Adrenal glands:
located on top of kidneys
Adrenal Hormones
n
Catecholamines: medullary
n
n
n
Adrenaline and Noradrenaline (or epinephrine
and norepinephrine).
Secreted in response to stress: cause rate of
heartbeat, invoke "fight or flight" response
Corticosteroids: cortex
n
Cortisol (reduces inflammation) and
Aldosterone (controls sodium readsorption in
kidney)
In adrenal medullary
Synthesis and Secretion of
Catecholamines
n
Synthesis of catecholamines
begins with the amino acid
tyrosine
1
Synthesis of the
catecholamines from tyrosine
Inactivation of catecholamines
Inactivation of catecholamines
n
At the sympathetic neuroeffector junction
can take place by one or more of several
mechanisms:
n
n
n
uptake or reuptake
O-methylation
oxidative deamination
MAO (mono-aminoxidase)
COMT (catechol-O-methyltransferase)
2
Figure 27-3 Metabolism of epinephrine &
norepinephrine
Norepinephrine
Norepinephrine
Methoxyhydroxyphenylglycol
MHPG MHPG
Figure 27-4 Metabolism of dopamine
Epinephrine
& VMA: HPLC
Two mains enzymes, COMT
and MAO, are involved in
catecholamine metabolism
Vanillymandelic acid
VMA
HPLC Method for Measuring
Urinary Catecholamines
HVA: HPLC
Trace Level Analysis Microbore
HPLC of Catecholamines
n
n
Amperometric detection system
n
a thin-layer glassy carbon or
carbon-paste working electrode
in conjunction with a silver-silver
chloride reference electrode and a
stainless steel auxiliary electrode
Microbore HPLC provides
access to lower detection
limits
3. DOPA
4. DA
0.2 pg
5. HVA
6. 5-HIAA
7. 3-MT
8. 5-HT
3
Serotonin
Clinical Significance
n
Excess catecholamines
n
n
Low levels of catecholamines
n
n
A fall in blood pressure or blood volume, thyroid
hormone deficiency, congestive heart failure,
arrhythmias, & stress
Idiopathic postural hypotension
Catecholamine-secreting neurochromaffin
tumors
n
Pheochromocytomas, paragangliomas, or
neuroblastomas
Clinical Significance
n
Enterochromaffin cells
synthesized
n
n
Located primarily in the GI
Metabolism
n
n
Oxidative deamination
5-hydroxyindoleacetic acid
(5-HIAA)
5-HT & 5-HIAA: HPLC
Many antidepressant
drugs (Prozac) act
on serotonin
receptor
Sleep, perception of pain, social behavior,
schizophrenia, & mental depression
Depression憂鬱症
n
n
n
n
A variety of behavior patterns
n
n
5-hydroxytryptamine, 5-HT
5-HT & 5-HIAA ÿ
Earlier antidepressant drugs: inhibit seronin
reuptake
Prozac: 百憂解
Carcinoid tumors
n
Serotonin-secreting neoplasm
4
5-HT & 5-HIAA: HPLC
5-HIAA:
photometric method
Summary
1. What is the
relationship between
the adrenal medulla
and the sympathetic
nervous system?
2. How are the actions
of epinephrine
similar to the
sympathetic nervous
system? Different?
Morphology of the Adrenal Gland
5
Major hormones of the adrenal
cortex: a reminder
n
The adrenal cortex has 3 layers:
n
n
n
Outer - Zona Glomerulosa secretes aldosterone
Middle - Zona Fasciculata secretes cortisol
Inner - Zona Reticularis secretes androgens
The adrenal medulla (innermost part of adrenal)
produces adrenallin(epinephrin)
Lag Time in Response of Stressor
Adrenal Steroids
The adrenal cortex is a factory for steroid hormones.
Class of Steroid
Major
Physiologic Effects
Representative
Mineralocorticoids Aldosterone
Na+, K+ and water
homeostasis
Glucocorticoids
Glucose
homeostasis and
many others
Cortisol
Like all steroids, adrenal "corticosteroids"
are synthesized from cholesterol
Figure 41-3, p65
6
The hormones of adrenal cortex
Pathways of adrenal steroid biosynthesis
n
Glucocorticoids : (zona fasciculata)
n
n
n
Adrenal androgens : (zona reticularis)
n
n
n
Androstenedione, 11bOH-androstenedione,
Dehydroepiandrostenedione (DHEA), DHEA sulfate
17OH-progesterone
precusor
Mineralo-corticoids : (zona glomerulosa)
n
n
Intracellular Mechanism of
Steroid Action
Cortisol, Corticosterone
Blood transport : bound to CBG (transcortine)
Aldosterone
Desoxy corticosterone (DOC)
Adrenal-Pituitary feedback regulation
nucleus
Plasma membrane
steroid
steroid+receptor
steroid+receptor
chromatin
binding
DNA
transcription
mRNA
translation
specific proteins
7
Glucocorticoids
n
n
n
Central control of the secretion
Cortisol is the major form
It is bound to transcortinin
(CBG) in circulation
Cortisol is essential for life
because its important
effects on intermediary
metabolism of carbohydrate,
protein & lipid
Within the pituitary gland, ACTH is
produced in a process that also
generates several other hormones
Hypothalamus-Pituitary-Adrenal Axis
n
n
減痛
n
Lipotropin: precursor to beta-endorphin
Beta-endorphin and Met-enkephalin: Opioid peptides with
pain-alleviation and euphoric effects
陶醉感
Melanocyte-stimulating hormone (MSH): control melanin
pigmentation
8
Corticosterone (B) Actions
Biological actions of glucocorticoids
n
n
Catabolic proteolytic action.
Hepatic deamination of aminoacids:
gluconeogenesis
elevation of blood glucose and insuline levels
increase of fat cellular stores and of cholesterol and
lipid blood levels.
n
n
n
n
n
Glucocorticoid actions
Enhances the resorption of bone material and
calcium urinary excretion.
Anti-inflammatory and anti-allergic action.
Adrenal Androgens
n
Dehydroepiandrosterone
(DHEA)
n
n
Major form of adrenal androgens
A weak androgen
n
n
DHEA
not important in males
Important source (50%) of
androgen in females
HO
9
Adrenal Mineralocorticoids
Biological actions of androgens
n
n
n
n
Anabolic action increasing muscular mass.
Decrease of blood cholesterol .
Increase of bone calcium load.
Increase gonades development.
n
n
n
Aldosterone is the major
form
It controls body fluid
volume by increasing
sodium reabsorption by
kidneys
Aldosterone secretion is stimulated by
n
n
Control of aldosterone secretion
Mainly by the action of renin-angiotensin system
ACTH has a minor role
Control of aldosterone secretion
minor
10
Pathological Conditions
Biological actions of aldosterone
n
Hormone regulating body's electrolytes.
n
n
n
n
A. Addison's Disease (Adrenocortical failure)
Na+
maintains
- water levels
+
increases K and H+ loss
trends to increase volemia
B. Cushing's Syndrome (Adrenocortical
excess)
Site of action : cells of distal tube where it
facilitates electrolytes-exchange.
Addison's Disease:
Major Adrenocortical abnormalities
(Deficiencies)
Hyposecretion of the adrenal cortices
n
Addison's disease has many causes, such as
n
n
n
destruction of the adrenal glands by infection
their destruction by an autoimmune attack
an inherited mutation in the ACTH receptor on adrenal cells
ACTH⁄, cortisolÿ
n
ACTHÿ, cortisolÿ
n
The essential role of the adrenal hormones means that
a deficiency can be life-threatening.
Fortunately, replacement therapy with glucocorticoids
and mineralocorticoids can permit a normal life.
11
Addison's Disease:
Hyposecretion of the adrenal cortices
Diagnosis of Addison's Disease
n
Screening tests
n
n
n
Challenge tests
n
Diagnosis of Addison's Disease
n
Rapid ACTH stimulation:
Peak cortisol > 20 mg/dL
Major Adrenocortical abnormalities
(Excess)
ACTH Stimulation Test
n
n
n
n
n
Plasma ACTH (0800 h) 10-85 pg/ml
Serum cortisol (0800 h) 5-23 mg/dL
Blood and/or urine cortisol levels are measured before and
after a synthetic form of ACTH is given by injection.
In the so called short, or rapid, ACTH test, cortisol
measurement in blood is repeated 30 to 60 minutes after an
intravenous ACTH injection.
The normal response after an injection of ACTH is a rise in
blood and urine cortisol levels.
Patients with either form of adrenal insufficiency respond
poorly or do not respond at all.
Insulin-Induced Hypoglycemia Test
12
Cushing's Syndrome:
Differential Diagnosis of Aldosteronism
(mineralocorticoid excess)
Plasma
Renin
Plasma
Aldosterone
Blood
Pressure
Primary
Aldosteronism
Low
High
High
Secondary
Aldosteronism
High
High
N, H
Renin-secreting
tumor
High
High
High
Excessive levels of glucocorticoids
n
n
Cushing's Syndrome:
Endogenous disorders
n
ACTH-dependent or ACTH-independent
Causes of Spontaneous
Cushing’s Syndrome
Table 41-6
Excessive levels of glucocorticoids
Urinary free cortisol, mg/day
ACTH Dependent
Exogenous glucocorticoid therapy is the most
common cause.
ACTH
independent
Underlying Disorder
ACTH Dependent (Secondary)
Cushing’s disease
Ectopic ACTH-secreting tumor
ACTH independent (Primary)
Adenoma
Carcinoma
Nodular adrenal hyperplasia
Adrenocortical rest tumor
Incidence (%)
68
15
5
3
9
<1
13
Differential Diagnosis in
Cushing’s Syndrome
n
Screening Tests
n
n
n
dexamethasone
suppression test
Urinary free cortisol <100 mg/day
Overnight dexamethasone suppression test:
Serum cortisol (0800 h) <3 mg/dL
N: ACTHÿ, cortisolÿ
Differential Diagnosis Tests
n
n
n
Plasma ACTH (0800 h) 10-85 pg/ml
Serum cortisol (0800 h) 5-23 mg/dL
High-dose overnight dexamethasone suppression
test: Serum cortisol (0800 h) 50% suppression
Enzyme deficiencies in CAH
(Congenital Adrenal Hyperplasia or
Adrenogenital Syndrome)
In CAH males, absence of
negative feedback on ACTH
17-ketosteroids
14
In AGS females, the cortex of the adrenal gland
fails to produce the steroid cortisol, producing
instead its chemical precursor which acts as an
androgen (male hormone).
Analytical Methodology
n
Cortisol, Aldosterone, 11-deoxycortisol, 17hydroxyprogesterone
n
n
Immunoassays
Renin & Angiotensin I
n
n
n
PRA: plasma renin activity
Rate of angiotensin I produced from
angiotensinogen by renin in plasma
ng angiotensin I /ml/hr
Questions
1. Define and give the physiological significance
(how or why it is important) for the following
terms:
n
n
Corticotropin Releasing Hormone (CRH)
Corticosterone, Glucocorticoid, Chromaffin cells
2. How do steroid hormones transmit their
message to target cells?
15