Cortisol is a steroid hormone belonging to the corticosteroid class known as glucocorticoids. It is produced and secreted by the adrenal gland and is involved in a variety of functions including the stress response, immune response, inflammation and carbohydrate metabolism. Cortisol is also available as a pharmaceutical therapeutic known as hydrocortisone.  This paper provides an overview of cortisol, its involvement in disease and its use as a therapeutic.

Although cortisol is involved in a variety of functions, it is best known as the stress hormone. So it is not surprising that cortisol production is induced by stressors that activate the hypothalamic-pituitary-adrenal (HPA) axis—a system of interactions and feedback loops between three major glands that secrete hormones into the bloodstream.

Following stress, the hypothalamus secretes corticotropin-releasing hormone (CRH). CRH then stimulates CRH receptors (CRHRs) in the pituitary gland to produce another hormone called adrenocorticotropin, or ACTH. Some stressors, such as hypoglycemia, hemorrhage and immune stimuli, can trigger the release of vasopressin—another hypothalamic substance that promotes ACTH production. ACTH then stimulates the adrenal cortex to produce cortisol. Other factors such as cytokines and fat cells can also stimulate the HPA at any level.

The produced cortisol is bound to corticosteroid-binding globulin (CBG) or cortisol-binding protein (CBP), which transports it through circulation to different tissues. There, cortisol activity is regulated by enzymes called 11β-hydroxysteroid dehydrogenase. Active cortisol binds to mineralocorticoid and glucocorticoid receptors (MRs and GRs) in the tissue to form a complex that is transported into the nucleus of cells where it modulates expression of genes sensitive to cortisol.

Cortisol and Circadian rhythm

Cortisol levels vary throughout the day and follow a circadian (24-hour) rhythm. Cortisol levels begin to increase significantly in the early morning, peaking around mid-morning. Their levels then gradually decline throughout the day until they reach their lowest levels during nighttime sleep. Approximately 77% of people also experience the cortisol awakening response (CAR), which is a sharp increase in cortisol 30min after waking that is independent of the normal circadian rhythm.

Cortisol and Stress

Stress is anything that strains homeostasis, which is the capacity of the body to maintain its biological processes such as temperature or heart rate. Stress can be external factors such as work and social stressors or internal such as dysregulation of vital processes. In response to these factors the body typically engages a stress response that serves to return it to a state of normalcy. This response involves increased cognition, lower sensitivity to painful stimuli, an increase in blood sugar levels, increased breakdown of fats and other lipids and an inhibition of reproduction.

Testing for Cortisol

Testing the level of cortisol in the body is used to assess the actibity of the HPA axis and as a test for many medication conditions. The most common way to test for cortisol is by collecting urine over a 24h period (known as urinary-free cortisol (UFC) and then testing the amount of cortisol in the urine. Another method is by examining the amount of cortisol in saliva. However, these methods have their drawbacks. Since cortisol levels fluctuate without the day, it can be difficult to get an idea of the overall levels of cortisol since these methods only capture one moment in time. Thus researchers and clinicians have moved toward using cortisol measurements in hair since hair can provide evidence of long term exposure to specific hormones.

Cortisol as a Therapeutic Treatment

As previously mentioned, glucocorticoids are often prescribed as anti-inflammatories for a variety of ailments, such as autoimmune diseases (multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, psoriasis, and eczema). In these diseases, inflammation can become so severe that immune cells begin to attack other host cells. This can cause pain, swelling, cramping and itching. Glucocorticoids work by reducing the inflammation, which alleviates these symptoms.

Glucocorticoids may also be used to treat allergies or asthma which are brought on by a strong immune response to allergens. A less common use is to compensate for an adrenal insufficiency caused by Addison’s disease or removal of the adrenal gland.  Another possible, but less likely use of glicocorticoids is to improve cardiovascular response to certain drugs after heart failure, or to attenuate side effects of chemotherapy.

There are a variety of synthetic glucocorticoids, including nasal formulations triamcinolone and beclomethasone, and oral forms such as prednisone, dexamethasone, and the cortisol equivalent, hydrocortisone.

As you can imagine, these therapies have a wide range of moderate to severe side effects. Such as immunosuppression, delayed wound healing, high blood sugar, psychological symptoms, gastrointestinal intestinal distress, osteoporosis, and of course Cushing’s syndrome. Patients taking prescription glucocorticoids have an increased risk for developing cardiovascular and cerebrovascular disease.

There are several tretments in development to rectify dysregulation of cortisol. One is tissue-specific inhibitors of 11β-HSD1. Clinical trials have revealed that treatment with these inhibitors can reduce body weight, and blood pressure. However, these results have been inconsistent (Shah, et al., 2011; Feig, et al., 2011; Rosenstock, et al., 2010).

Another option is inhibition of cortisol production in the adrenal gland. This method is typically used to treat Cushing syndrome. Inhibitors of aldosterone synthase may also reduce cortisol since aldosterone synthase is similar to the enzymes that produce cortisol. These inhibitors would be particularly useful in conditions in which both aldosterone and cortisol are dysregulated.

The final option utilizes antagonists for the GRs and MRs. MR inhibitors are easily accessible, have low side effects and are currently used to improve survival following heart failure. Blocking this receptor has the additional benefit of blocking activation due to both cortisol and aldosterone. It has already been shown to stave off hypertension and abnormalities in the muscles of the heart in patients with metabolic syndrome.

While a short-term stress response can be beneficial, a prolonged response can have negative impacts on the body. Too much cortisol over an extended period of time can lead to fatigue, obesity, and other medical conditions like cushions disease. Below is a summary of medical conditions that can result from dysregulation of cortisol.

Cushing’s Syndrome

Cushing’s syndrome, or hypercortisolism, is a rare condition in which the patient experiences an excess of glucocorticoids, primarily cortisol. It is usually caused by prescription steroids (glucocorticoids) that are used as anti-inflammatories. However, it can also be caused by tumors on the adrenal or pituitary gland.

Common symptoms include weight gain, insulin resistance, muscle weakness, high blood concentration of lipids, such as cholesterol (hyperlipidemia), high blood pressure (hypertension), high blood sugar (hyperglycemia), osteoporosis and thin skin. If left untreated, Cushing disease can be life threatening. Prognosis for patients with untreated Cushing’s syndrome is approximately 50% for 5-year survival.

Fortunately, the Cushings is treatable. When caused by medications it can be remedied by reducing the dosage or stopping the medication. When caused by tumors, treatment typically revolves around removal of the tumors through surgery or radiation.

Metabolism Disorders

Recent studies have suggested that morbidity associated with obesity and other metabolic syndromes may be due to the dysregulation of cortisol. Mounting evidence suggests that excess cortisol is linked to obesity, hypertension, dyslipidemia, diabetes, metabolic syndrome and fatty liver.

Cortisol tissue levels are regulated by 11β-HSD enzymes. These enzymes influences cortisol activity in tissues by inducing the conversion of inactive cortisone into active cortisol.  This process takes place in the muscle, liver, bone and fat (adipose) tissues. In reverse, enzyme 11β-HSD2 converts active cortisol back into inactive cortisone. Since these enzymes found in adipose tissue and adipose can significantly increase in obese people, the activity of these enzymes may play a significant role in dysregulation of cortisol in obesity and related conditions. The influence of 11β-HSD1 on metabolic conditions was demonstrated in a study by Masuzaki et al (2001) that found that mice that overexpress 11β-HSD1 in adipose tissue developed obesity, diabetes and dyslipidemia. A similar study using mice that did not express 11β-HSD1 had less fat and did not develop diabetes even on a high calorie diet (Morton, et al., 2004).

Cortisol may contribute to obesity by interacting with regulators of weight and food intake. Leptin, the satiety hormone is secreted by fat cells in order to inform the brain of fat levels in the body and to control eating. High levels of leptin result in an inhibition of hunger.  A study that removed the adrenal gland in mice with low levels of leptin found that these mice lost weight, suggesting that glucocorticoids may contribute to leptin metabolism (Dubuc & Wilden, 1986).

Another study found that administration of a steroid medication, dexamethasone, increased leptin levels when administered after eating in both average and obese patients (Laferrère, et al., 2002; Laferrère, Fried, Osborne, & Pi-Sunyer, 2000; Dagogo-Jack, Selke, Melson, & Newcomer, 1997). Ghrelin, the hunger hormone, induces feelings of hunger and promotes food intake. This hormone has been found to have an inverse relationship with cortisol during fasting, suggesting that cortisol may be used to mediate the effects of ghrelin. However, more research is needed before any solid conclusions can be drawn.

Based on the previous evidence, it’s not a surprise that researchers have been investigating the link between stress and hunger. This association is also likely due to the fact that dysregulation of the HPA has been associated with multiple eating disorders such as binge eating disorder, bulimia and anorexia. Changes in cortisol metabolism have also been associated with changes in peptides involved in food regulation like insulin.

Links between cortsiol, stress, sleep, and obesity

Cortisol also has an influence on sleep, evident by the studies linking obesity and sleep deprivation. Sleep deprivation has been shown to be associated with increased body mass index (BMI) and increased risk for obesity and diabetes. This association between sleep deprivation and obesity is thought to occur because sleep deprivation is considered a type of prolonged stress that may eventually lead to dysregulation of the HPA. Current studies on the topic have conflicting results, however.

Stress at an early age has also been associated with an increased risk for development of obesity. For example, a recent study found that macaque monkeys were more likely to weigh more and have a higher body mass index if their mother was exposed to food insecurity while her offspring were young.  In fact, there is even evidence that significant malnutrition during pregnancy resulting in low birth weight increases the risk of obesity development in the offspring.

While cortisol dysregulation gets the most attention for its link to weight and stress, it is also connected to medical conditions like hypertension, reproduction issues, PTSD, addiction, depression, and autism.

Hypertension

A primary function of cortisol is regulation of blood pressure. Thus, when cortisol is dysregulated, blood pressure is often affected. In cases of Cushing’s syndrome, when there is an excess of glucocorticoids, a common response (nearly 80% of cases) is the development of hypertension (high blood pressure). Nearly 30% of hypertension cases are thought to occur in response to cortisol dysregulation, specifically, This increase in cortisol related to hypertension is due to stimulation by ACTH.

Reproduction

Cortisol is not only involved in fat tissues, but it can also play a role in the function of reproductive organs.  The ovaries have GRs and they are influenced directly by the HPA through glucocorticoids, primarily cortisol (Andersen C. , 2002). In addition to the cortisol-binding protein (CBP), sex-hormone-binding globulin (SHBG) may also bind to cortisol. However, this interaction is not nearly as strong as the bond between CBP and cortisol. Like in other tissues, cortisol expression is regulated by 11β-HSD enzymes, which fluctuate over the course of the menstrual cycle.

Post-traumatic Stress Disorder

Being the stress hormone, it may come as no surprise that cortisol levels are altered in individuals with post-traumatic stress disorder (PTSD). In a meta-analysis examining the relationship between cortisol and PTSD, it was determined that while in general there is no difference in cortisol levels between people with PTSD and those without, a difference could be seen within subgroups of people (Meewisse, Reitsma, Vries, Gersons, & Olff, 2007). For example, when comparing cortisol levels collected from plasma, people with PTSD had lower levels. Women experiencing PTSD also had lower levels of cortisol than those without the disorder. Thus, suggesting a role for cortisol regulation in PTSD.

Addiction

HPA and cortisol response can also be significantly altered by drug use and addiction. Substances such as alcohol, nicotine or illegal drugs cause a small HPA response. And so it is likely that constant high intake of drugs can lead to dysregulation of the HPA. During heavy use, the HPA is chronically activated and can remain activated during withdrawal and for weeks. The circadian rhythm of HPA activity is also altered. And although, it may return back to a normal rhythm once the substance is no longer being used, HPA response, and thus cortisol response, to normal stimuli is remains blunted.

Depression

Stress has been linked to depression, and it is believed that treatment with antidepressants may treat depression in part by correcting dysregulation of HPA activity. People with depression have been found to secrete higher amounts of ACTH and cortisol and have a higher concentration of CRH in their cerebral spinal fluid —the fluid located in the ventricles of the brain, around the spinal cord, and other regions within the nervous system. These individuals have also been shown to have a higher number of CRH secreting nerve cells in regions connected to the HPA such as the limbic system (a region in the brain related to emotion). Furthermore, depression has been linked to other diseases associated with cortisol dysregulation. For example, several studies have linked Type 2 diabetes to an increased risk for major depressive disorder (MDD) (Demakakos, Pierce, & Hardy, 2010; Rustad, Musselman, & Nemeroff, 2011). In turn, the risk of developing diabetes is 60% higher in people with depression (Mezuk B, 2008). Taken together, the evidence suggests that cortisol dysregulation is a contributing factor in depression.

Autism

Autism is a neurodevelopmental disorder that presents as impaired social communication, limited interests, and repetitive behaviors. HPA dysregulation has also been implicated in autism disorders. As mentioned above, cortisol levels follow a diurnal (daily waking hours) rhythm. They rise in the morning and slowly decline throughout the day. Many studies have found that children with autism were more likely to show a disruption in this oscillation (Yamazaki, Saito, Okada, Fujieda, & Yamashita, 1975; Hill, Wagner, Shedlarski, & Sears, 1977; Hoshino, et al., 1987; Corbett, Schupp, Levine, & Mendoza, 2009; Richdale & Prior, 1992). Despite abnormal fluctuations in cortisol levels, the amount of cortisol secreted is similar to those with regularly regulated cortisol. People with autism also typically display slow HPA response activity to stress. The HPA also recovers from stress more slowly.