You are driving down a busy highway when the car in front of you makes an abrupt stop. You slam on your breaks and come to a halt, immediately before striking the back of the other car. Your heart rate and blood pressure increased rapidly, and you feel shaky; this is your body's response to a stressful situation. Cortisol, the stress hormone, is one of the many hormones responsible for this physiological change. Cortisol is a glucocorticoid hormone produced by the adrenal glands and released for a variety of reasons. The hypothalamus-pituitary-adrenal axis regulates its release and when not controlled, overproduction and underproduction of cortisol cause Cushing’s syndrome and Addison disease, respectively.
Cortisol is a corticosteroid hormone that gets synthesized from cholesterol in the adrenal cortex. Its full scientific name is 11-beta,17-alpha,21-trihydroxypregn-4-ene-3,20-dione, It is metabolized by 11-beta-hydroxysteroid dehydrogenase. Due to its molecular similarity to aldosterone, 11-beta-hydroxysteroid dehydrogenase is responsible for converting active cortisol to inactive cortisone to prevent the over-stimulation of the aldosterone receptor. The molecular structure of cortisol and cortisone differ by a hydroxyl group found at C11.
Due to the presence of glucocorticoid receptors in almost every cell of the body, cortisol affects many organ systems.
The cells in the human body receive and use the hormone in various ways.
Cortisol has many functions in the human body, such as controlling stress response, blood glucose levels, inflammatory responses, and blood pressure.
Stress response: The human body is continually responding to internal and external stressors. The body processes the stressful information and elicits a response depending on the degree of threat. The bodies autonomic nervous system is broken down into the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). In times of stress, the SNS gets activated. The SNS is responsible for the fight or flight response, which causes a cascade of hormonal and physiological responses. The amygdala is responsible for processing fear, arousal, and emotional stimuli to determine the appropriate response. If necessary, the amygdala sends a stress signal to the hypothalamus. The hypothalamus activates the SNS, and the adrenal glands release a surge of catecholamines, like epinephrine; this causes tachycardia, hypertension, diaphoresis, increase in respiratory rate and an increase in blood glucose. As the body continues to perceive the stimuli as a threat, the hypothalamus activates the HPA axis. Cortisol is released from the adrenal cortex and allows the body to continue to stay on high alert. When the threat passes, the parasympathetic nervous system reduces the SNS response.
Blood glucose: Blood glucose levels drive key systemic and intracellular pathways. The presence of glucocorticoids, such as cortisol, increase the availability of blood glucose to the brain. Cortisol acts on the liver, muscle, adipose tissue, and the pancreas. In the liver, high cortisol levels increase gluconeogenesis and decrease glycogen synthesis. Gluconeogenesis is a metabolic pathway that results in the production of glucose from glucogenic amino acids, lactate, or glycerol 3- phosphate found in triglycerides. Gluconeogenesis reverses glycolysis, a cytoplasmic pathway used to convert glucose into pyruvate molecules. This pathway is used to release energy through substrate-level phosphorylation and oxidation reactions. Unlike glycolysis, gluconeogenesis becomes active when the body needs energy. Muscles have their own internal glycogen supply that allows them to respond to changes in ATP requirements rapidly. In the presence of cortisol, muscle cells decrease glucose uptake and consumption and increase protein degradation; this supplies gluconeogenesis with glucogenic amino acids. In adipose tissues, cortisol increases lipolysis. Lipolysis is a catabolic process that results in the release of glycerol and free fatty acids. These free fatty acids can be used in B oxidation and as an energy source for other cells as they continue to produce glucose. Lastly, cortisol acts on the pancreas to decrease insulin and increase glucagon. Glucagon is a peptide hormone secreted by the pancreatic alpha cells to increase liver glycogenolysis, liver gluconeogenesis, liver ketogenesis, lipolysis, as well as decrease lipogenesis. Cortisol enhances the activity of glucagon, epinephrine, and other catecholamines.
The production of cortisol starts in the hypothalamus. Corticotrophin-releasing hormone, CRH, is secreted from the paraventricular nucleus of the hypothalamus. CRH stimulates the anterior pituitary gland to release ACTH: adrenocorticotrophic hormone. ACTH is a tropic hormone that stimulates the adrenal cortex to release glucocorticoids, such as cortisol.; this is the hypothalamic-pituitary-adrenal axis. The HPA axis is a negative feedback system, where the presence of cortisol inhibits the production of CRH and ACTH.
The adrenal glands, located on top of each kidney, are composed of an inner medulla and outer cortex. The outer cortex is responsible for the production of steroid hormones, such as mineralocorticoids, glucocorticoids, and sex hormones. The cortex is composed of three layers, the zona glomerulosa, zona fasciculate, and zona reticularis. The zona fasciculate is responsible for producing cortisol.
Steroid hormones, such as cortisol, are primary messengers. They can cross the cytoplasmic membrane because of their fat-soluble properties. Cell membranes are composed of phospholipid bilayers; these prevent fat-insoluble molecules from passing through. Once cortisol passes through the cell membrane and enters into the cell, it binds to specific receptors in the cytoplasm. In the absence of cortisol, the glucocorticoid receptor binds to an Hsp90 chaperone protein in the cytosol. The binding of cortisol to the glucocorticoid receptor dissociates the Hsp90. The cortisol-receptor complex then enters the nucleus of the cell and affects gene transcription.
Cortisol level test is used to monitor the function of the adrenal and pituitary gland as well as a diagnostic measurement. Addison disease and Cushing syndrome can be diagnosed based on the results of a cortisol level test. Cortisol levels are at their highest in the morning, so physicians recommend having blood drawn early.
Cortisol levels are continuously monitored in the body to maintain homeostasis. Unregulated levels can be detrimental.
Hypercortisolism: Hypercortisolism, known as Cushing syndrome, occurs when the human body suffers exposure to high cortisol levels for an extended period. There are two different causes of Cushing syndrome; exogenous and endogenous. Exogenous Cushing syndrome results from an outside source, such as taking oral or injectable corticosteroids. Oral corticosteroids, like prednisone, increase the amount of cortisol in the body. They are usually prescribed to help alleviate symptoms associated with inflammatory diseases, like lupus and rheumatoid arthritis. The consistently high levels of excess cortisol cause Cushing syndrome. Endogenous Cushing syndrome is due to the bodies overproduction of cortisol. It is extremely rare for the adrenal cortex to produce excess cortisol in the absence of a tumor. The most prevalent etiology of endogenous Cushing syndrome is a hormone-releasing tumor on the adrenal glands or pituitary gland. Adrenal gland tumors cause the production of too much cortisol, while pituitary gland tumors cause the overproduction of ACTH. The excess ACTH production causes the release of too much cortisol from the adrenal cortex. The symptoms of Cushing syndrome are dependent on how high the cortisol levels are. Some common signs and symptoms are weight gain in the upper body and face, fatty deposits between the shoulder blades, diabetes, hypertension, hirsutism in women, weakness, and osteoporosis. The treatment for Cushing syndrome is dependent on the cause. The most common treatment is through surgical intervention. However, glucocorticoid-receptor antagonists are also an option when there are contraindications to surgery.
Hypocortisolism: Hypocortisolism, also known as Addison disease, occurs when the adrenal glands do not produce enough corticosteroids. Primary adrenal insufficiency results from the body’s attacking its adrenal cortex. Patients with primary adrenal insufficiency usually have other autoimmune diseases. Secondary adrenal insufficiency is when the pituitary gland does not produce enough ACTH, which can be caused by pituitary tumors and inflammation. Symptoms of Addison disease are weight loss, hyperpigmentation, and fatigue. Steroid replacement therapy is required to treat the symptoms of hypocortisolism. This therapy includes taking oral corticosteroids, like hydrocortisone and prednisone.
High doses of corticosteroids are prescribed to suppress the acute inflammatory cascade in asthma exacerbation, COPD exacerbation, septic shock and flare of autoimmune diseases.
|||Yaribeygi H,Panahi Y,Sahraei H,Johnston TP,Sahebkar A, The impact of stress on body function: A review. EXCLI journal. 2017; [PubMed PMID: 28900385]|
|||Hakamata Y,Komi S,Moriguchi Y,Izawa S,Motomura Y,Sato E,Mizukami S,Kim Y,Hanakawa T,Inoue Y,Tagaya H, Amygdala-centred functional connectivity affects daily cortisol concentrations: a putative link with anxiety. Scientific reports. 2017 Aug 16; [PubMed PMID: 28814810]|
|||Exton JH, Regulation of gluconeogenesis by glucocorticoids. Monographs on endocrinology. 1979; [PubMed PMID: 386091]|
|||Lee DY,Kim E,Choi MH, Technical and clinical aspects of cortisol as a biochemical marker of chronic stress. BMB reports. 2015 Apr; [PubMed PMID: 25560699]|
|||Chaudhry HS,Bhimji SS, Cushing Syndrome 2018 Jan; [PubMed PMID: 29261900]|
|||Lila AR,Sarathi V,Jagtap VS,Bandgar T,Menon P,Shah NS, Cushing's syndrome: Stepwise approach to diagnosis. Indian journal of endocrinology and metabolism. 2011 Oct; [PubMed PMID: 22145134]|
|||Neary N,Nieman L, Adrenal insufficiency: etiology, diagnosis and treatment. Current opinion in endocrinology, diabetes, and obesity. 2010 Jun; [PubMed PMID: 20375886]|
|||Sharma S,Chakraborty RK, Asthma Medications . 2018 Jan [PubMed PMID: 30285350]|