3. HORMONE / RECEPTOR INTERACTIONS
1- Peptides & Amines interact with cell surface receptors
activation of a second messenger (cAMP) modification
of the cell functions.
2- Steroid Hormones interact with cytoplasmic or intranuclear
receptors & bind to nuclear DNA activation of specific
genes, transcription and translation of new proteins
hormone effects.
3- Thyroid Hormones first bind to cell surface receptors, then
are internalized to interact with receptors within the
cytoplasm or nucleus activation of specific genes and
transcription & translation of proteins hormone effects.
4. THE ENDOCRINE SYSTEM
How does the endocrine orchestra work?
1- Nervous Stimuli to the Hypothalamus production of
releasing (stimulatory) or inhibitory hormones, transported
via a portal system of vessels to the anterior pituitary gland
2- Anterior Pituitary Gland pituitary trophic hormones
3- Pituitary trophic hormones stimulate Peripheral Endocrine
Glands production of peripheral hormones
4- Hormone/Receptor Interactions in target organs
hormone actions
5- Peripheral hormones exert Negative Feedback Mechanisms
supression of hypothalamic & pituitary hormones.
5. ADRENAL GLAND
- Composed of two functional units: catecholamine producing
medulla & steroid secreting cortex.
- In the adult, the normal adrenal weighs 4 gm.
- The cortex consists of three functional zones:
1 - zona glomerulosa
2 - zona fasciculata (75% of the cortex)
3 - zona reticularis
- The cortex secretes three types of steroid hormones:
1 - mineralocorticoids (aldosterone) - zona glomerulosa.
2 - glucocorticoids (cortisol) - zona fasciculata mainly.
3 - sex steroids (testosterone) - zona reticularis mainly.
6. Adrenal Anatomy
• small, triangular glands loosely attached
to the kidneys
• divided into two morphologically and
distinct regions
- adrenal cortex (outer)
- adrenal medulla (inner)
9. Anatomy and Origin
• embryologically derived from
pheochromoblasts
• differentiate into modified neuronal cells
• acts like sympathetic ganglion
• more gland than nerve
• chromaffin cells
10. Function of the Adrenal Medulla
• an extension of the sympathetic nervous
system
• acts as a peripheral amplifier
• activated by same stimuli as the
sympathetic nervous system
(examples – exercise, cold, stress,
hemorrhage, etc.)
11.
12. Hormones of the Adrenal Medulla
• adrenaline, epinephrine
• noradrenaline, norepinephrine
•80% of released catecholamines are
epinephrine
•Hormones are secreted and stored in
the adrenal medulla and released in
response to appropriate stimuli
13. Normal physiology
• Cortex
– Zona glomerulosa aldosterone
– Zona fasciculata mostly glucocorticoids
– Zona reticularis mostly androgens
• Medulla catecholamines
14.
15. Adrenal Medulla
• Arises from Ectoderm
• Composed of Chromaffin cells
• Secretes Epinephrine (14%), Norepinephrine
(73%), Dopamine (13%)
• Phenylethanolamine N-methyltransferase (PNMT)
– catalyzes formation of norepinephrine to epinephrine
– located almost exclusively in medulla, but also Organ
of Zuckerkandl
• In addition to adrenal medulla, catecholamine
synthesis also occurs in CNS, adrenergic nerve
terminals
16. ADRENAL MEDULLA
- Composed of specialized neural crest cells (neuroendocrine),
and is a major source of catecholamines: epinephrine,
norepinephrine and dopamine. The cells can also secrete a
wide variety of bioactive amines and peptides; such as
histamine, serotonin, chromogranin-A & neuropeptide
hormone.
- Clusters of similar neuroendocrine cells form the extra-adrenal
paraganglia, closely associated with the autonomic nervous
system. The branchiomeric (carotid body) & intravagal
paraganglia are parasympathetic, and the aorticosympathetic
(organs of Zuckerkandl) are sympathetic.
17. The adrenal cortex: three zones
Cortex
Zona glomerulosa
(mineralocorticoids)
Zona fasiculata
(glucocorticoids)
Zona reticularis
(androgens)
Medulla
21. Morphology of the adrenal gland
Adrenal medulla Secretion is controlled by preganglionic fibers
of the sympathetic nerve.
Epinephrine (80 %)
Norepinephrine
Dopamine
Steroids of 21 carbon :
Mineralocorticoids (Aldosterone)
secreted by the zona glomerulosa and affect the excretion of Na+, K+
Glucocorticoids (Cortisol)
secreted by the zona fasiculata and affect
the metabolism of glucose and protein
Steroids of 19 carbon :
Androgens and Estrogens
secreted by the zona reticularis
Adrenal cortex
22. Anatomy and Origin
• embryologically derived from
pheochromoblasts
• differentiate into modified neuronal cells
• acts like sympathetic ganglion
• more gland than nerve
• chromaffin cells
23. CATECHOLAMINES
- Norepinephrine functions as a local neurotransmitter of
sympathetic postganglionic neurons.
- Epinephrine (adrenaline) is secreted into the blood, and it
reacts with alpha-adrenergic and beta-adrenergic receptors on
effector cells, which then activate second messengers and a
cascade of enzymatic reactions mediating its actions;
increasing the force and rate of myocardial contractions, and
causing vasoconstriction of most vessels.
- The metabolites of catecholamines include: metanephrine,
normetanephrine, vanillylmandelic acid (VMA) and
homovanillic acid (HVA).
26. Catecholamines
• Stored in vesicles
• Released by exocytosis with stimulation of
preganglionic sympathetic nerves during
stress, pain, cold, heat, hypotension, etc.
• Binds adrenergic receptors on target cells
• Degrades to VMA, metanephrine,
normetanephrine
• Half life 20 sec
27. Adrenal Catecholamine
Biochemistry
CHCH2 NH2
OH
HO
HO
CH2 CHCOOH
HO
HO
CHCH2 NH2
HO
HO
CHCH2 NH2CH3
OH
HO
HO
CH2CHCOOH
HO
NH2
LKS
TYROSINE
* Tyrosine Hydroxylase
DIHYDROXYPHENYLALANINE
(DOPA)
A.A. Decarboxylase
NH2
DOPAMINE
Dopamine beta Hydroxylase
NOREPINEPHRINE
EPINEPHRINE
* PNMT +
Cortisol
* = Key Enzymes
PNMT=Phenylethanolamine-n-
methyltransferase
28. DHBR
NADP+
NADPH
from phe, diet, or protein
breakdown
Tyrosine L-Dopa
H2OO2
Tyrosine hydroxylase
(rate-determining step)
BH2BH4
1
Dopa
decarboxylase
CO2
Dopamine
pyridoxal
phosphate
2
Dopamine hydroxylase
ascorbate
H2O
Norepinephrine
O2
3
PNMT
SAM SAH
Epinephrine
4
Figure 1. Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin;
DHBR, dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH3 transferase;
SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine
Parkinson’s disease: local
deficiency of dopamine
synthesis; L-dopa boosts
productionPNMT specific to
adrenal medulla
SAM from
metabolism of
Met
DPN OHase in neuro-
scretory granules
29. Tyrosine hydrogenase: rate-limiting enzyme
1. TH is a homotetramer, each subunit has m.w. of 60,000
2. Catalyzes –OH group to meta position of tyrosine
3. Km = M range; saturation under normal condition
4. Cofactor: biopterin; competitive inhibitor: -methyl-p-
tyrosine
5. Sequence homology: phenylalanine hydroxylase and
tryptophan hydroxylase
6. Phosphorylation at N-terminal sites:
31. Modulation of catecholamine synthesis
1. Neuronal activity increase would enhance the amount of
TH and DBH at both mRNA and protein levels
2. TH is modulated by end-product inhibition
(catecholamine competes with pterin cofactor)
3. Depolarization would activate TH activity
4. Activation of TH involves reversible phosphorylation
(PKA, PKC, CaMKs and cdk-like kinase)
32. Dopa decarboxylase
1. Cofactor: pyridoxine; low Km but high Vmax
2. Also decarboxylate 5-HTP and other aromatic a.a.: aromatic
amino acid decarboxylase (AAAD)
3. Inhibitor: -methyldopa
Dopamine -hydroxylase
1. Cofactor: ascorbate; substrate: dopamine
2. Inhibitor: diethyldithiocarbamate (copper chelator)
3. DBH is a tetrameric glycoprotein (77kDa and 73kDa)
4. Store in the synaptic vesicle and releasable
Phenylethanolamine N-methyltransferase (PNMT)
Substrate: S-adenosylmethionine; regulated by corticosteroids
33. ........
acetylcholine
Adrenal Medulla
Chromaffin Cell
Neuron
Acute
regulation
Tyrosine
L-Dopa DPN
DPN
NE
granule
induction
Chronic
regulation
Stress
Hypothalamus
ACTH
Cortisol
from adrenal
cortex via intra-
adrenal portal
system
Epinephrine
PNMT
NE
neuro-
secretory
granules
E E E
NE E
Figure 2. Regulation of the release
of catecholamines and synthesis of
epinephrine in the adrenal medulla
chromaffin cell.
promotes
exocytosis
................
E
EE
ENE
E
E E
NE
E
Ca2+
34. Important fetures of catecholamine biosynthesis,
uptake and signaling
1. Biosynthesis
2. Release
3. Uptake (transporter)
4. Receptor-mediated
signaling
5. Catabolism
35. Uptake transporters
1. Released catecholamines will be up-take back into
presynaptic terminals (DAT, NET)
2. Transporter is a Na+ and Cl+-dependent process (ouabain
[Na,K-ATPase inhibitor] and veratridine [Na channel open]
block uptake process)
39. Actions of Catechols, Effects
• Epinephrine = Norepinephrine
• Metabolic
– gluconeogenesis
• Decreases Insulin secretion
• Vasoconstrictor in most tissues, including skeletal muscle
• Increases Mean Arterial Pressure
• Dilation of Pupils
• Sweating
• Sphincter Contraction
• Indirect CNS actions
40. Actions of Catechols, Effects
• Epinephrine > > Norepinephrine
• Metabolic
– glycogenolysis
– lipolysis (Stim Hormone Sensitive Lipase)
– calorigenesis
• Increases Insulin secretion
• Vasodilation in skeletal muscle (Epi)
• No change in Mean Arterial Pressure
• Bronchodilation
41. CLINICAL PREMISE
J.P. noticed tremors in his right hand when sitting
quietly. However, if he began writing he could cause
the tremor to cease. More recently he has complained
of muscle stiffness, which has slowed his movements.
His wife has observed that he now takes short,
shuffling steps and leans forward as he walks.
Medical history and physical examination failed to
show any secondary causes of dysfunction of the
basal ganglia in the brainstem. Treatment with L-
dopa improved the symptoms of his disease.
43. Table 2. Metabolic and muscle contraction responses to catecholamine binding to
various adrenergic receptors. Responses in italics indicate decreases of the indicated
process (i.e., decreased flux through a pathway or muscle relaxation)
Process
1-receptor
(IP3, DAG)
2-receptor
( cAMP)
1-receptor
( cAMP)
2-receptor
( cAMP)
Carbohydrate
e
metabolism
liver
glycogenolysis
No effect No effect
liver/muscle
glycogenolysis;
liver gluconeogenesis;
glycogenesis
Fat
metabolism
No effect lipolysis lipolysis No effect
Hormone
secretion
No effect
insulin
secretion
No effect
insulin and glucagon
secretion
Muscle
contraction
Smooth muscle -
blood vessels,
genitourinary
tract
Smooth
muscle -
some
vascular;
GI tract
relaxation
Myocardial
- rate,
force
Smooth muscle relaxation
- bronchi, blood vessels,
GI tract, genitourinary
tract
44.
1 or 2
receptor
ATP cyclic AMP
Gs
s
GTP
inactive
adenylyl
cyclase
GTP
ACTIVE
adenylyl
cyclase
inactive
adenylyl
cyclase
2 receptor
Figure 5. Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity
Gi
i
GTP
s
GTP
i
X
45. Actions of Catecholamines
“Fight or Flight”
• Inotrope and chronotrope
• Vasoconstriction
• Bronchdilation
• Lipolysis
• Increased metabolic rate
• Pupillary dilation
• Inhibition of “nonessential” processes
46. "FIGHT OR FLIGHT" RESPONSE
epinephrine/ norepinephrine major elements in the "fight or flight"
response
acute, integrated adjustment of many complex processes in organs vital
to the response
(e.g., brain, muscles, cardiopulmonary system, liver)
occurs at the expense of other organs less immediately involved (e.g.,
skin, GI system).
epinephrine:
rapidly mobilizes fatty acids as the primary fuel for muscle action
increases muscle glycogenolysis
mobilizes glucose for the brain by hepatic glycogenolysis/
gluconeogenesis
preserves glucose for CNS by insulin release leading to reduced
glucose uptake by muscle/ adipose
increases cardiac output
norepinephrine elicits responses of the CV system - blood flow and
insulin
secretion.
47. OH OP
[2]
degradation
to VMA
insulin activation of protein
phosphatase to dephosphorylate
enzymes[7]
[5]
GTPase
GDP
epinephrine
phosphorylation
of -receptor by
-ARK decreases
activity even with
bound hormone
OH OH
[3]
OP OP
[4]
OPOP
binding of -arrestin
further inactivates
receptor despite
bound hormone
AC
cAMPATP
activated PKA
phosphorylates
enzymes
[6]
AMP
phosphodiesterase
GTP
[1]
dissociation
Figure 6. Mechanisms for terminating the signal generated by epinephrine binding to a
-adrenergic receptor
48. Adrenal Catechol Degradation
Epinephrine Metanephrine
COMT
Dihydroxymandelic
acid
Norephinephrine
Vanillymandelic
acid
Normetanephrine
MAO
MAO MAO
MAO
COMT
COMT
49. Norepinephrine Normetanephrine
COMT
Epinephrine Metanephrine
COMT
Vanillylmandelic acid
MAO
MAO
Dihydroxymandellic acidMAO
COMT
Dopamine COMT
MAO
3-Methoxytyramine
Dihydroxyphenylacetate
COMT
Homovanillic acid
MAO
Figure 3. Pathways for the degradation of epinephrine, norepinephrine and dopamine
via monoamine oxidase (MAO) and catechol-O-methyl-transferase (COMT)
Neuronal re-uptake and degradation of catecholamines quickly
terminates hormonal or neurotransmitter activity.
Cocaine binds to dopamine receptor to block re-uptake of dopamine
Dopamine continues to stimulate receptors of the postsynaptic nerve.
50.
51. Monoamine oxidase (MAO)
1. Cofactor: flavin; located on the outer membrane of
mitochondria
2. Convert amine into aldehyde (followed by aldehyde
dehydrogenase to acids or aldehyde reductase to glycol)
3. MAO-A: NE and 5-HT (inhibitor: clorgyline); MAO-B:
phenylethylamines (DA) (inhibitor: deprenyl)
4. Patient treated for depression or hypertension with MAO
inhibitors: severe hypertension after food taken with high
amounts of tyramine (cheese effect)
Catechol-O-methyltransferase (COMT)
1. Enzyme can metabolize both intra- or extracellularly
2. Requires Mg2+ and substrate of S-adenosylmethionine
53. PHEOCHROMOCYTOMA
= Catecholamine producing neoplasm (0.1% of all cases of
hypertension).
- The “10%” tumor: 10% extra-adrenal (para-gangliomas),
10% familial (associated with MEN IIa & MEN IIb, von
Hippel-Lindau, Sturge-Weber & von Recklinghausen’s
diseases), 10% in children, 10% bilateral (in sporadic
cases, but 70% in familial cases), 10% malignant (in
adrenal cases, but up to 40% in paragangliomas).
Clinical effects: hypertension (paroxysmal), arrhythmias, and
high urinary & plasma catecholamines.
54. Pheochromocytoma
• Originate from adrenal medulla or
extraadrenal paraganglia cells
• Autopsy series: 1%
• Secrete norepinephrine, epinephrine, rarely
dopamine and other neurohormones
56. Pheochromocytoma, Presentation
• Episodic headaches, tachycardia, diaphoresis
• HTN
– Sustained HTN
– Sustained HTN with paroxysm
– Paroxysmal HTN with intermittent normotension
• Nausea/vomiting
• Flushing
• Raynaud’s phenomenom
• 10% present in “pheocrisis”
• 50% found as incidentaloma
57. Pheochromocytoma, Diagnosis
• 24hr urinary catecholamines (NE, Epi, Dop) and
metabolites (metanephrine, normetanephrine,
VMA)
• Plasma catecholamine or metabolites during
episode
• Elevated serum epinephrine suggests pheo in
medulla or Organ of Zukerkandl
• NO FNA! (can precipitate hypertensive crisis)
58. Pheochromocytoma, Diagnosis
• Plasma catecholamine >2000 pg/ml indicative of
pheo
• clonidine suppression test
– Plasma catecholamine 1000-2000 pg/ml
– 0.3 mg po clonidine
– If HTN essential, decrease plasma catecholamines to
<500pg/ml.
• glucagon stimulation test
– Catecholamine < 1000 pg/ml
– 2mg IV glucagon
– If pheo, 3 fold increase in catecholamines to >2000
59. Pheochromocytoma, Diagnosis
• Localizing studies: CT, MRI, MIBG scan
– Thin cut CT detects most lesions: 97%
intraabdominal
– MRI: 90% pheos bright on T2 weighted scan
– MIBG: used for extraadrenal, recurrent,
multifocal, malignant disease
• Malignant disease
– Local invasion, disease outside of
adrenal/paraganglionic tissue
– No histological or clinical criteria can
differentiate malignant disease
60. Pheochromocytoma, Treatment
• Treatment is surgery
• Must medically optimize prior to surgery
– Treat HTN
– Expand intravascular volume
– Control cardiac arrhythmias
• Phenoxybenzamine (α-adrenergic antagonist)
– most commonly given 1-3 wks prior to OR.
– Other α-adrenergic antagonists, CCB, ACEI used
• PO salt and fluid repletion
• May need β-blocker as antiarrhythmic. Do not
start until after pt α-blocked
• Metyrosine – decreases catecholamine synthesis
61. Pheochromocytoma, Treatment
• Intraop- avoid anesthetic agents that precipitate
catecholamine secretion.
– Induce with thiopental/isoflurane
– Phentolamine (short acting α-blocker)
– Sodium nitroprusside for BP control
– Norepinephrine if needed for hypotension
– Lidocaine and esmolol to control arrhythmias.
• Medical options: chemo, high dose I131 MIBG,
XRT – symptomatic relief
62. Pheochromocytoma, follow up
• 6.5% of benign pheochromocytomas recur
• 50% of malignant dz have residual dz
• F/u with biochemical testing
• Imaging not routinely necessary
63. NEUROBLASTOMA
Childhood tumor, arise before the age of 5-years.
Histology: sheets of undifferentiated small cells with Homer-
Wright pseudo-rosettes. Cells may differentiate to ganglion
cells (ganglioneuroblastoma).
- Right sided tumors metastasize early to the liver (Pepper’s
syndrome), left sided tumors metastasize to bones (skull)
proptosis (Hutchinson’s syndrome).
Prognosis: used to be rapidly fatal, now is much better with
recent therapeutic modalities.
65. MEN IIA (Sipple’s) SYNDROME
- Inherited mutation of the RET proto-oncogene on
chromosome 10.
1. Medullary thyroid carcinoma (dominates the syndrome;
being the only “malignant” lesion).
2. Pheochromocytoma (mostly benign), often bilateral and
extra-adrenal (paragangliomas).
3. Parathyroid hyperplasia or adenoma.
66. MEN IIB (or MEN III) SYNDROME
- Related to RET proto-oncogene mutation different from
that of MEN IIa. Neoplasms are as in MEN IIa:
1- Medullary thyroid carcinoma,
2- Pheochromocytoma &
3- Parathyroid adenoma,
plus
4- Neuromas of the skin and mucous membranes of the
mouth, GI tract, respitatory tract, bladder, ..
5- Marfanoid body habitus.
--------------------------------------------------------------------------
68. Incidentaloma
• Found on work up for another cause, not on
cancer workup
– US 0.1%
– CT 0.4 to 4.4%
– MRI
• 70-94% are benign and nonfunctional
• >3cm more likely to be functional
• Up to 20% may be subclinically active
• Increase with age, no change in sex
• 5-25% will increase in size by at least 1cm
70. Adrenal incidentaloma
Evaluation of
Hormonal function
24 hour urine catechol
& metanephrines
Single dose
dexamethasone Hypertension
Hyperkalemia
If +, plasma
ACTH, urine free
cortisol
Upright
PAC:PRA
Consider high-dose dexamethasone
71. Functioning mass Nonfunctioning mass
adrenalectomy >4.5 cm
Atypical CT
appearance
<4.5 cm
Benign
appearance
History of
Extraadrenal
malignancy
adrenalectomy
Repeat CT/MRI
3 and 12 months
Consider
FNA
+ FNA - FNA
adrenalectomy observe
Adapted from Camerons, Current Surgical Therapy 7th ed. Pg 635
72. Adrenal Carcinoma
• 1 per 1.7 million
• 0.02% of cancers
• 0.2% of cancer deaths
• 5 yr survival after surgery 35%
• Classify functional (79%) vs nonfunctional
– Glucocorticoids
– Aldosterone
– Testosterone
– Estrogen
– Mixed
73. Adrenal Carcinoma, Presentation
• Abdominal sx (mass, pain, bloating,
fullness)
• Constitutional sx (wt loss, fever, sweats)
• Endocrine excess
• Found as incidentaloma
• Metastasize to: lung (60%), liver (50%),
lymph nodes (48%), bone (24%),
pleura/heart (10%)
74. Adrenal Carcinoma, Treatment
• Surgery if no metastatic disease.
• En-bloc resection of LN and local structures
if necessary
• Medical treatment if metastatic, recurrent
– Palliative XRT
– Mitotane – induce response in 35%, but no
survival advantage
– Ketoconazole
– chemo
75. Adrenal metastasis
• More common than adrenal carcinoma
• 50% of pts with melanoma, breast, lung cancer
• 40% of pts with RCC
• Also contralateral adrenal ca, bladder, colon,
esophagus, gall bladder, liver, pancreas, prostate,
stomach, uterus (in decreasing frequency)
• Surgery indicated only if this represents isolated
metastasis
• Biochemical workup