CVD & the HPA Axis: How Adrenal Dysfunction Contributes to CV Disease
Lauren Beardsley, NMD
Alan Christianson, NMD
The evidence is strong that adrenal balance is one of the most important factors in preventing heart disease. Specifically, studies suggest that daily cortisol rhythm may a powerful influencing factor related to the development of cardiovascular disease (CVD), other chronic health conditions, and even death.
The Whitehall II Study,1 aka the “Stress and Health Study,” was conducted in the mid-1980s and examined over 10 000 male and female civil servants aged 35-55. This study, which investigated the relationships between work, stress, and health, found a steep inverse association between stress (assessed by social class and grade of employment) and mortality due to a wide range of diseases.1 Specific findings included an inverse association between employment grade and prevalence of angina, ECG evidence of ischemia, and symptoms of chronic bronchitis. It was also found that high blood pressure at work was associated with greater “job stress,” including “lack of skill utilization,” “tension,” and “lack of clarity” in assigned tasks. Hypertension among the lowest-grade servants was related to the highest job-stress score. Overall, this ongoing, long-term study revealed – and continues to reveal – the significant relationship between stress and chronic disease.1
Fatigue vs Dysregulation vs Disease
The nomenclature of “adrenal fatigue” is somewhat misleading in that in most cases adrenal glands are not fatigued but rather are fatiguing. The difference is that in most cases the body is not incapable of producing cortisol, but rather is likely intentionally and effectively producing less cortisol in an attempt to heal. This phenomenon is more appropriately defined as hypothalamic-pituitary-adrenal axis dysregulation (HPAD). This is important to understand for the sake of treatment purposes.
HPAD often develops over time. The HPA axis functions by responding to an acute stressor, generating a physiologic response to protect the body and ensure survival. In most circumstances, this is incredibly useful. However, this response can become dysfunctional in the event of major stressors early in life. When this occurs, the HPA axis prepares the body for continual catastrophe, as if the body is anticipating worst possible outcomes. The body’s “calibration” via the HPA axis is critical to overall health, and early childhood stressors can set the stage for future HPAD. This means that events that would ordinarily be considered small can trigger very large stress responses in the body. When early-life traumatic events occur or stressors persist for long periods of time, the HPA axis responds by downregulating its stimulus, to allow the body the opportunity to heal. Again, it is not an inability of the adrenal glands to produce cortisol, but more likely an intentional decline to protect energy levels and overall health.
In rare cases, the adrenals are legitimately fatigued and unable to make cortisol. The most common cause of this is Addison’s disease or adrenal insufficiency. Adrenal fatigue and insufficiency are more directly related in this case; the body is beginning to fatigue and total cortisol output by the adrenal glands is declining. This can be due to a problem within the adrenal gland itself or a problem with stimulation of the gland from higher up the axis.
What can help distinguish between adrenal fatigue/insufficiency and HPA dysregulation is the ACTH test. The pituitary releases adrenocorticotropic hormone (ACTH) to stimulate cortisol production in the adrenals. Elevated serum ACTH levels indicate that adrenal cortisol output is low. In the case of HPAD, serum ACTH values are low, not high. Further evaluation using the ACTH Stimulation Test allows for the diagnosis or exclusion of adrenal insufficiency and also distinguishes whether the cause is primary (adrenal, with low cortisol and aldosterone production) or secondary (pituitary, with low ACTH production). The Insulin Tolerance Test is recognized as the gold-standard assay of adrenal insufficiency; however, due to the high risk of adverse events following the test as well as the labor-intensive process, the ACTH Stimulation Test is commonly employed as an easier and safer alternative.
How Adrenal Dysfunction Can Trigger Heart Disease
With an understanding of the significant role stress plays in the development of chronic disease and of the difference between dysregulation and disease, let’s examine how cortisol can influence CVD.
The role of the adrenal glands, especially with respect to cortisol, has been very well researched as it concerns cardiovascular health. It has been studied in 3 unique ways:
- In studies involving Cushing’s disease
- In studies involving short-term glucocorticoid excess
- In studies involving non-Cushing’s disease cortisol excess
Excess cortisol has been shown to increase blood pressure, which increases risk for CVD.2 Blood pressure is strongly regulated by glucocorticoid metabolism.2 This likely contributes to the theory that salt intake and blood pressure are linked. Salt intake has been observed to influence blood pressure; however, in many instances it does not. For this reason we can identify glucocorticoids, eg, cortisol, as key players. About one-third of people have been shown to have hypertension based entirely on cortisol excess.3 Even in the short term, high cortisol can radically influence blood pressure. Thus, evaluating cortisol in patients with hypertension becomes crucial, while also keeping an eye on salt intake and how that affects one’s cortisol levels.
Glucocorticoid levels, influenced by cortisol metabolism and adrenal function, play a huge contributory role in truncal obesity (increased waist circumference, or WC) and disease risk. In fact, the further WC expands beyond 36 inches in men, the higher the risk of heart disease.3 For women, the risk begins at a WC of around 32 inches.
Adrenal secretion of cortisol is controlled by the HPA axis; however, in-vitro studies have demonstrated increased activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue of obese patients. This enzyme regenerates cortisol from cortisone. This increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration.4
It has been shown that disrupted cortisol rhythm is one of the strongest predictors of hyperglycemia, which is ultimately associated with early diabetes risk. Patients with impaired glucose tolerance have been shown to have increased sensitivity to glucocorticoids both centrally and peripherally, as reflected by increased excretion of cortisol metabolites.5
Hyperlipidemia is commonly found in Cushing’s syndrome, with hypercholesterolemia and hypertriglyceridemia being most prominent. Often, HDL-C is lower, and LDL-C is higher, compared to controls.3 Data also suggests that more prolonged periods of cortisol excess are required to produce dyslipidemia, as opposed to acute episodes of excess.3
Some individuals are genetically predisposed to elevated homocysteine due to defects in methylation. Homocysteine generation is also influenced by cortisol metabolism.6 Homocysteine has been shown to be an independent risk factor for CVD, especially in those with Cushing’s disease.3
Carotid Intima-Media Thickness
The cortisol curve plays a large role in the thickness of, and therefore the cardiovascular risk associated with, carotid intima-media thickness (CIMT). Studies have revealed that salivary cortisol and the nocturnal rise in cortisol are associated with CIMT. For example, in overweight and obese youth, a blunted nocturnal cortisol rise was shown to be inversely correlated with CIMT and atherosclerosis risk.7 These findings are consistent with studies showing an association between cardiovascular risk and a flattened diurnal cortisol curve due to HPAD.7 Additional studies have shown higher CIMT in individuals with Cushing’s disease3 and that blocking cortisol in healthy subjects can prevent stress-related endothelial dysfunction.8 Still other studies have attributed the link between morning cortisol and CIMT to the effect of HPAD on the vasculature.9
Heart Rate Variability
Impaired heart rate variability (HRV), which indicates decreased vagal tone, is a significant predictor of cardiovascular mortality.10 A healthy heart rate will show variability, and this is reliant upon the influence of the nervous system.
When the 2 systems of the autonomic nervous system – the sympathetic and parasympathetic – are balanced, there is a steady and consistent HRV. When in balance, these systems are constantly generating a gentle ebb and flow between the two. What this means is that a heart rate of 60 bpm might consist of: 1.1 seconds, followed by 0.9 seconds, and so forth – a gentle variability. If these 2 nervous systems are not well balanced, as in the case of an exaggerated stress response, a state of impaired HRV results.10
One’s cortisol cycle is one of the strongest determining factors in HRV. We can see this in shift workers, in whom an extremely disturbed HRV is associated with a lack of a consistent cycle.11
Coronary Artery CT Scoring
In Cushing’s syndrome patients, elevated cortisol or previously elevated cortisol is associated with greater amounts of both calcified and non-calcified plaque observed on coronary artery CTs.12 In patients with cortisol excess, atherosclerosis increases the risk of fatal cardiovascular episodes.
Clinical Approach to HPAD
Evaluation of HPAD
There are multiple established means of evaluating HPA dysfunction:
- Symptom surveys can serve as a helpful tool in evaluating HPAD, as patterns can be associated with this condition. A symptom survey is often a good starting point for investigating adrenal function and adrenal health.
- Hair cortisol measurement is a rather new form of testing, so not commonplace. Results provide a 3-month average of peripheral cortisol metabolism as well as total cortisol excretion.13
- Serum cortisol testing reflects total cortisol values at a given testing time. Elevated AM levels are significant, but overall this has low value for helping to rule out HPAD.
- Salivary cortisol testing allows for multiple testing samples throughout the day, hence is useful for assessing diurnal cortisol excretion. Because of the ease of specimen collection, this method is widely applied. Test results depict a rhythm or slope of cortisol, and capture the “cortisol awakening response,” which helps predict CVD.10
- Urinary free cortisol testing over a 24-hour period is useful for assessing total cortisol excretion in Cushing’s disease. However, its predictive value is likely greater when accompanied by additional screening tests.14 The test, however, has a low negative predictive value for Cushing’s disease or hypercortisolemia, and is not useful for evaluating diurnal cortisol variations.
- Lastly, blood testing is highly encouraged to assist in ruling out disease, including primary or secondary Addison’s disease, primary or secondary Cushing’s disease, and autoimmune adrenal insufficiency. If disease is suspect, testing for serum cortisol, ACTH, adrenal antibodies, and DHEA is recommended.
Treatment of HPAD
One initial lifestyle therapy to consider for a patient with HPAD is light therapy, ie, treating the body to a certain level of light to intentionally manipulate the body’s natural circadian rhythm of cortisol. So much of what we do is dependent on our schedule of waking and sleeping; light therapy can be used to help correct a dysregulation. When the circadian rhythm (in this case, cortisol) is disrupted, exposure to bright light in the morning can help restore it.15
Light is a strong determinant of cortisol concentration. Bright light exposure (up to 10 000 lux) has been shown to elicit a suppressive effect when applied either during the rise or descent phase of cortisol rhythm, whereas lower intensities (less than around 5000 lux) failed to induce significant changes.16 To maintain an ideal cortisol rhythm, 15 minutes of 10 000 lux exposure is recommended within the first hour of waking. For other stages of dysfunction, other variations of light exposure are recommended.
Blue light exposure also influences the biochemical release of both melatonin and cortisol, suppressing the first and increasing the second. Specifically, avoiding or exposing oneself to blue light can serve as a manipulative tool for resetting circadian rhythm.17
The Adrenal Reset Diet
We conducted an in-house clinical trial to test the effectiveness of a specific dietary strategy in influencing cortisol rhythm. This trial comprised 42 individuals, 80% female, with a mean age of 45 years; all participants were given the same dietary regimen. After 30 days, significant improvements in adrenal rhythm were observed, as reflected by 4-point salivary diurnal cortisol measurements. Additional observations included weight loss (mean, 9 lb), 2% loss of body fat, and 2-in reduction in waist circumference.
This study demonstrated that strategic timing of different portions of proteins, fats, and carbohydrates throughout the day could radically improve the cortisol cycle. This “reset” diet18 is based on the premise that because insulin release triggered by carbohydrate ingestion is antagonistic to cortisol, strategically timing carbohydrate intake can restore a normal cortisol curve (higher in the morning and lower in the evening). Specifically, participants ate <10 grams of healthy carbs along with 20+ grams of protein and 8+ grams of fiber within the first waking hour, some additional carbs at lunch, and 30-45 grams of carbs in the evening. This simple shift in dietary habits can improve one’s cortisol rhythm, decrease cardiovascular risk, improve sleep, boost energy, and support successful weight loss.
- Marmot MG, Smith GD, Stansfield S, et al. Health inequalities among British civil servants: the Whitehall II study. Lancet. 1991;337(8754):1387-1393.
- Walker BR, Connacher AA, Webb DJ, Edwards CR. Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man. Clin Sci (Lond). 1992;83(2)171-178.
- Whitworth JA, Williamson PM, Mangos G, Kelly JJ. Cardiovascular consequences of cortisol excess. Vasc Health Risk Manag. 2005;1(4):291-299.
- Stimson RH, Andersson J, Andrew R, et al. Cortisol release from adipose tissue by 11β-hydroxysteroid dehydrogenase type 1 in humans. Diabetes. 2009;58(1):46-53.
- Andrews RC, Herlihy O, Livingstone DE, et al. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. J Clin Endocrinol Metab.2002;87(12):5587-5593.
- Cascalheira JF, Parreira MC, Viegas AN, et al. Serum homocysteine: relationship with circulating levels of cortisol and ascorbate. Ann Nutr Metab. 2008;53(1):67-74.
- Toledo-Corral CM, Myers SJ, Li Y, et al. Blunted nocturnal cortisol rise is associated with higher carotid artery intima-media thickness (CIMT) in overweight African American and Latino youth. Psychoneuroendocrinology. 2013;38(9):1658-1667.
- Broadley AJ, Korszun A, Abdelaal E, et al. Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment. J Am Coll Cardiol. 2005;46(2):344-350.
- Yener S, Genc S, Akinci B, et al. Carotid intima media thickness is increased and associated with morning cortisol in subjects with non-functioning adrenal incidentaloma. Endocrine.2009;35(3):365-370.
- Marques AH, Silverman MN, Sternberg EM. Evaluation of stress systems by applying noninvasive methodologies: measurements of neuroimmune biomarkers in the sweat, heart rate variability and salivary cortisol. Neuroimmunomodulation.2010;17(3):205-208.
- Jensen MA, Garde AH, Kristiansen J, et al. The effect of the number of consecutive night shifts on diurnal rhythms in cortisol, melatonin and heart rate variability (HRV): a systematic review of field studies. Int Arch Occup Environ Health.2016;89(4):531-545.
- Neary NM, Booker OJ, Abel BS, et al. Hypercortisolism is associated with increased coronary arterial atherosclerosis: analysis of noninvasive coronary angiography using multidetector computerized tomography. J Clin Endocrinol Metab.2013;98(5):2045-2052.
- Stalder T, Steudte-Schmiedgen S, Alexander N, et al. Stress-related and basic determinants of hair cortisol in humans: A meta-analysis. Psychoneuroendocrinology.2017;77:261-274.
- Odeniyi IA, Fasanmade OA. Urinary free cortisol in the diagnosis of Cushing’s syndrome: how useful? Niger J Clin Pract. 2013;16(3):269-272.
- Bechtold DA, Gibbs JE, Loudon AS. Circadian dysfunction in disease. Trends Pharmacol Sci. 2010;31(5):191-198.
- Jung CM, Khalsa SB, Scheer FA. et al. Acute effects of bright light exposure on cortisol levels.J Biol Rhythms. 2010;25(3):208-216.
- Figueiro MG, Rea MS. The effects of red and blue lights on circadian variations in cortisol, alpha amylase, and melatonin. Int J Endocrinol. 2010;2010:829351.
- Christianson AG. The Adrenal Reset Diet. New York, NY: Harmony Books; 2014.
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Lauren Beardsley, NMD, is a naturopathic physician, having received her medical degree from the Southwest College of Naturopathic Medicine and Health Sciences (SCNM). She currently practices with Integrative Health in Scottsdale, AZ, and specializes in natural endocrinology, focusing primarily on thyroid and adrenal health.
Alan Christianson, NMD, is a Phoenix, AZ-based naturopathic medical doctor specializing in natural endocrinology with a focus on thyroid and adrenal disorders. He is the author of the best-selling Adrenal Reset Diet; The Complete Idiot’s Guide to Thyroid Disease; and Healing Hashimoto’s: A Savvy Patient’s Guide. Media appearances include The Doctors, The Today Show, and Shape Magazine. As a child, cerebral palsy left him with seizures, poor coordination, and eventual obesity. His experience of resurrecting his own health taught him that becoming healthy through knowledge and persistence transforms both how you feel and how others treat you. Dr Christianson resides in Scottsdale, AZ, with his wife Kirin and their 2 children.