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(Review 09)

BELLA MARILOU BAXA-DAGUPLO, MD

Department of Biochemistry & Nutrition


Fatima College of Medicine
Our Lady of Fatima University
Hormones
from the Greek term ( ) "impetus
- to arouse to activity

substance synthesized in one tissue & transported


by circulatory system to act on another organ

ON

Cell Target
origin cell

OFF (Effects)
Hormone Meta
Functions of Hormones
Endocrine
Paracrine
Autocrine

Hormone Metabolism
Hormone and Neurotransmitters

Norepinephrine/Serotonin depression

oversensitivity to serotonin OCD behaviors

norepinephrine (NE) aggression

Dopamine Parkinsons disease

Too much dopamine in the limbic system and


not enough in the cortex personality given
to bouts of paranoia or (-) social interaction

Hormone Metabolism
Hormone and Neurotransmitters

Phenylethylamine + dopamine mild anti-


depressant effect
Phenylethylamine in the limbic system
feelings of bliss
norepinephrine w/ dopamine & phenylethylamine
give us the feeling of infatuation
oxytoxin impulse to cuddle; multiple orgasm

too much stress in children can create permanently


levels of serotonin and levels of NE creating
a potential of violent behavior

Hormone Metabolism
General
Characteristics
of Hormones
Not secreted at a uniform rate
Exert their effects in biocatalytic amounts
Turnover is varied and usually rapid
Exert multiple actions
Exhibit high degree of specificity
Different tissues may respond
differently to a given hormone

Hormone Metabolism
Regulation of Hormone Secretio

A. Feedback Control
1) Negative Feedback
2) Positive Feedback

B. Neural Control
- visual/ olfactory/ gustatory

C. Chronotropic Control
- sleep-wake cycle/ physiologic cycle

Hormone Metabolism
Regulation of Hormone Secretion

Feedback Control HPT Axis

Negative Feedback Hypothalamus


+
TRH
-

T3 and T4 Anterior
Pituitary

inhibits secretion + TSH


of TRH and TSH Thyroid
-
+

T3 , T4

Increased
metabolism

Hormone Metabolism
Regulation of Hormone Secretion

Feedback Control Female HPG Axis

Positive Feedback Hypothalamus


+ GnRH

estrogen level Anterior


Pituitary

results to LH surge - +
+

during ovulation - + LH FSH


+

Ovaries

Estrogen Progesterone

Hormone Metabolism
Forms of Hormone in the
Circulation
A. Free Molecules (unbound)
- water-soluble hormones

B. Bound Molecules
- water insoluble hormones
- bound with specific globulins or
transport proteins such as
albumin, cortisol-binding globulin,
and thyroid-binding globulin

Hormone Metabolism
Fates of Hormone

A. Target cell uptake

B. Metabolic degradation

C. Urinary or biliary excretion

kidney and liver are the major sites of


hormone metabolism and degradation

Hormone Metabolism
Classification of Hormones
I. According to Structure
A. Protein hormones
1) Simple or polypeptide [insulin, glucagon,
somatostatin, growth h., ACTH, MSH, PRL, CS ]
2) Complex or glycoprotein [TSH, FSH, LH, hCG]

B. Steroid hormones [glucocorticoids,


mineralocorticoids, sex androgens, retinoic a., calcitriol]

C. Biogenic amine hormones [thyroxine,catecholamines]

II. According to Mechanism of Action


A. Group 1
B. Group 2
Hormone Metaboli
Classification of Hormones [Protein]

Insulin and C-peptide Formation

B-Chain

A-Chain

Ribosome ER Golgi A. Vesicles

Hormone Metabolism
Classification of Hormones [Protein]

Pro-opiomelanocortin Peptide Family

Hormone Metabolism
Classification of Hormones [Steroids]

Hormone Metabolism
Classification of Hormones [Amines]

Some Biogenic Amines

HO CH2 - CH2 NH2 HO CH - CH2 NH2


OH
HO HO

Dopamine Norepinephrine

HO CH - CH2 NHCH3
OH
HO

Epinephrine Tetraiodothyronine

Hormone Metabolism
Classification of Hormones
According to Mechanism of Action
Group 1 Group 2

Type Steroids, thyroid h., Polypeptides and


retinoic acid . catecholamines
Solubility Lipophilic Hydrophilic
Transport Protein Yes No
Plasma T1/2 Longer Shorter
Receptor Intracellular Plasma membrane

Mediator HRC/HRE 2nd messengers

Hormone Metabolism
Steps Involved in Eliciting
Response of Target Cell

1) Recognition and binding of the hormone


to specific receptor

2) Coupling to generate signal

3) Changes in intracellular processes


brought about by the generated signal

Hormone Metabolism
Receptors

specific proteins that must first bind a


hormone before cellular response can
be elicited

have at least 2 Functional domains:

1) Recognition domain - binding domain


2) Coupling domain - generates signal that
couples hormone recognition to some
intracellular function

Hormone Metabolism
Receptors

Classes:

A. Cell surface receptors

B. Intracellular receptors

1) Nuclear receptors
2) Cytoplasmic receptors

Hormone Metabolism
Receptors

Cell Membrane Receptors Extracellular


N

Functional Domains:

1) Ligand-binding domain
2) Transmembrane domain
3) Cytoplasmic domain
Intracellular
C

Typical cell membrane receptor


(seven membrane-spanning domain)

Hormone Metabolism
Receptors

Intracellular Receptors (3) (2) (1)

N C

Functional Domains:

1) A hormone binding region in the C-terminal


2) An adjacent DNA binding region
3) A specifier region (N-terminal) necessary for
high-affinity binding to the proper region of
DNA
4) One or more regions that activate or repress
gene transcription

Hormone Metabolism
Signal Transduction

process which occurs after a hormone


binds to a receptor

an intracellular signal is generated


[second messenger] which delivers
the hormonal message

amplifies the original signal converting


substrate molecules to products

Hormone Metabolism
Signal Transduction
Signal Transduction Pathways

Insulin, EGF, Growth hormone


IGF-1 Prolactin
Peptides
Catecholamines Steroids
Neurotransmitters Thyroid hormones
Estrogen, RA

Enzyme Activation Nucleus

Hormone Metabolism
Mechanism of Action [Group 1]

Hormone receptor
Cytoplasm
complex (HRC)
Nucleus
Activation
Hormone response
element (HRE)
+



Thyroid h. Transcription
+ mRNA

mRNA
Translation
Receptor Specific Protein
Steroid/Thyroid h.
Metabolic response

Hormone Action with intracellular receptors

Hormone Metabolism
Mechanism of Action [Group 1]

Hormone response Promoter


elements (HRE) element (PE) Gene
5 3

1+ Termination
Transcription Site
Initiation site

Regulatory DNA region Structural


DNA region

Structural requirements for hormonal regulation of


gene transcription

Hormone Metabolism
Mechanism of Action [Group 1]
Hormones that bind to Intracellular receptors
(Group 1)

Mineralocorticoids
Glucocorticoids
Androgens
Progestins
Estrogens
Calcitriol (1,25[OH]2-D3)
Retinoic acid
Thyroid hormones (T3 and T4)

Hormone Metabolism
Mechanism of Action of Group 2 Hormones

Effector Systems

I. Effector systems that produce cytosolic


second messengers (couple w/ G-protein)
for signal transduction

Adenylyl cyclase - cAMP


Guanylyl cyclase - cGMP
Phospholipase C - phosphoinositides
(DAG & IP3)
Calcium - calmodulin (Ca++)

Hormone Metabolism
Mechanism of Action [Group 2]

Effector Systems

II. Effector system as an intrinsic part of the


receptor
- does not require G-protein to transduce the
physiologic action of the ligand
- contains an enzymatic activity within the
intracellular domain that phosphorylates
tyrosine kinase residues

Hormone Metabolism
Mechanism of Action [Group 2]
Mechanism of Action [Coupling w/ G-protein
G-protei
Mechanism of Action [Coupling w/ G-protein
G-protei
Mechanism of Action [Coupling w/ G-protein
Mechanism of Action [Group 2]
Adenylate cyclase cAMP ES
Regulation through cAMP-dependent
protein kinases
te
en yla
Ad clase
cy 5-AMP
Phosphodiester
ase
ATP Mg2+ cAMP ()
4 cAMP
C

R Inactive
R protein kinase
C


R
Protein
+ 2 C
R Phosphatase
Active
protein Phosphoproteins
kinase

Physiologic effects

Hormone Metabolism
Mechanism of Action [Group 2]
Adenylate cyclase cAMP ES

1. Activators of adenylyl cyclase


Cholera toxin inactivates GTPase;
s is frozen in active form

Pertussis toxin prevents activation of


i subunit
2. Inhibitor of adenylyl cyclase
Phosphodiesterase hydrolyzes cAMP
to 5-AMP

Hormone Metabolism
Mechanism of Action [Group 2]

(-)
(+) Muscles
Liver Adenylate
cyclase (+)

ATP
cAMP
Phosphorylase
Protein kinase Protein kinase Glycogen
kinase (inactive)
(Inactive) (Active) synthase a
Phospho- Phosphoprotein
(+) (+) phosphatase
protein
phosphatase Phosphorylase Glycogen
kinase (active) synthase b (+)
(+) Glycogen Insulin
(+)
Glycogen Glycogen
Phosphorylase b Phosphorylase a Glucose-1-PO4

GLYCOGENOLYSIS

Hormone Action using cAMP Second Messenger

Hormone Metabolism
Mechanism of Action [Group 2]

(-)
(+) Muscles
Liver Adenylate
cyclase (+)

ATP
cAMP CREB
Protein kinase Protein kinase
(Inactive) (Active)
CREB-P
Metabolic response cAMP response
element (CRE)

Specific Protein

Translation or Transcription
mRNA mRNA

Hormone Action using cAMP Second Messenger

Hormone Metabolism
Mechanism of Action [Group 2]
Phosphatidylinositol Cycle and Calcium

(+)
Receptor Phospholipase C

GTP GDP PIP2

GDP GTP
(+) DAG

Physiologic responses Protein kinase C IP3


Calmodulin kinases
Phosphoproteins (+)
Ca -Calmodulin
++

Proteins
Ca++

Hormone Action using DAG, IP3 and Ca++


as Second Messengers
Hormone Metabolism
Mechanism of Action [Group 2]
Kinase Cascade System 1 [Autophoshorylation]

P P
(Autophosphorylation)
Phosphorylation of
protein substrates
Enzyme Activity
(Tyrosine)

Protein Translocation

Cell growth
Gene Expression DNA synthesis
Early response genes

ES utilized by Insulin, EGF PDGF and IGF-1

Hormone Metabolism
Mechanism of Action [Group 2]
Kinase Cascade System 2

JAK JAK P JAK JAK P P JAK JAK P


P P P P ) STATs P
P P P SH2 ( P P
X

X = SHC
GRB2
PLC Dimerization
PI-3K Regulates transcription
GAP
Nucleus

ES utilized by Growth hormone, Prolactin, EPO, cytokines

Hormone Metabolism
Mechanism of Action [Group 2]
Hormones that bind to CM receptors

2a second messenger is cAMP

2b second messenger is cGMP

2c second messenger is Ca++or


phosphoinositols or both

2d second messenger is kinase/


phosphatase cascade

Hormone Metabolism
Factors Affecting Response of
Target Cells to Hormones
concentration of the hormone
number of receptors
duration of exposure
intracellular conditions such as
conc. of rate-limiting enzymes,
substrates or cofactors
antagonistic or synergistic hormones

Hormone Metabolism
Hormones That Affect
Fuel metabolism
Insulin
Glucagon
Somatostatin
Catecholamines
Steroid Hormones
Thyroid Hormones
Growth Hormones

Hormone Metabolism
Metabolic Effects of Hormones
Pathways Insulin Glucagon Epi T3, T4 Cortisol GH
Glycolysis
(+) (-) (+) (+) (-) (-)

Glycogenesis (+) (-) (-) (-) (+) (+)

Glycogenolysis (+) (+)


(-) (+) (+) (-)
Liver L & M
Gluconeogenesis (-) (+) (+) (+) (+) (+)

Lipogenesis
(+) (-) (-) (-) (+) (-)
central
Lipolysis (+)
(-) (+) (+) (+) peripheral (+)
Protein Synthesis (+) (-) (-) (+) (+) (++)

Pathology DM, Graves D. Cushings


Parkinsons Dwarfism
Lepre- Myxedema Conns
Glucagonoma Pheochromo-
Cretinism Gigantism
chaunism cytoma Addisons
Goiter

(+) Stimulated; (-) Inhibited


Insulin
Mechanism of Action

Transduction thru tyrosine kinase

Autophosphorylation [-subunit]

(+) of tyrosine kinase activity

Phosphorylation of proteins

(+)/(-) of cytoplasmic proteins

Biologic effects [long term effects]

Hormone Metabolism
Insulin
Mechanism of Action

Second Messengers

Release of glycoinositol derivative

(+) Phosphoprotein phosphatase

Dephosphorylation of proteins

(+)/(-) of cytoplasmic proteins

Biologic effects [short term effects]

Hormone Metabolism
Insulin
Mechanism of Action

Hormone Metabolism
Insulin
Effects on Metabolism
Enzyme Change in Activity Possible Mechanism

cAMP metabolism
Phosphodiesterase (low Km) Increase Phosphorylation
Protein kinase (cAMP-dependent) Decrease Association of R
and C subunits
Glycogen metabolism
Glycogen synthase Increase Dephosphorylation
Phosphorylase kinase Decrease Dephosphorylation
Phosphorylase Decrease Dephosphorylation

Glycolysis & Gluconeogenesis


Pyruvate dehydrogenase Increase Dephosphorylation
Pyruvate kinase Increase Dephosphorylation
Phosphofructokinase Increase Dephosphorylation
Fructose-2,6-bisphosphatase Decrease Dephosphorylation

Hormone Metabolism
Insulin
Effects on Metabolism
Enzyme Change in Activity Possible Mechanism

Lipid metabolism
Acetyl-CoA carboxylase Increase Dephosphorylation
HMG-CoA reductase Increase Dephosphorylation
Triacylglycerol lipase Decrease Dephosphorylation

Signaling molecules
p42/44MAP kinase Increase Dephosphorylation
p90RSK Increase Dephosphorylation
GSK3 Decrease Dephosphorylation
p70 S6 kinase Increase Dephosphorylation
Phosphoprotein phosphatase Increase Dephosphorylation
1G

Hormone Metabolism
Insulin
Pathophysiology

Diabetes Mellitus

Type 1 Insulin dependent DM (IDDM)

Type 2 Non-insulin dependent DM


(NIDDM)

Hormone Metabolism
Insulin

Leprechaunism

[Donohues Syndrome]
Insulin

Metabolic Syndrome / Insulin Resistance Syndrome


Syndrome X,
Reaven Syndrome
Dysmetabolic S.
The H phenomenon
The Deadly Quartet

Hormone Metabolism
Insulin
Pathophysiology

Somogyi Effect [rebound hyperglycemia]

- rapid in blood glucose that generates


the release of counterregulatory hormones
(Epi, glucagon, cortisol) rapid of glucose

- hypoglycemia results from:


1) autonomic neuropathy
2) inappropriate timing of insulin
3) exercise w/o adequate caloric intake
4) excessive insulin treatment

Hormone Metabolism
Insulin
Pathophysiology

Dawn Phenomenon

- early morning (5:00 to 6:00AM) increase


in blood glucose associated with the
release of nocturnal growth hormone

- 3:00 AM glucose is normal, while


8:00 AM glucose is

Hormone Metabolism
Insulin
Pathophysiology

Maillard reaction

- non-enzymatic glycosylation of proteins


due to high blood glucose levels

- sugar aldehyde or ketone group condenses


with a free amino group Schiff base
Amadori products (stable ketoamines)
degrade into reactive carbonyl-containing
products react w/ amino groups
cross-linkages and adducts DAMAGE

Hormone Metabolism
Catecholamines
Synthesis & Structures

COOH COOH
CH2 - C NH2 HO CH2 - C NH2

HO H H Dopa
HO
Tyrosine hydroxylase decarboxylase
Tyrosine Dopa

HO CH2 - CH2 NH2


HO CH - CH2 NHCH3 HO
OH
HO
Dopamine
Epinephrine
HO CH - CH2 NH2
PNMT
OH Dopamine
HO -hydroxylase
Norepinephrine

Hormone Metabolism
Catecholamines
Chromaffin Cell

Tyrosine Tyrosine E
TH E

Dopa PNMT
E
DD NE
NE
Dopamine
NE
NE (+) - adrtenergic
& cholinergic
DBH agents
(-) -adrenergic
Granule agents

Biosynthesis
Hormone Metabolism
Catecholamines
Blood
Stress

Tyr, Phe
Chromaffin Cell
Hypothalamus

Tyrosine

ACTH Blood glucose

NEP EP
PNMT

Cortisol EP EP

Secretion of Stress Hormones


Hormone Metabolism
Catecholamines
Metabolism

rapidly metabolized in the liver and


skeletal muscles

metabolized by:
catechol-O-methyl transferase (COMT)
monoamine oxidase (MAO)

free catecholamines may also be


inactivated by conjugated with sulfate or
glucoronide in the liver

Hormone Metabolism
Catecholamines
Mechanism of Action

act through 2 major classes of receptors:


-Adrenergic (1, 2)
-Adrenergic (1, 2)

Epinephrine binds and (+) both and R:


- much greater affinity with R

Norepinephrine primarily binds with R

Hormone Metabolism
Catecholamines Mechanism of Action

Binding of catecholamines to:

1, 2 (+) adenylyl cyclase

2 (-) adenylyl cyclase

1 couples to processes that


alter Ca++ concentration or
modify phosphatidylinositol
metabolism or both

Hormone Metabolism
Catecholamines
Pathophysiology

Parkinsons disease

Pheochromocytoma

Hormone Metabolism
Thyroid Hormones
Pathophysiology

Hypothyroidism/Myxedema
- T3 and T4; BMR

Hyperthyroidism/Thyrotoxicosis
- T3 and T4; BMR
- Graves disease

Goiter
- enlarged thyroid gland ; elevated TSH
- due to iodine deficiency or excess
- defect in any steps in the synthesis

Hormone Metabolism
Steroids
Synthesis
Cholesterol

Pregnenolone
(1) SCC

(2) Oxidation &


isomerization

Cortisol,
Aldosterone , Progesterone
etc. (3) Hydroxylation

Hormone Metabolism
Steroids
Subcellular comparmentalization of
Glucocorticoid biosynthesis
LDL

ACTH Cholesterol
Ester
AC Lipase
G cAMP
Protein kinase A
R Cholesterol
ATP

ER
Cholesterol
Cortisol Progesterone
Pregnenolone

11-Deoxycortisol Cortisol

Hormone Metabolism
Steroids Mechanism of Action
Steroids
Pathophysiology

Cushings syndrome
- glucocorticoid excess
- due to pharmacologic use of steroids
- ACTH-secreting pituitary adenoma or ca.
- hyperglycemia or glucose intolerance;
truncal obesity; severe CHON metabolism

Conns syndrome
- primary aldosteronism
- hypertension, hypokalemia, hypernatremia
and alkalosis
Hormone Metabolism
Steroids
Pathophysiology

Addisons disease
- primary adrenal insufficiency
- severe hypoglycemia
- decrease BP, decrease GFR, decrease
ability to excrete a water load
- skin pigmentation

2 Adrenal Insufficiency
- deficiency of ACTH from tumors, infarct,
or infection
- metabolic syndrome w/o hyperpigmentation

Hormone Metabolism
Steroids
High level of serum cortisol may
be responsible for stress-induced
memory loss.

Physiologic response to stress


does not impair the learning aspect
of memory but only the free recall
of information.

Elevated glucocorticoid level may


induce impairment in such
stressful conditions as job
interviews, combat, courtroom
testimony and examinations.

[Nature Neuro-science 2000; 3:313-4 (April)]

Hormone Metabolism
Growth H. Secretion
Growth H.
Mechanism of Action
Growth H. Pathophysiology

GH deficiency dwarfism

Laron type dwarfism

Pygmies

Hormone Metabolism
Growth H. Pathophysiology

Pygmies
Pygmies
Growth H. Pathophysiology

Gigantism
Growth H. Pathophysiology

Acromegaly
Calcium
neuromuscular excitability
blood coagulation
secretory processes
membrane integrity/plasma
membrane transport
enzyme regulation
release of hormones and
neurotransmitters

Hormone Metabolism
Calcium

Ca and phosphate are necessary


for bone mineralization
1 kg Ca [human body]
99% bone (hydroxyapatite)
miscible pool (1% of the skeletal
muscle Ca and 1% periosteal space)
7.5-10.5 mg/dl or 1.1-1.3 mmol/L

Hormone Metabolism
Hormones That Affect
Calcium metabolism

PTH
Calcitriol
Calcitonin

Hormone Metabolism
Parathyroid Hormone [PTH]

84 amino acid peptide


regulates plasma Ca++ level
synthesized in the parathyroid gland
t = 20 min after proPTH is synthesized
metabolized in the parathyroid tissue
and liver

Hormone Metabolism
PTH

preproPTH proPTH PTH


(115 a.a) (84 a. a.)
Ribosome ER GA

PTH 1-34 (full biologic activity)


PTH 25-34 (receptor binding)

Hormone Metabolism
Fates of PTH

Transport to a storage pool

Degradation

Immediate secretion

Hormone Metabolism
PTH Secretion

Regulated by plasma Ca++:

acute Ca++ PTH mRNA


PTH synthesis

1,25(OH)2-D3 VDRC/VDHRE
PTH mRNA transcription

(+) G-protein (+) phospholipase C


IP3 Ca++ secretion

Hormone Metabolism
PTH Metabolism

metabolized in the parathyroid tissue

Cathepsins B and D
Cathepsins B cleaves:

PTH [1-36 and 37-84]

principal site of peripheral proteolysis


occurs in the liver (Kuppfer cells)

excretion of metabolites (kidneys)

Hormone Metabolism
PTH Actions

PTH

(+) G-protein

cAMP

BONES KIDNEYS INTESTINES

Hormone Metabolism
PTH Actions

BONES KIDNEYS INTESTINES

Direct Effects Indirect Effect

Increase bone Increase Ca++


resorption absorption
(CALCITRIOL)
Decrease renal
Ca++ excretion

Hormone Metabolism
CALCITRIOL

derivative of vitamin D
regulates plasma Ca++ level
synthesized in the kidney
ensures Ca and phosphate for
bone mineralization

Hormone Metabolism
Synthesis of Calcitriol

7-dehydrocholesterol
SKIN (Photolysis)
Vit D3
LIVER (25-hydroxylase)

25-OH-D3
KIDNEY (1-hydroxylase)
[placenta]
1, 25-(OH)2-D3

Hormone Metabolism
Mechanism of Action

Nuclear action
(+) VDRE

Induces Ca binding protein (CBP)


Increases transfer of Ca & PO4 across
the intestinal mucosa

Hormone Metabolism
When you do not succeed in taking giant
steps on the road to your goal,
be satisfied with little steps,
and wait patiently till the time that you are
able to run, or better still, to fly.
Be satisfied to be a little bee in the hive
who will soon become a big bee capable of
making honey (Padre Pio)

Thank you