrenal activity, which can help to maintain cortisol levels within a healthy range. This adaptogenic effect is thought to be achieved by modulating the hypothalamic-pituitary-adrenal axis, a key regulator of the body’s stress response and cortisol production. By dampening the HPA axis activation and reducing excessive adrenal output, adaptogens like Ashwagandha, Schisandra, Bacopa, Maca and others may assist in keeping cortisol levels balanced and mitigate the detrimental effects of chronic stress 7-10.

By incorporating these adaptogenic herbs and other cortisol-regulating ingredients into food supplements, individuals may be able to better manage the physiological and psychological consequences of chronic stress and maintain a healthier balance of cortisol levels.

Hydrolysed casein in cortisol regulation

Hydrolysed casein, a milk-derived protein, has also been investigated for its potential to modulate cortisol levels. Studies have suggested that hydrolyzed casein may help to reduce cortisol levels and improve the body’s stress response. Specifically, research has found that hydrolyzed casein, when consumed as a food supplement, may help lower elevated cortisol levels and mitigate the negative physiological and psychological effects of chronic stress. By regulating cortisol, hydrolysed casein may support overall well-being and resilience to stressful situations.

A total of 63 volunteers participated in a double-blind, randomized, crossover, placebo-controlled study11. Subjects were randomly allocated to receive either tablets containing αs1-casein hydrolysate or placebo at the dose of 150 mg/day for 30 days. After a 3-week washout period, they were crossed over for a new 30-day period of tablet intake. The outcome measure was a questionnaire including 44 items of symptoms that may be related to stress in which the severity of each sign was evaluated using a 10-degree scale. These measures were studied repeatedly at the day of 0, 15 and 30 after the start of each interventional period.

The 30-day treatment by αs1-casein hydrolysate in females with stress-related symptoms reduced their symptoms, particularly in digestion, cardiovascular, intellectual, emotional and social problems.

This study showed that a 30-day ingestion of αs1-casein hydrolysate decreased the stress-related symptoms in females suggesting that this product may be used as an effective functional ingredient alleviating such symptoms11.

Saffron extract and cortisol regulation

In addition to the above-mentioned ingredients, saffron extract has also been explored for its potential benefits in regulating cortisol levels. Some studies have indicated that saffron extract may help to reduce cortisol levels and alleviate the symptoms of chronic stress. Specifically, saffron has been found to possess antioxidant and anti-inflammatory properties, which may contribute to its ability to modulate the body’s stress response and maintain healthy cortisol levels. Additionally, saffron extract has been shown to have a calming effect on the nervous system, which could further help in managing the psychological aspects of stress. Overall, the inclusion of saffron extract in food supplements shows promise as a natural approach to supporting healthy cortisol regulation and stress management.

Omega-3 fatty acids

Furthermore, the omega-3 fatty acids found in fish oil have been shown to exert anti-inflammatory effects and potentially influence cortisol regulation, though the mechanisms are not yet fully understood.

In particular, findings from researchers have shown that cortisol, used at physiological concentration, can detrimentally affect cell proliferation and inhibit early hippocampal progenitor cell differentiation into neurons. Furthermore, impaired neurogenesis in the hippocampal region may disrupt the HPA-axis functions and ultimately contribute to the onset of brain diseases

An interesting study on cell culture reveals the ability of both EPA and DHA to prevent cortisol-induced reduction in proliferation and neurogenesis and increase apoptosis. While during proliferation both EPA and DHA exert similar proliferative and anti-apoptotic effects, during differentiation, EPA acts more effectively against apoptosis whereas DHA exerts more neurogenic properties. Such effects were putatively mediated by common signalling pathways involved in oxidative stress and inflammation (both EPA and DHA), and by unique signalling pathways involved in cell development and differentiation (DHA only). Overall, the presence of a cell population in the hippocampus that is highly sensitive to EPA and DHA, responding with significant activation of n-3 PUFAs-induced genes, highlights the potential role of the hippocampus in the beneficial effects of these nutritional compounds as potential therapeutic strategies for patients with stress-related neuropsychiatric and neuroinflammatory conditions12.

Long-term magnesium supplementation and its impact on glucocorticoid metabolism: a potential mechanism for cardiovascular protection 

A recent posthoc analysis of a randomized clinical trial focuses on magnesium supplementation’s beneficial effects on glucocorticoid metabolism, offering a potential explanation for its role in reducing cardiovascular disease (CVD) risk. The study13, published in Clinical Endocrinology, highlights the intricate link between dietary magnesium intake, cortisol metabolism, and cardiovascular health.  

Low magnesium intake has been consistently associated with increased CVD risk, with previous research pointing to magnesium’s role in reducing arterial stiffness – a major risk factor for cardiovascular events. However, the underlying mechanisms remain unclear. Recognizing that cortisol also plays a significant role in cardiovascular health, the researchers sought to explore how magnesium might influence cortisol metabolism. 

The study focused on glucocorticoid metabolism, specifically the activity of key enzymes such as 11β-hydroxysteroid dehydrogenases (11β-HSDs) and A-ring reductases, which regulate cortisol and its inactive form, cortisone. 

The trial employed a double-blind, placebo-controlled design with 49 overweight and slightly obese participants aged 45–70 years. Over a 24-week period, one group received a daily dose of 350 mg of magnesium citrate, while the control group received a placebo. Cortisol, cortisone, and their metabolites were measured in 24-hour urine samples, with enzyme activity inferred from specific urinary metabolite ratios. 

The results revealed significant improvements in cortisol metabolism among participants who received magnesium supplementation:

1. Reduction in cortisol levels: a decrease in 24-hour urinary cortisol excretion was observed in the magnesium group compared to the placebo group.

2. Enhanced 11β-HSD Type 2 activity: Magnesium supplementation increased the activity of 11β-HSD type 2, a kidney enzyme responsible for converting active cortisol into its inactive form, cortisone. 

3. No effect on A-ring reductase activity: The study found no changes in A-ring reductase activity, which converts cortisol and cortisone to their inactive metabolites. 

These findings suggest that magnesium promotes the inactivation of cortisol, a mechanism that may help alleviate its harmful effects on the cardiovascular system. Elevated cortisol levels have been linked to arterial stiffness and endothelial dysfunction, both of which are precursors to cardiovascular events. By improving glucocorticoid metabolism, magnesium supplementation may serve as an adjunctive strategy for mitigating CVD risk. 

The trial’s strengths include its double-blind, placebo-controlled design and long intervention period. The use of 24-hour urine samples provided comprehensive insights into glucocorticoid metabolism. However, as a post-hoc analysis, the findings are exploratory and require validation in future studies. Additionally, the study could not differentiate the effects of magnesium citrate from those of other magnesium compounds. 

This study highlights a novel pathway by which magnesium supplementation may exert cardiovascular benefits—through its effects on glucocorticoid metabolism. The observed reduction in cortisol levels and increased 11β-HSD type 2 activity underscore the potential of dietary magnesium as a preventive measure against cardiovascular diseases. 

Further research is warranted to confirm these results and explore the broader implications of magnesium supplementation on metabolic and cardiovascular health. As dietary magnesium intake remains below recommended levels for many individuals, addressing this gap could yield significant public health benefits. 

Caffeine effect on cortisol levels

Caffeine is proven to increase cortisol secretion in people at rest or undergoing mental stress.

Caffeine in dietary doses increases both: adrenocorticotropin (ACTH) and cortisol secretion in humans). Caffeine’s effect on glucocorticoid regulation therefore has the potential to alter circadian rhythms and to interact with stress reactions. By extension, these cortisol alterations may have implications for health if maintained in the face of daily caffeine intake.

A double-blind, crossover trial on 48 men and 48 women was conducted during over 4 weeks period. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totalling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected 8 times from 7:30 AM to 7:00 PM. After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period.

Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine daily. This study suggests that daily caffeine intake causes a partial but not complete tolerance to caffeine’s effects on cortisol secretion. The responsiveness of the HPAC was particularly evident in persons consuming moderate doses of 300 mg per day at home but was effectively abolished in those consuming higher doses. The potential for a persistent response to caffeine in consumers of moderate dietary doses suggests that an elevation of cortisol may occur in the afternoon hours in those consuming repeated doses throughout the day. This finding may have implications for health status in persons who are especially reactive to caffeine, such as persons developing hypertension14.

Conclusion

The regulation of cortisol, a vital stress hormone, is a complex and essential aspect of maintaining overall health. Dysregulated cortisol levels, whether elevated or suppressed, can lead to significant health implications, including metabolic, immune, cardiovascular, and neuropsychiatric conditions. The exploration of food supplement ingredients for cortisol modulation has highlighted the potential of various compounds in supporting balanced cortisol dynamics and mitigating the effects of chronic stress. 

Adaptogens, hydrolysed casein, saffron extract, omega-3 fatty acids, and even caffeine demonstrate diverse mechanisms of action in cortisol regulation. While adaptogens modulate the HPA axis and reduce adrenal hyperactivity, hydrolysed casein targets stress-related symptoms, and omega-3 fatty acids offer neuroprotective and anti-inflammatory benefits. However, caffeine’s impact on cortisol underscores the need for cautious use, as excessive intake can disrupt circadian cortisol patterns and contribute to stress-related disorders. 

The integration of these ingredients into food supplements offers promising avenues for stress management and cortisol regulation, but their effectiveness varies based on individual health profiles, lifestyle factors, and dosage. Further research is needed to refine these findings, optimize formulations, and ensure efficacy and safety in diverse populations. By addressing cortisol dysregulation, these dietary interventions could play a significant role in preventing chronic stress-related conditions and promoting long-term well-being.


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