Adrenocortical Hormones

Adrenocortical Hormones
• Adrenal Glands- lie at the superior poles of the kidneys (suprarenal
glands); each gland is made up of a medulla and cortex

• Adrenal medulla-makes up 20% of the gland and is functionally

related to the sympathetic nervous system; secretes epinephrine and
norepinephrine

• Adrenal cortex-secretes the corticosteroids which are synthesized

from cholesterol
Adrenocortical Hormones
Corticosteroids

• Mineralocorticoids-especially affect the electrolytes such as sodium and

potassium

• Glucocorticoids-exhibit important effects that increase blood glucose

concentrations

• Androgenic hormones-exhibit the same effects as testosterone

• Over 30 isolated from the cortex but the two most important are aldosterone
and cortisol
Adrenocortical Hormones
Synthesis and Secretion of Adrenocorticoid Hormones

Three Distinct Layers of the Adrenal Gland

1. Zona glomerulosa-thin layer just beneath the capsule;

secrete aldosterone; the secretion is controlled by ECF
concentrations of angiotensin II and potassium

2. Zona fasciculata-middle and widest layer; secretes the

glucocorticoids, cortisol and corticosterone as well as small
amounts of androgens; secretion is controlled by ACTH

3. Zona reticularis-deepest layer of the cortex; secretes the

adrenal androgens DHEA, and androstenedione as well as
small amounts of estrogens; under the control of ACTH

• Adrenocortical H or mone s are Steroids Derived

from Cholesterol
• Synthesis and Secretion of Adrenocortical Hormones

• Adrenocortical Hormones are Bound to Plasma Proteins

• Adrenocortical Hormones are Metabolized in the Liver

Functions of the Mineralocorticoids-Aldosterone
• Mineralocorticoid Deficiency Causes Severe Renal Sodium
Chloride Wasting and Hyperkalemia-

Without mineralocorticoids, potassium ion concentration

in the ECF rises markedly, sodium and chloride are rapidly
lost from the body, and the total ECF and blood volume
become greatly reduced
 Functions of the Mineralocorticoids-Aldosterone

• Aldosterone is the Major Mineralocorticoid

a. 90% of the mineralocorticoid activity comes from aldosterone and 10% comes
from cortisol
b. Aldosterone increases renal tubular absorption of sodium and the secretion
potassium
c. Excess aldosterone increases ECF volume and arterial pressure but has
only a small effect on plasma sodium concentration
d. Excess aldosterone causes hypokalemia and muscle weakness
e. Too little aldosterone causes hyperkalemia and cardiac toxicity
f. Excess aldosterone increases tubular hydrogen ion secretion and causes
alkalosis
g. Aldosterone stimulates sodium and potassium transport in sweat glands,
salivary glands, and intestinal epithelial cells
 Functions of the Mineralocorticoids-Aldosterone

• Cellular Mechanism of Aldosterone Action

a. Because of its lipid solubility, aldosterone diffuses readily into the

tubular epithelial cell
b. It then combines with a receptor protein, mineralocorticoid
receptor
c. This complex or a product of the complex diffuses into the nucleus
eventually causing DNA to form a mRNA
d. The mRNA diffuses back into the cytoplasm where it induces protein
synthesis
e. The proteins formed are a mixture of (1) one or more enzymes, and (2)
membrane transport proteins that all act together and are required for
sodium, potassium, and hydrogen transport through the cell membrane.
Functions of the Mineralocorticoids-Aldosterone
Cellular Mechanism of Aldosterone Action
 Functions of the Mineralocorticoids-Aldosterone

• Nongenomic Actions of Aldosterone and Other Steroid

Hormones

a. Can increase the formation of cAMP in smooth muscle cells and

epithelial cells of the renal collecting tubules

b. Can also stimulate the phosphatidylinositol second messenger

system
 Functions of the Mineralocorticoids-Aldosterone

• Regulation of Aldosterone Secretion

a. Increased k+concentration in ECF greatly increases aldosterone

secretion
b. Increased angiotensin II in ECF greatly increases aldosterone secretion
c. Increased Na+ concentration in the ECF very slightly decreases
aldosterone secretion
d. ACTH is necessary for aldosterone secretion but has little effect on the
rate of secretion in most physiological conditions
 Functions of the Glucocorticoids
• Effects of Cortisol on Carbohydrate Metabolism

a. Stimulation of gluconeogenesis

1) Cortisol increases the enzymes required to convert amino acids into

glucose in the liver cells

2) Cortisol causes mobilization of amino acids from the extra-hepatic

tissues (mainly from muscle)

b. Decreased glucose utilization by cells (moderate decrease)

c. Elevated blood glucose concentration and "adrenal diabetes" (when the

blood sugar is 50% greater than normal)
 Functions of the Glucocorticoids

• Effects of Cortisol on Protein Metabolism

a. Reduction in cellular protein (decreased synthesis and increased catabolism)

b. Increase in liver and plasma proteins

c. Increased blood amino acids, diminished transport of amino acids into

extra-hepatic cells, and enhanced transport into hepatic cells
 Functions of the Glucocorticoids

• Effects of Cortisol on Fat Metabolism

a. Increases the concentration of free fatty acids in the plasma, increasing

their utilization for energy

b. Obesity caused by excess cortisol (chest and head region-"moon face"

 Functions of the Glucocorticoids

• Cortisol is Important in
Resisting Stress and
Inflammation

a. Physical or neurogenic stress causes

an immediate increase in the
secretion of ACTH, followed by an
increase in cortisol
 Functions of the Glucocorticoids
• Anti-Inflammatory Effects of High Levels of Cortisol
a. Five main stages of inflammation:
1) Release of inflammatory chemicals from damaged tissues and cells (i.e. histamine,
prostaglandins, leukotrienes, bradykinin, etc.)
2) Erythema-increased blood flow due to vasodilation
3) Leakage of fluids leading to edema
4) Infiltration by leukocytes
5) Ingrowth of fibrous tissue in the healing process
b. Basic anti-inflammatory effects of cortisol
1) It can block the early stages of inflammation before it actually begins
2) Causes rapid resolution of the inflammation and increased rapidity of healing
c. Cortisol prevents development of inflammation by stabilizing lysosomes & by other effects
1) Cortisol stabilizes the lysosomal membranes
2) Decreases the permeability of the capillaries
3) Decreases the migration of WBCs and phagocytosis
4) Suppresses the immune system-decreasing lymphocyte production
5) Attenuates fever (inhibits interleukin I production)
 Functions of the Glucocorticoids

• Regulation of Cortisol Secretion by ACTH

a. ACTH stimulate cortisol secretion

b. ACTH secretion is controlled by
corticotropin releasing factor from the
hypothalamus
c. ACTH activates adrenocortical cells to
produce steroids by increasing cAMP
 Functions of the Glucocorticoids

• Regulation of Cortisol Secretion byACTH

Feedback mechanism
Cortisol has direct negative feedbacks on the hypothalamus to
decrease formation of CRH
High circulating levels of cortisol inhibit secretion and
formation of ACTH, decreasing response of anterior pituitary
gland to CRH.
High levels of ACTH also inhibit CRH secretion by a negative
feedback mechanism.
These feedbacks help regulate the plasma concentration of
cortisol toward a normal control level.
* Clinical treatment of cortisol (large does and long time)
always cause the atrophy of the adrenal gland.
Functions of the Glucocorticoids
• Abnormalities of Adrenocortical Secretion

a. Hypoadrenalism (Addison's Disease)

b. Hyperadrenalism (Cushing's Syndrome)

Cushing’s Syndrome
People with excess cortisol
secretion
develop a peculiar type of obesity
excess deposition of fat in the
chest and head regions of the
body
a buffalo-like torso and a
rounded “moon-face”.
Adrenal Medulla (inner/nervous)
–CNS synapses directly with adrenal medulla (neural response)

–Adrenal medulla releases Epinephrine (adrenalin) & NorEpinephrine

(noradrenalin) during fight or flight mechanism
–Stimulates use of glucose and glycogen and release of lipids from
adipocytes
–Increases HR, BP and vasoconstricts blood vessels
Insulin, Glucagon, and
Diabetes Mellitus
 Physiologic Anatomy of the Pancreas

a. Composed of two major

types of tissues, the acini,
which secrete digestive
juices, and the islets of
Langerhans, which secrete
insulin and glucagon
directly into the blood
b. Alpha cells of the islets-
secrete glucagon
c. Beta cells-secrete insulin
d. Delta cells-secrete
somatostatin
 Insulin and Its Metabolic Effects
• Insulin is a Hormone Associated with Energy
Abundance

a. Composed of two amino acid chains,

MW 5808
b. Preproinsulin to a proinsulin to insulin
c. In the blood, it circulates as an unbound
form
d. Half-life in circulation is about 6
minutes

By proteolytic cleavage, four basic amino acids (31,32, 64, 65)

and the connecting peptide are removed and proinsulin is
converted to insulin
A schematic of the human proinsulin molecule, which is cleaved in
the Golgi apparatus of the pancreatic beta cells to form connecting
peptide (C peptide), and insulin, which is composed of the A and B
chains connected by disulfide bonds. The C peptide and insulin are
packaged in granules and secreted in equimolar amounts, along
with a small amount of proinsulin
• Activation of Target Cell Receptors by Insulin and the Resulting Cellular Effects
To initiate its effects on target cells, insulin first binds with and
activates a membrane receptor protein.
• The insulin receptor is a tetramer made up of two α-subunits
that lie outside the cell membrane and two β-subunits that
penetrate the cell membrane and protrude into the cytoplasm
• When insulin binds with the alpha subunits on the outside of the cell,
portions of the beta subunits protruding into the cell become
autophosphorylated.
• The insulin receptor is an example of an enzyme-linked receptor.
• Autophosphorylation of the beta subunits of the receptor activates
a local tyrosine kinase, which in turn causes phosphorylation of
multiple other intracellular enzymes including a group called insulin-
receptor substrates (IRS).
• The net effect is to activate some of these enzymes while
inactivating others.
• In this way, insulin directs the intracellular metabolic machinery to
produce the desired effects on carbohydrate, fat, and protein
A schematic of the insulin receptor. Insulin binds to the α
metabolism. subunit of its receptor, which causes autophosphorylation of
the β-subunit receptor, which in turn induces tyrosine kinase
activity. The receptor tyrosine kinase activity begins a cascade
of cell phosphorylation that increases or decreases the activity
of enzymes, including insulin receptor substrates, that mediate
the effects on glucose, fat, and protein metabolism. For
example, glucose transporters are moved to the cell membrane
to assist glucose entry into the cell.
• Activation of Target Cell Receptors by Insulin and the
Resulting Cellular Effects
a. Within seconds after insulin binds to its receptors,
80% of the cells increase their uptake of glucose
b. Cell membrane becomes more permeable to
many amino acids, potassium ions, and phosphate
ions, causing increased transport of these
substances into the cell
c. Slower effects occur during the next 10-15 minutes
to change the activity levels of many more
intracellular metabolic enzymes
d. Much slower effects continue for hours and even
several days; enzymatic functions and protein
synthesis
• Effect of Insulin on Carbohydrates Metabolism
a. Promotes muscle glucose uptake and metabolism; if the muscle is not exercising, the glucose is
stored as muscle glycogen
b. Promotes liver uptake, storage, an use of glucose
1) Insulin inactivates liver phosphorylase and prevents the splitting of glycogen into glucose
2) Insulin causes the enhanced uptake of glucose from the blood by liver cells; increases the
activity of glucokinase
3) Increases the activity of the enzymes that promote glycogen synthesis
c. Glucose is released from the liver between meals
1) Decreasing blood glucose causes the pancreas to decrease insulin secretion
2) Lack of insulin reverses the effects of glycogen storage
3) Lack of insulin activates the splitting of glycogen into glucose; glucose phosphatase is
activated
d. Insulin promotes the conversion of excess glucose into fatty acids and inhibits gluconeogenesis in
the liver
e. In the brain most of the cells are permeable to glucose and can use glucose without the
intermediation of insulin
• Effect of Insulin on Fat Metabolism
a. Promotes fat synthesis and storage
1) Increases the transport of glucose into liver cells; after the liver glycogen
concentration reaches 5-6%, the glucose becomes available to form fat (split to acetyl
CoA from pyruvate to make fatty acids)
2) Excesses of citrate and isocitrate are formed when excess amounts of glucose are
being used for energy—activate enzymes for the first steps of fatty acid synthesis
3) Most of the fatty acids are then synthesized within the liver and used to form
triglycerides
b. Role of insulin in the storage of fat in the adipose cells
1) Insulin inhibits the action of hormone sensitive lipase
2) Promotes glucose transport through the membrane into the fat cells
c. Insulin deficiency causes lipolysis of storage fat and the release of fatty acids
d. Insulin deficiency increases plasma cholesterol and phospholipid concentrations
e. Excess usage of fats during insulin lack causes ketosis and acidosis
Some of the acetoacetic acid is also converted into beta- hydroxybutyric acid and acetone.
Ketone bodies: beta-hydroxybutyric acid, acetone and acetoacetic acid. And their presence in large
quantities in the body fluids is called ketosis.
In severe diabetes the acetoacetic acid and the beta-hydroxybutiric acid can cause severe acidosis
and coma…death
• Effect of Insulin on Protein Metabolism
a. Insulin promotes protein synthesis and storage of amino
acids
1) Stimulates the transport of many of the aa into cells
2) Increases the translation of mRNA
3) Increases the rate of transcription of selected DNA
genetic sequences
4) Inhibits the catabolism of proteins
5) In the liver, insulin depresses the rate of gluconeogenesis
b. Insulin deficiency causes protein depletion and increased
plasma amino acids
c. Insulin and growth hormone interact synergistically to
promote growth
 • Mechanisms of Insulin Secretion
• The beta cells have a large number of glucose transporters
( GLUT-2) that permit a rate of glucose influx that is
proportional to the blood concentration in the
physiological range.
• Inside the cells, glucose is phosphorylated to glucose-6-
phosphate by glucokinase. ( rate-limiting step for glucose
metabolism)
• The glucose-6- phosphate is subsequently oxidized to form
adenosine triphosphate (ATP), which inhibits the ATP-
sensitive potassium channels of the cell.
• Closure of the potassium channels depolarizes the cell
membrane, thereby opening voltage-gated calcium
channels, which are sensitive to changes in membrane
voltage. This effect produces an influx of calcium that
stimulates fusion of the docked insulin-containing vesicles
with the cell membrane and secretion of insulin into the
extracellular fluid by exocytosis.
Basic mechanisms of glucose stimulation of insulin secretion
by beta cells of the pancreas
• Control of Insulin Secretion

a. Increased blood glucose stimulates insulin

secretion
b. Feedback relation between blood glucose
concentration and insulin secretion rate- a
rise in blood glucose increases the
secretion of insulin which in turn increases
the transport of glucose into liver, muscle, Increase in plasma insulin concentration after a sudden increase in
blood glucose to 2-3x the normal range
and other cells
c. Other factors that stimulate insulin
secretion-amino acids, GI hormones, other
hormones, ANS

Approximate insulin secretion at different plasma glucose levels

Factors and conditions that increase and decrease insulin secretion

Increase insulin secretion decrease insulin secretion

-increase blood glucose -Decrease blood glucose

-increase blood free fatty acid -fasting
-increase blood amino acid -somatostatin
-gastrointestinal hormones (gastrin, -Alfa-adrenergic activity
choleccystokinin ,secretin, gastric
inhibitory peptide )
-glucagon, growth hormone, cortisol.
-parasympathetic stimulation
-insulin resistance ;obesity
Role of Insulin (and Other Hormones) in “Switching”
Between Carbohydrates and Lipid Metabolism

• The signal that controls the switching mechanism is principally the blood glucose concentration.
When the glucose concentration is low, insulin secretion is suppressed and fat is used almost
exclusively for energy everywhere except in the brain.

• When the glucose concentration is high, insulin secretion is stimulated and carbohydrate is used
instead of fat, and the excess blood glucose is stored in the form of liver glycogen, liver fat, and
muscle glycogen.

• At least four other known hormones also play important roles in this switching mechanism: growth
hormone from the anterior pituitary gland, cortisol from the adrenal cortex, epinephrine from the
adrenal medulla, and glucagon from the alpha cells of the islets of Langerhans in the pancreas.
 Glucagon and it’s functions

• Glucagon is a hormone secreted by the alpha cells of the

islets of Langerhans ,when the blood glucose concentration
falls.
• has several functions that are diametrically opposed to those
of insulin .Most important of these functions is to increase
the blood glucose concentration ,an effect that is exactly the
opposite that of insulin
• Like insulin ,glucagon is a large polypeptide, it is composed
of a chain of 29 amino acids
• Glucagon is also called the hyperglycemic hormone.
 Glucagon and Its Functions
• Effects on Glucose Metabolism
a. Causes glycogenolysis and increased blood glucose concentration
1) Glucagon activates adenyl cyclase in the hepatic cell membrane
2) Which causes the formation of cAMP
3) Which activates protein kinase regulator protein
4) Which activates protein kinase
5) Which activates phosphorylase b kinase
6) Which converts phosphorylase b to a
7) Which promotes the degradation of glycogen into glucose-1-phosphate
8) Which is dephosphorylated and glucose is released
b. Glucagon increases gluconeogenesis
c. Glucagon activates adipose cell lipase-makes increased quantities of free fatty
acids available
d. Inhibits the storage of triglycerides
e. In high concentrations-enhances the strength of the heart, increases blood
flow in some tissues (kidney), enhances bile secretion, and inhibits gastric
acid secretion
 Glucagon and Its Functions
• Regulation of Glucagon Secretion

a. Increased blood glucose inhibits

glucagon

b. Increased blood amino acids

stimulates glucagon
secretion

c. Exercise stimulates glucagon

secretion
Approximate plasma glucagon concentration at different blood glucose levels
• Somatostatin Inhibits Glucagon and Insulin Secretion

a. Almost all factors related to the ingestion of food

stimulate somatostatin secretion (increased amino acids,
fatty acids, GI hormones, blood glucose)
b. Acts locally within the islets to decrease secretion of
insulin and glucagon
c. Decreases the motility of the stomach, duoenum, and gall
bladder
d. Decreases secretion and absorption in the GI tract
• the principal role of somatostatin is to extend the period over which the food
nutrients are assimilated into the blood.
• the effect of somatostatin in depressing insulin and glucagon secretion decreases
utilization of the absorbed nutrients by the tissues, thus preventing rapid
exhaustion of the food and therefore making it available over a longer period.
• Somatostatin is also the same chemical substance as growth hormone inhibitory
hormone, which is secreted in the hypothalamus and suppresses secretion of
growth hormone by the anterior pituitary gland.
Blood Glucose Regulation
• The blood glucose concentration is narrowly controlled, usually between 80 and 90 mg/ 100 ml of
blood in the fasting person each morning before breakfast.
• This concentration increases to 120 to 140 mg/100 ml during the first hour or so after a meal, but
the feedback systems for control of blood glucose return the glucose concentration rapidly back
to the control level, usually within 2 hours after the last absorption of carbohydrates.

• In severe hypoglycemia, a direct effect of low blood glucose on the hypothalamus stimulates the
sympathetic nervous system. In turn, the epinephrine secreted by the adrenal glands causes still
further release of glucose from the liver.
• Over a period of hours and days, both growth hormone and cortisol are secreted in response to
prolonged hypoglycemia, and they both decrease the rate of glucose utilization by most cells of
the body, converting instead to greater amounts of fat utilization. This, too, helps return the blood
glucose concentration toward normal.
Importance of Blood Glucose Regulation
• Glucose is the only nutrient that normally can be used by the brain, retina, and germinal
epithelium of the gonads in sufficient quantities to supply them optimally with their required
energy.
• Glucose can exert a large amount of osmotic pressure in the extracellular fluid, causing cellular
dehydration.
• An excessively high level of blood glucose concentration causes loss of glucose in the urine,
causing osmotic diuresis by the kidneys.
• Long-term increases in blood glucose may cause damage to many tissues, especially to blood
vessels. Vascular injury, associated with uncontrolled diabetes mellitus, leads to increased risk
for heart attack, stroke, end-stage renal disease, and blindness
 Diabetes Mellitus

• Diabetes Mellitus

Syndrome of impaired carbohydrate, protein, and fat

metabolism caused by either lack of insulin secretion or
decreased sensitivity of the tissues to insulin

a. Type I-insulin dependent diabetes mellitus; lack of insulin

secretion

b. Type II-non insulin dependent diabetes mellitus; initially

caused by the decreased sensitivity of tissues to insulin
(insulin resistance)