Adrenal Biomarkers: Cortisol to DHEA-S Ratio

Optimal Takeaways

Cortisol and DHEA are hormones produced by the adrenal glands, and both can affect immunity, resilience to stress, brain function, and behavior. Evaluating the ratio between cortisol and DHEA-S (the most abundant form of DHEA) can provide information about the risk of infection, cognitive dysfunction, and metabolic health.

A higher ratio of cortisol to DHEA-S is associated with stress, metabolic syndrome, immune dysfunction, and all-cause mortality. A decreased ratio has been associated with behavioral disorders and antisocial behavior.

Standard Range: 0.09

The ODX Range: Below 0.09

Low cortisol:DHEA-S ratio has been associated with conduct disorders, aggression, and antisocial behavior (Kamin 2017).

High cortisol to DHEA-S ratio has been associated with stress, immune dysfunction, cognitive deterioration, treatment-resistant depression, ADHD, athletic training (Kamin 2017), critical illness, all-cause mortality, aging (Phillips 2010 vol. 163.2), metabolic syndrome, high blood pressure, high blood glucose, high triglycerides, low HDL (Phillips 2010 vol. 162), sarcopenia (Yanagita 2019), and increased risk of atherosclerosis, diabetes, and osteoporosis (Chehab 2007).

Overview

The hormones cortisol and dehydroepiandrosterone (DHEA) help maintain homeostasis in the face of various threats and stressors. Both are produced in the adrenal gland from cholesterol. However, DHEA is also synthesized in the brain, ovaries, and testes and can be converted to androstenedione, testosterone, and estradiol. DHEA-S is the sulfated form of DHEA and the most abundant form in circulation. DHEA-S has the same physiological effects as DHEA. Both cortisol and DHEA-S affect neurotransmitters, cognition, behavior, motivation, and emotional stability. An imbalance in their relative ratio can negatively affect these factors. Higher cortisol to DHEA-S ratio has been associated with cognitive deterioration, immune dysfunction, treatment-resistant depression, and schizophrenia. DHEA-S can offset some of the neurotoxic effects of cortisol on memory and cognitive performance if present in adequate amounts. DHEA-S can also moderate the adverse effects of cortisol on the immune system, including suppression of T-cells, lymphocytes, and antibody production. An increase in the cortisol:DHEA-S ratio is associated with higher mortality and infection rates following injury (Kamin 2017).

Prolonged stress can lead to higher cortisol levels and a higher cortisol to DHEA-S ratio due to dysregulated HPA axis feedback and a shift in the use of cholesterol-based pregnenolone from DHEA to cortisol. An increased ratio has also been associated with recent stressful events; workdays versus weekends; training stress in athletes; poorer military performance; ADHD; and symptoms of negative affect and dissociation. Chronic stress and HPA activation can lead to adrenal fatigue and downregulation of both DHEA-S and, eventually, cortisol. Interestingly, a low cortisol:DHEA-S ratio has been associated with conduct disorders, aggression, and antisocial behavior in adolescents (Kamin 2017).

The cortisol:DHEA-S ratio can increase with age as adrenal production of DHEA decreases, and cortisol remains stable, a change associated with reduced immunity, mood disturbances, anxiety, confusion, and compromised cognitive performance (Phillips 2010 vol. 163). The higher cortisol:DHEA-S ratio seen with aging may be mitigated with aerobic exercise and conditioning, especially in those under more significant stress (Heaney 2014).

Under normal circumstances, circulating DHEA-S is approximately 5 to 10 times higher than circulating cortisol (Ritsner 2005). However, stress, aging, and illness can alter this ratio. A prospective cohort analysis of 4,255 Vietnam veterans evaluated in the Vietnam Experience Study found that a higher cortisol:DHEA-S ratio was significantly associated with all-cause mortality, including cancer and infectious disease, but not CVD. The mean cortisol:DHEA-S ratio for the entire group was 0.09. Researchers conclude that a higher DHEA-S was protective against all-cause mortality (Phillips 2010 vol. 163).

An increased cortisol ratio to DHEA-S is also observed in metabolic syndrome. Further evaluation of the 4,255 Vietnam veterans revealed that high cortisol was associated with metabolic syndrome while higher levels of DHEA-S were protective. Increasing cortisol:DHEA-S ratio was associated with incident metabolic syndrome and four related components, i.e., high blood pressure, high blood glucose, high triglycerides, and low HDL. The mean cortisol:DHEA-S ratio for those with metabolic syndrome was 0.102 versus 0.088 in those without metabolic syndrome (Phillips 2010, vol. 162).

A decreasing DHEA-S and increasing cortisol:DHEA-S ratio may contribute to the progression of diabetes, atherosclerosis, osteoporosis, cognitive decline, and dementia. Repletion of DHEA-S in the case of adrenal insufficiency may correct some associated symptoms, including cognitive impairment, depression, anxiety, and immune dysfunction (Chehab 2007).

A higher cortisol:DHEA-S ratio is associated with sarcopenia, possibly due to the muscle wasting and catabolic effects of cortisol. It can also be associated with a decline in DHEA-S, which is anabolic. One study of 108 diabetic subjects 65 years or older found a cortisol:DHEA-S ratio of 0.2 or above to be a significant independent risk factor for the presence and severity of sarcopenia. The elevated ratio was due to higher cortisol and lower DHEA-S in those with sarcopenia. A cut-off of 0.14 and above should be investigated further for sarcopenia (Yanagita 2019).

Cortisol and DHEA-S influence immunity as well, with cortisol suppressing immunity and DHEA-S enhancing it. An imbalance can contribute to immunosuppression and subsequent infection. In one study of hip fracture patients aged 65 or over, those who developed an infection had a significantly higher cortisol:DHEA-S ratio (0.56) than age-matched controls (0.36) and young patients with fractures (0.087). A significantly higher ratio was seen in elderly patients who died of infection (0.803) than those who did not (0.467). Researchers note that fracture patients had a robust increase in circulating neutrophils but a decrease in neutrophil function and production of superoxide, making them more susceptible to infection (Butcher 2005).

A significantly higher cortisol:DHEA-S ratio and suppressed neutrophil superoxide production was also seen in 24 elderly bereaved subjects compared to controls. Researchers note an increased incidence of infection in older bereaved subjects (Khanfer 2011).

References

Butcher, Stephen K et al. “Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity.” Aging cell vol. 4,6 (2005): 319-24. doi:10.1111/j.1474-9726.2005.00178.x

Chehab, Olfa et al. “Hormonal status of cortisol and dehydroepiandrosterone sulfate in an elderly Tunisian population.” Comptes rendus biologies vol. 330,10 (2007): 755-63. doi:10.1016/j.crvi.2007.08.004

Heaney, Jennifer L J et al. “Physical activity, life events stress, cortisol, and DHEA: preliminary findings that physical activity may buffer against the negative effects of stress.” Journal of aging and physical activity vol. 22,4 (2014): 465-73. doi:10.1123/japa.2012-0082

Kamin, Hayley S, and Darlene A Kertes. “Cortisol and DHEA in development and psychopathology.” Hormones and behavior vol. 89 (2017): 69-85. doi:10.1016/j.yhbeh.2016.11.018

Khanfer, Riyad et al. “Neutrophil function and cortisol:DHEAS ratio in bereaved older adults.” Brain, behavior, and immunity vol. 25,6 (2011): 1182-6. doi:10.1016/j.bbi.2011.03.008

Phillips, Anna C et al. “Cortisol, DHEAS, their ratio and the metabolic syndrome: evidence from the Vietnam Experience Study.” European journal of endocrinology vol. 162,5 (2010): 919-23. doi:10.1530/EJE-09-1078

Phillips, Anna C et al. “Cortisol, DHEA sulphate, their ratio, and all-cause and cause-specific mortality in the Vietnam Experience Study.” European journal of endocrinology vol. 163,2 (2010): 285-92. doi:10.1530/EJE-10-0299

Ritsner, Michael et al. “Cortisol/dehydroepiandrosterone ratio and responses to antipsychotic treatment in schizophrenia.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 30,10 (2005): 1913-22. doi:10.1038/sj.npp.1300747

Yanagita, Ikumi et al. “A High Serum Cortisol/DHEA-S Ratio Is a Risk Factor for Sarcopenia in Elderly Diabetic Patients.” Journal of the Endocrine Society vol. 3,4 801-813. 5 Mar. 2019, doi:10.1210/js.2018-00271