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Kortizol Fizyoloji
Kortizol Fizyoloji
Kortizol Fizyoloji
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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]
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Cellular Level
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]
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.
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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]
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
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.
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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]
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]
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Related Testing
Clinical Significance
To cite;