Glucocorticoids- Cortisol & Corticosterone in human body. Medicine is Life WinnerzKlub

1. Glucocorticoids
Cortisol (a.k.a. hydrocortisone) &
Cortisterone
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2. Glucocorticoids:
• Cortisol and corticosterone are referred to as
glucocorticoids.
• because they increase hepatic glucose output by:
– stimulating the catabolism of peripheral fat and
protein to provide substrate for hepatic
gluconeogenesis.
• The glucocorticoids help regulate the metabolism
of carbohydrates, proteins, and fat.
• They act on virtually all cells of the body.
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3. A. SYNTHESIS AND BINDING TO
PLASMA PROTEINS
• Both cortisol and corticosterone are secreted in
an unbound state but circulate bound to plasma
proteins.
• They bind mainly to corticosteroid-binding
globulin (CBG) (or transcortin) and to a lesser
extent to albumin.
• Protein binding serves mainly to distribute and
deliver the hormones to target tissues, but it also
delays their metabolic clearance and prevents
marked fluctuations of glucocorticoid levels
during episodic secretion by the gland.
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4. B. CORTICOSTEROID-BINDING
GLOBULIN (CBG)
• CBG (MW ~50,000) is an α-globulin synthesized in the
liver.
• Its production is increased by pregnancy, estrogen or
oral contraceptive therapy, hyperthyroidism, diabetes,
certain hematologic disorders, and familial CBG excess.
• When the CBG level rises, more cortisol is bound, and
the free cortisol level falls temporarily.
• This fall stimulates pituitary adrenocorticotropin
(ACTH) secretion and more adrenal cortisol production.
• Eventually, the free cortisol level and the ACTH
secretion return to normal but with an elevated level
of protein-bound cortisol.
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5. Adrenal Gland Product(s):
Stimulatory Mechanism(s): Adrenal Gland Zone: Product(s):
Renin-angiotensin, ACTH Zona glomerulosa Aldosterone
ACTH, hypothalamic CRH Zona fasciculata Cortisol, sex hormones
ACTH, hypothalamic CRH Zona reticularis Sex hormones, ?cortisol
Preganglionic fibers of SNS Medulla Catecholamines
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6. D. METABOLISM
• The glucocorticoids are metabolized in the liver and conjugated to
glucuronide or sulfate groups.
• The inactive conjugated metabolites are excreted in the urine and
stool.
• The metabolism of cortisol is decreased in:
– infancy
– old age
– pregnancy,
– chronic liver disease,
– hypothyroidism,
– anorexia nervosa,
– surgery,
– starvation,
– and other major physiologic stress.
• Catabolism of cortisol is increased in thyrotoxicosis.
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7. (cont’d)
• Variety of neurotransmitters Corticotropin releasing
hormone(CRH) Adrenocorticotropic hormone(ACTH)
• The hypothalamus is subject to regulatory influences from
other parts of the brain, including the limbic system.
• CRH is transported in the portal-hypophysial vessels to the
anterior pituitary.
• The control of ACTH & CRH secretion involves three
components:
– episodic secretion & diurnal rhythm of ACTH
– stress responses of the hypothalamic-pituitary-adrenal axis
– negative feedback inhibition of ACTH secretion by cortisol
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8. Inhibitory effect of
cortisol on the
hypothalamus
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9. A. Episodic & Diurnal Rhythm of
ACTH:
• ACTH is secreted in episodic bursts throughout the day, after a
diurnal (circadian) rhythm, with bursts most frequent in the early
morning and least frequent in the evening.
• The peak level of cortisol in the plasma normally occurs between
6:00 and 8:00 am (during sleep, just before awakening) and the
nadir at around 12:00 am.
• It is lost in Cushing's syndrome.
• The diurnal rhythm is altered also by changes in patterns of sleep,
light-dark exposure, or food intake; physical stress such as major
illness, surgery, trauma, or starvation; psychologic stress, including
severe anxiety, depression, and mania; CNS and pituitary disorders;
liver disease and other conditions that affect cortisol metabolism;
chronic renal failure; alcoholism; and antiserotonergic drugs such as
Cyproheptadine.
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10. B. Stress Response:
• Plasma ACTH and cortisol secretion are also triggered by various
forms of stress.
• Emotional stress (such as fear and anxiety) and bodily injury (such
as surgery or hypoglycemia) release CRH from the hypothalamus
and thus ACTH from the pituitary.
• This, in turn, results in a transient increase in cortisol secretion.
• If the stress is prolonged, it may abolish the normal diurnal rhythm
of ACTH and cortisol secretion.
• The stress response of plasma ACTH and cortisol is abolished in
Cushing's syndrome but is exaggerated after adrenalectomy. The
circulating catecholamines, epinephrine and norepinephrine, do not
increase ACTH secretion.
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11. Types of stress that increase cortisol
release:
Stress:
Trauma of almost any type
Infection
Intense heat or cold
Injection of norepinephrine & other sympathomimetic drugs
Surgery
Injection of necrotizing substances beneath the skin
Restraining an animal so that it cannot move
Almost any debilitating disease
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12. C. Negative Feedback:
• ACTH secretion is inhibited in a negative feedback fashion by high
circulating levels of free cortisol.
• This feedback inhibition occurs at both the pituitary and the
hypothalamus.
• A rising level of plasma cortisol inhibits release of ACTH from the
pituitary by both inhibiting CRH release from the hypothalamus and
interfering with the stimulatory action of CRH on the pituitary.
• The fall in plasma ACTH leads to a decline in adrenal secretion of
cortisol.
• ACTH secretion is also inhibited by chronic treatment with
exogenous corticosteroids in proportion to their glucocorticoid
potency.
• When prolonged corticosteroid treatment is stopped, the adrenal is
atrophic and unresponsive and the patient is at risk for acute
adrenal insufficiency.
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13. Effects of ACTH on the Adrenal:
• Circulating ACTH binds to high-affinity
receptors on adrenocortical cell membranes,
activating adenylyl cyclase, increasing
intracellular cyclic adenosine monophosphate
(cAMP), and promoting synthesis of the
enzyme that converts cholesterol to steroid
hormone precursors.
• Increased glucocorticoid synthesis and
secretion result within minutes.
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14. Effects:
• In most tissues, glucocorticoids have a catabolic effect, promoting
degradation of protein & fat to provide substrate for intermediary
metabolism.
• In the liver, however, glucocorticoids have a synthetic effect,
promoting the uptake & use of carbohydrates (in synthesis of
glucose & glycogen), amino acids (in synthesis of RNA & protein
enzymes), and fatty acids (as an energy source).
• During fasting, glucocorticoids help to maintain plasma glucose
levels by several mechanisms.
• In peripheral tissues, glucocorticoids antagonize the effects of
insulin.
• Glucocorticoids inhibit glucose uptake in muscle and adipose
tissue.
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15. (cont’d):
• The brain and heart are spared this antagonism, and the extra
supply of glucose helps these vital organs to cope with stress.
• In diabetics, the insulin antagonism may worsen control of blood
sugar, raise plasma lipid levels, and increase the formation of
ketone bodies.
• However, in nondiabetics, the rise in blood glucose stimulates a
compensatory increase in insulin secretion that prevents these
sequelae.
• Small amounts of glucocorticoids must be present for other
metabolic processes to occur (permissive action).
• For example, glucocorticoids must be present for catecholamines to
produce their calorigenic, lipolytic, pressor, and bronchodilator
effects and for glucagon to increase hepatic gluconeogenesis.
• Glucocorticoids are also required to resist various stresses.
• Indeed, the increased secretion of pituitary ACTH and consequent
increase in circulating glucocorticoids after injury are essential to
survival.
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16. Effects of Cortisol:
• On carbohydrate metabolism:
1. Stimulation of gluconeogenesis.
2. Decreased glucose utilization by cells.
• On protein metabolism:
1. Reduction in cellular protein.
2. It increases liver & plasma proteins.
3. Increased blood amino acids, Diminished transport
of amino acids into extrahepatic cells, & Enhanced
transport into hepatic cells.
• On fat metabolism:
1. Mobilization of fatty acids.
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17. Cortisol & Inflammation:
• Cortisol has the following effects in preventing
inflammation:
– Cortisol attenuates fever mainly because it
reduces the release of IL-1 from WBCs.
– Cortisol suppresses the immune system.
– Cortisol decreases both migration of WBCs &
phagocytosis of the damaged cells.
– Cortisol decreases the permeability of capillaries.
– Cortisol stabilizes the lysosomal membranes.
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