Introduction

Glucocorticoids are steroid hormones produced from the cortex of adrenal glands (gluco-corti-coids: glucose-cortex-steroids). Glucocorticoids have a pivotal role in the glucose, protein, and fat metabolism of the body. They originate from steroid precursors and are synthesized primarily in the zona fasciculata of the adrenal cortex. Their medical significance arises from their anti-inflammatory, anti-allergic, and immune-suppressive role in the body, and this particular role used for medical treatment purposes. One should remember that glucocorticoids are not the infamous anabolic steroids that are used by athletes for muscle buildup. Instead, these are the catabolic steroids that cause peripheral muscle breakdown. The essential glucocorticoid in the body is cortisol. It is released in a diurnal circadian pattern, with the highest levels released at around 8 AM and its lowest levels between midnight and 4 AM.[1]

Cellular Level

The release of cortisol is under the feed-back control of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotrophin-releasing hormone (CRH) is released from the hypothalamus and stimulates the adrenocorticotropic hormone (ACTH). ACTH acts by binding to a G protein-coupled receptor (the melanocortin two receptor- MC2R). This binding results in the activation of adenylyl cyclase, cAMP production, and activation of protein kinase A (PKA). PKA modifies the activity of specific transcription factors via phosphorylation.

ACTH actions include, the activation of HMG CoA reductase (the rate-limiting enzyme in cholesterol synthesis), increased LDL-C esters uptake (that are either stored or converted into cholesterol), activation of hormone-sensitive lipase (HSL) and lastly inhibition of acyl-coenzyme A (CoA): cholesterol acyltransferase (ACAT). The above actions of ACTH increased the available cholesterol pool for steroidogenesis. The first step in the steroidogenesis pathway occurs in mitochondria; StAR (induced by ACTH) moves cholesterol to the inner mitochondrial membrane. Desmolase, a CYP450 enzyme, exerts its action by catalyzing a break in the cholesterol side chain.[2][3] 

Glucocorticoid production in zona fasciculata involves cholesterol desmolase, 17a-hydroxylase, 21-hydroxylase, 11β-hydroxylase. The end product of this pathway is Cortisone. Cortisone (the inactive form of cortisol) is converted by type 1 hydroxysteroid dehydrogenase in the liver to its active form cortisol. Cortisol is released in the blood bound to cortisol binding protein (CBP), which is a globulin protein.[4] Cortisol has the potential to bind and activate both the glucocorticoid receptors and aldosterone receptors. 11β-hydroxysteroid (type II) dehydrogenase by converting cortisol to its inert form cortisone, prevents the cortisol- activation of mineralocorticoid receptors. However, when cortisol levels are high, and 11β-HSD is saturated, cortisol can activate mineralocorticoid receptors. Usually, this is a result of treatment with exogenous glucocorticoids at supra-physiologic doses.[5] 

Upon binding to an intracellular cytoplasmic glucocorticoid receptor (GR), the Cortisol-GR complex is translocated inside the nucleus. The compound acts at the DNA level, affecting the expression in a variety of genes and inducing various effects on different cells of the body like fibroblasts, white blood cells, etc.[6]

Cortisol half-life is 66 minutes, under normal conditions. The enzymatic system for cortisol metabolism is primarily in the liver. Corticosteroid metabolites are excreted in the urine—the primary urinary metabolite of cortisol Tetrahydrocortisol. A small amount of free/ unbound serum cortisol is not reabsorbed in the distal tubule of the kidney and is excreted into the urine. This small amount of cortisol is of diagnostic importance.

Function

The release of glucocorticoids is pulsatile throughout the day, peaking in the morning at around 8 am. Glucocorticoids are necessary for normal bodily functions. However, any form of stress (physical, psychological) is an acute inducer of cortisol secretion. Due to its role in stress, cortisol also called the stress hormone of the body.[7]

Metabolic Functions

Cortisol acts on glucose metabolism to cause hyperglycemia. This effect is not only involved in maintaining normal glucose homeostasis but at times of stress, glucose happens to be the only substrate that provides energy to the critical organs of the body such as the brain and skeletal muscles during times of stress such as an illness or exercise. Hyperglycemia is caused by increasing the synthesis of enzymes involved in glycogenolysis and gluconeogenesis.[8] 

Cortisol upregulates or activates or induces enzymes involved in gluconeogenesis and glycogenolysis. It antagonizes the actions of insulin and decreases the cellular uptake of glucose to increase the availability of glucose for the brain, red blood cells, and skeletal muscles. Cortisol increases gluconeogenesis by inducing the gene expression of the PEPCK enzyme. This step occurs in the cytosol; fructose-1,6-bisphosphate converts to fructose-6-phosphate. By antagonizing the actions of insulin, it decreases (a) glycogen synthesis and (b) glucose uptake by glut four transporters.  Glucocorticoids, to further increase the gluconeogenetic substrates, establish a catabolic state in muscles, inducing peripheral muscle breakdown and mobilizing amino acids towards the liver to be used in gluconeogenesis (formation of glucose from amino acids).

Furthermore, glucocorticoids activate hormone-sensitive lipase (HSL) in the adipose tissue resulting in increased availability of free fatty acids for beta-oxidation. These metabolic actions of glucocorticoids explain many of the effects of exogenous glucocorticoid medication. Glucocorticoids result in decreased muscle mass; skin gets thinner, fragile, and easy to bruise. Glucocorticoids also result in hyperglycemia and lipodystrophy (redistribution of fat in the back of the neck- buffalo hump, face -moon face- and decrease of adipose tissue in extremities). The mechanism of this fat redistribution is unknown.[9]

Αnti-inflammatory and Immune-suppressive Function

Glucocorticoids result in a net increase in the WBC count. The increased WBC count, is a combination of a decrease in neutrophil migration in tissues, an inhibition of neutrophil apoptosis, and promote WBC maturation in the Bone Marrow, and release in circulation. With regards to eosinophils, glucocorticoids induce apoptosis and sequestration of eosinophils in the periphery. Inhibition of interleukin-2 (IL-2) signaling (inhibition of T cell proliferation), the impaired release of cells from lymphoid tissues, T lymphocyte apoptosis, inhibition of NF-kB (decrease in cytokine gene expression) and degranulation inhibition of mast cells are effects of glucocorticoids in lymphatic tissue. In the setting of increased glucocorticoid levels in the blood, the macrophages of the reticuloendothelial system fail to recognize and phagocytose antigens (even opsonized antigens). A sequela of these effects is the regression in size of lymphoid tissue (thymus, spleen and lymph nodes.)[10]

Neurologic Effects

Several individuals who present with hypercortisolemia ( by receiving exogenous doses of glucocorticoids or suffer from Cushing syndrome) may present with depression. This effect of hypercortisolemia, a possible result of glucocorticoid-induced neuronal excitation, may have a role in the pathogenesis of the major depressive disorder. Affected hypercortisolemic patients present with difficulty falling asleep, a decrease in REM sleep latency, and slow-wave sleep. Also, alterations in electroencephalogram patterns are frequent in these individuals. Conversely, cortisol insufficiency is associated with an inability to perform tasks requiring mental concentration.[11]

HPA axis feedback control regulates levels of endogenously produced glucocorticoids and prevents such drastic effects in the bodily functions. Chronic exogenous glucocorticoid administration has such detrimental effects.

Mechanism

The majority of the effects of glucocorticoids result from the binding of cortisol to intracellular glucocorticoid receptors (GR). This complex translocates in the nucleus to change gene expression in a variety of ways. Intracellular GR receptors are bound to stabilizing proteins like Hsp-90 in their steroid-free state.

Once bound to the glucocorticoid, the steroid-GR complex moves towards the DNA and acts on the GRE (glucocorticoid response element) elements of DNA.  In this way, the complex induces transcription of the target DNA sequence (transactivation), or it acts in combination with other transcription factors to act on other parts of DNA to transactivate or to repress gene transcription. This complex may also attach itself to nGRE (negative glucocorticoid response elements) to downregulate or repress gene transcription directly.[12]

There is a hypothesis that glucocorticoids act at a post-translational level. They stabilize or destabilize specific mRNAs to further modulate protein formation.[13] 

The anti-inflammatory effects of glucocorticoids are exerted via transpression while the metabolic effects via “transactivation.” About 20% of all genes are under the control of glucocorticoids. Transactivation induces the formation of lipocortin-1. Lipocortin 1 decreases the production of phospholipase A2 (PLA2 is involved in the formation of prostaglandins and leukotrienes), inhibits COX-2 (post-transcriptional activity), promotes neutrophil detachment from the endothelium, and reduces neutrophil migration through the endothelium of blood vessels. These events result in an increased WBC count.

Transpression or gene inhibition decreases (a) the production of COX-2, (b) inducible NOS, and(c) most inflammatory cytokines (IL-1 thru IL-6, IL-8, IL-10, IL-13, GM-CSF, TNF-α, Interferon-γ). Other effects of glucocorticoids on protein, fat, and glucose metabolism are also exerted via the same mechanism of action, i.e., by modulating enzyme synthesis, which in turn controls subsequent events.[14]

Related Testing

Some points that one must recall about cortisol testing:

(a) Cortisol secretion exhibits a circadian rhythm.

(b) Cortisol concentrations increase during stress.

(c) The level of cortisol binding protein becomes increased in hyper-estrogenic states such as pregnancy, hyperthyroidism, diabetes, and in certain hematological disorders; these cause an increase in serum cortisol levels to help maintain equilibrium between the bound and unbound state of cortisol. CBG may decrease in familial CBG deficiency, hypothyroidism, and protein deficiency states such as severe liver disease and nephrotic syndrome. Cortisol levels are also increased by drugs containing estrogen, synthetic glucocorticoids, such as prednisone, pregnancy, and decreased by drugs such as androgens and phenytoins.[15][16][17][18][19][20] 

Cortisol levels can be established by measurement of cortisol levels in serum/plasma, saliva, or urine. A 24-hour urine collection is required to measure cortisol levels successfully. Normal values range from 2 to 6 μg/24 hours in women and 3 to 10 μg/24 hours in men. Salivary cortisol is in equilibrium with free cortisol and can be employed in children as an alternative to serum measurement.[21][22]

Clinical Significance

Glucocorticoids, both synthetic and natural, are used in various disorders.

1. Endocrinologists use the treatment of adrenal insufficiency and congenital adrenal hyperplasia.
2. Pharmacologic doses of the glucocorticoids are used to treat various allergic, immunological, and inflammatory disorders.