Adrenal glands and
hormones
Adrenal glands
The adrenals are orange-colored
glands that sit on top of the kidneys
near the spine, just underneath the
last rib and extending down about an
inch. The right adrenal is shaped
something like a pyramid, whereas
the left is shaped more like a half
moon.
Each adrenal gland is composed of
two endocrine components: a medulla
(inner part) that constitutes 20% of
the gland and a cortex (outer part) that
constitutes the remaining 80%. The
cortex consists of three zones. The
medulla and each of the zones in the
cortex each produce different
hormones that serve a variety of
functions in your body.
Adrenal Glands
The Adrenal Cortex
The adrenal cortex is divided into
three zones which each secrete
different hormones that carry out
specific functions throughout your
body.
1. Zone of glomerulosa
Cortex
1. Zone of glomerulosa
2
3
Medulla
Aldosterone is secreted from this zone which is the major hormone
controlling the sodium and potassium levels, and thus fluid balance,
within your bloodstream, cells and interstitial fluids. It is also called
mineralocorticoids.
Cortex
The Adrenal Cortex
1. Zone of glomerulosa
2. Zone of fasciculata
2
Coritsol (hydrocortisone) is produced,
affects glucose, amino acid and fat
metabolism, which is called glucocorticoids.
Cells of this zone are arranged into fascicles
separated by venous sinuses.
3. Zone of reticularis
3
Medulla
Dehydroepiandrosterone (DHEA)-precursor for androgen is
synthesized. This zona manufactures an ancillary portion of sex
hormones for each sex and also produces male hormones in women
and female hormones in men to keep the effects of the dominant sex
hormones in balance .
Adrenals
CORTEX
Zona Glomerulosa
Mineralocorticoids (Aldosterone)
Na+, K+ and water homeostasis
Zona Fasciculata
Glucocorticoids (Cortisol)
Glucose homeostasis and many
others
Zona Reticularis
Sex steroids (androgens)
Medulla: “Catecholamines”
Epinephrine, Norepinephrine, dopamine
Synthesis of adrenocorticosteroids
All steroid hormones have in common the 17-carbon cyclopentaoperhydrophenanthrene nucleus. Additional carbons can be added at
positions 10 and 13 or as a side chain attached to C17.
Synthesis of adrenocorticosteroids
Steroid hormones and their precursors and metabolites differ in
1. number and type of substituted groups,
2. number and location of double bonds,
3. stereochemical configuration.
21
18
18
17
19
3
Synthesis of adrenocorticosteroids
1. Uptake of cholesterol by the adrenal cortex is mediated by the LDL
receptor. With long-term stimulation of the adrenal cortex by ACTH, the
number of LDL receptors increases. Much of the cholesterol in the
adrenal is esterified and stored in cytoplasmic lipid droplets.
Synthesis of adrenocorticosteroids
2. Upon stimulation of the adrenal by ACTH or cAMP, an esterase is
activated, and the free cholesterol formed is transported into the
mitochondria.
Synthesis of adrenocorticosteroids
3. In the mitochondria, a cytochrome P450 side chain cleavage
enzyme (P450SCC) converts cholesterol to pregnenolone.
Synthesis of adrenocorticosteroids
4. Pregnenolone may be converted by dehydrogenase/isomerase to
progesterone or else by P450c17 (17-α-hydroxylase) to 17αhydroxypregnenolone. Progesterone can also be converted to 17αhydroxyprogesterone by P450c17.
17-α-hydroxylase
dehydrogenase/isomerase
17-α-hydroxylase
Synthesis of adrenocorticosteroids
5. After the synthesis of progesterone and 17-hydroxyprogesterone,
P450c21(21-hydroxylase) can hydroxylate these steroids at the 21
position, resulting in 11-deoxycorticosterone and 11-deoxycortisol,
respectively.
21-hydroxylase
21-hydroxylase
6. The final step in the synthesis of adrenal mineralocorticoids and
glucocorticoids is mediated by P450c11 (11-β-hydroxylase), which
also mediates the final steps in the synthesis of aldosterone from
deoxycorticosterone.
11
11-β-hydroxylase
11-β-hydroxylase
Synthesis of adrenocorticosteroids
7. P450c17 has two activities, that of a 17α-hydroxylase and that of a C17,20 lyase capable of breaking up the C-17,20 carbon bond of 17αhydroxypregnenolone or 17α-hydroxyprogesterone, yielding
dehydroepiandrosterone (DHEA) or androstenedione, respectively.
Synthesis of adrenocorticosteroids
8. 17-hydroxysteroid dehydrogenase
convert androstenedione to
testosterone. P450aro mediates the
aromatisation of androgens to
estrogens in the gonads. In peripheral
target tissues, testosterone can further
be converted to 5αdihydrotestosterone by 5α-reductase.
Biosynthesis
Of human
steroid
Hormones
Some autosomal recessive mutations in biosynthetic enzymes
responsible for converting cholesterol to androgens generally lead to
partial male-to-female sex reversal.
CAH (congenital adrenal hyperplasia): For P450c21 is deficiency,
cortisol synthesis decreases, leading to overproduction of ACTH. When
this occurs adrenal steroid synthesis is stimulated and 17hydroxyprogesterone is converted to androstenedione and further to
testosterone, leading to severe virilization of the female fetus. This
disorder is known as CAH which disrupts the synthesis of all adrenal
and gonadal steroids. Affected genetic males are born with normal
female external genitalia.
Biochemical actions of adrenocorticosteroids
A. Mineralocorticoids: aldosterone
It promotes Na+ reabsorption at the distal
convoluted tubules of kidney. Na+ retention
is accompanied by corresponding excretion
of K+,H+ and NH4+ ions.
Biochemical actions of adrenocorticosteroids
B. Glucocorticoids: Cortisol
Biochemical actions of adrenocorticosteroids
B. Glucocorticoids: Cortisol
1. Effects on glucose metabolism: They promote gluconeogenesis.
They work in tandem with insulin from the pancreas to maintain blood
glucose levels in the proper balance.
2. Effects on lipid metabolism: They increase lipolysis in adipose
tissue and reduce synthesis of TAG.
3. Effects on protein and nucleic acid metabolism: They promote
transcription and protein synthesis in liver. They also cause catabolic
effects in extrahepatic tissues results in enhanced degradation of protein.
4. Effects on water and electrolyte metabolism: Deficiency of them
cause increased production of ADH which can decrease glomerular
filtration rate causing water retention in the body.
5. Effects on immune system: Cortisol suppress the immune response
directly and indirectly by affecting most cells that participate in immune
reactions and inflammatory reactions. It is powerful anti-inflammatory
even when secreted at normal levels. It also reduces the rate at which
lymphocytes multiply and accelerates their programmed cell death to
further protect the body from this overreaction. This is one of the
reasons why strong corticosteroids (prednisone, prednisolone, etc.) are
used with all diseases involving inflammatory processes, including autoimmune diseases.
6. Effects on cardiovascular system: Cortisol could control the
contraction of the walls of the mid-sized arteries in increasing blood
pressure, but this hypertensive effect is moderated by calcium and
magnesium. It also directly affects the heart by regulating sodium and
potassium in the heart cells and increasing the strength of contraction of
the heart muscle.
7. Effects on central nervous system: The changes of behavior, mood,
excitability and even the electrical activity of neurons in the brain
frequently occur in cases of excess and deficient cortisol levels. Many
signs and symptoms of adrenal fatigue involve moodiness, decreased
tolerance, decreased clarity of thought and decreased memory. These
occur because the brain is affected by both too little and too much
cortisol.
Stress
 Adrenal glands are the anti-stress glands of the body.
 There are four major categories of stress:
1. Physical stress: such as overwork, lack of sleep, athletic overtraining.
2.Chemical stress: environmental pollutants, allergies to foods, diets
high in refined carbohydrates, endocrine gland imbalances.
3. Thermal stress: over-heating or over-chilling of the body
4. Emotional and mental stress
Stress: During stress cortisol must
simultaneously provide more blood glucose,
mobilize fats and proteins for a back-up
supply of glucose, modify immune reactions,
heartbeat, blood pressure, brain alertness and
nervous system responsiveness. If cortisol
level cannot rise in response to these needs,
maintaining your body under stress is nearly
impossible.
Hypothalamopituitary adrenal (HPA) axis
Immune
system:
altered
Stress
Circadian
rhythm
Hypothalamus
CRH
Anterior
Pituitary Gland
(-)
Posterior
Pituitary Gland
ACTH
Glucocorticoids,
Adrenals Catecholamines,
etc..
Kidney
Muscle:
Net loss of amino
Acids (glucose)
Liver:
Deamination of
proteins into amino
acids,
gluconeogenesis
(glucose)
Fat Cells:
Free fatty
acid
mobilization
Heart rate:
Increased
(Figure 9-40)
Fasting
People have considerable difficulty when on a prolonged fasting.
They will always rationalize the problems encountered on a fasting
as being due to the body detoxifying.
During a fasting, the body will call on the adrenals to produce
glucocorticoids to maintain blood glucose level which is adequate for
normal level of activity. The glucocorticoids can elevate blood
glucose by breaking down protein into carbohydrates through the
process of gluconeogenesis.
Regulation of glucocorticoids
The Secretion of glucocorticoids from the adrenal cortex is regulated
by negative feedback involving the CRH secretion by the hypothalamus.
CRH then acts on the anterior pituitary to stimulate ACTH secretion,
which then stimulates the adrenal cortex into cortisol secretion. About
70% of blood cortisol is bound to a carrier protein called corticosteroidbinding globulin. Another 15% is bound to albumin, the remaining 15%
exists free in solution.
※ The Hypothalamus/Pituitary/Adrenal (HPA) Axis
The HPA axis or HPA system, a negative
feedback system, is one of the most
important elements of homeostasis, the
process that maintains a steady internal
biochemical and physiological balance in
your body. The HPA Axis adjusts cortisol
level according to the needs of the body,
under normal and stressed conditions, via
ACTH. ACTH is secreted from the pituitary
gland in response to orders form the
hypothalamus and travels in the
bloodstream to the adrenal cortex.
Addison's Disease: Primary Chronic Adrenocortical
Insufficiency
People who suffer from adrenal fatigue almost always have some
form of irregular blood sugar pattern, of which hypoglycemia is the
most common.
When your adrenals are fatigued, their cortisol output is diminished
and you have lower levels of circulating blood cortisol, your liver has a
more difficult time converting glycogen into glucose.
Cushing's syndrome (hyperadrenocorticism or hypercorticism) is a
endocrine disorder caused by high levels of cortisol (hypercortisolism)
in the blood. This can be caused by taking glucocorticoid drugs, or by
tumors that produce cortisol or ACTH.
Cortex
The Adrenal Medulla
The functional unit of the adrenal
medulla is the chromaffin cell, which
functions as a neuroendocrine cell. In
response to stimulation, chromaffin cells
secrete the hormones epinephrine
(adrenaline) and norepinephrine
(noradrenalin) directly into the blood.
1
2
3
Medulla
The medulla is involved in extreme stress and, within this context,
epinephrine and norepinephrine both work with cortisol from the
adrenal cortex. Epinephrine and norepinephrine are important mainly in
crisis situations.
Catecholamines Biosynthesis
1. Tyrosine is precursor for the synthesis of catecholamines.
2. The catecholamine are produced in response to fight,
fright and flight (3F). These include emergencies like
shock, cold, fatigue, emotional condition like anger.
Biochemical function of catecholamine
1. Effect on carbohydrate metabolism: Both of them can increase
glycogenolysis and gluconeogenesis and decrease glycogenesis.
①Catecholamine promote the release of glucose from liver and decrees
its utilization by muscle; ②Epinepherine inhibits insulin secretion
but promote glucagon secretion.
2. Effect on lipid metabolism: Both of them enhance the breakdown of
TAG in adipose tissue. This cause increase in the free fatty acid in the
circulation which are effectively utilized by the heart and muscle as
fuel source.
3. Effect on physiological function: Cateccholamines increase cardiac
output, blood pressure and oxygen consumption. They cause smooth
muscle relaxation in bronchi, GIT and blood vessels supplying
skeletal muscle.
phaeochromocytoma (PCC) or
pheochromocytoma:
a neuroendocrine tumor of the medulla of the adrenal
glands (originating in the chromaffin cells), or extraadrenal chromaffin tissue that failed to involute after birth
and secretes excessive amounts of catecholamines,
usually adrenaline (epinephrine) if in the adrenal gland
and not extra-adrenal, and noradrenaline (norepinephrine).
17% of adrenal cases are bilateral (suggesting hereditary disease)
18.4% in children (also suggesting hereditary disease)
5% are extra-adrenal (located in any orthosympathetic tissue):
of these 9% are in the abdomen and 1% are located elsewhere.
Some extra-adrenal phaeochromocytomas are probably actually
paragangliomas, but the distinction is only possible after surgical
resection.
11.1% malignant, but this rises to 30% for extra-adrenal cases
26% are hereditary
3% recur after being resected
14% of affected individuals do not have arterial hypertension
Here's a look at the extra-adrenal sites of pheochromocytomas
1. Within the sympathetic nerve chain along the spinal cord (orange spots)
2. Overlying the distal aorta (the main artery from the heart) (green spots)
3. Within the ureter (collecting system from the kidney (yellow spot)
4. Within the urinary bladder (blue spot)
5. Remember, 90% are in the adrenal glands (red spots on the kidneys)