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Me taboli c c le arance

rate (MCR)
 Defines the quantitative removal of hormone
from plasma
 The bulk of hormone is cleared by liver and
kidneys
 Only a small fraction is removed by target
tissue
 protein and amine hormones bind to receptors and
are internalized and degraded
 Steroid and thyroid hormones are degraded after
hormone-receptor complex binds to nuclear
chromatin
MC R of so me h ormo nes
Hormone Half-life

Amines 2-3 min

Thyroid hormones: T4 6.7 days


T3 0.75 days

Polypeptides 4-40 min

Proteins 15-170 min

Steroids 4-120 min


Ho rmone-Re ceptor
in te ra ctions
 Definition: a protein that binds a ligand with
high affinity and low capacity.
 A tissue becomes a target for a hormone by
expressing a specific receptor for it. Hormones
circulate in the blood stream but only cells with
receptors for it are targets for its action.
Or ig in al b io assa y
syst ems defin ed the
endocrine syst em
 Remove endocrine gland and observe what
happened
 Prepare crude extract from gland, inject back
into animal and observe what happened
 In isolated organ or cell systems, add extract
or purified hormonal preparations and
measure biological response
Ho rmonal
measu rements
 Chemical methods
 chromatography
 spectrophotometery
Ra dioimmu noassa y
 Radioactive ligand and unlabeled ligand
compete for same antibody. Competition is
basis for quantitation
 saturate binding sites with radioactively
labeled hormone (ligand)
 in parallel incubate complex with unknown
and determine its concentration by
comparison
Cla sse s o f hormo nes
 
 The hormones fall into two general
classes based on their solubility in water.

The water soluble hormones are the


catecholamines (epinephrine and
norepinephrine) and peptide/protein
hormones.
The lipid soluble hormones include thyroid
hormone, steroid hormones and Vitamin D3
Typ es of r eceptors
 Receptors for the water soluble hormones are
found on the surface of the target cell, on the
plasma membrane.
 These types of receptors are coupled to various
second messenger systems which mediate the
action of the hormone in the target cell.
 Receptors for the lipid soluble hormones reside
in the nucleus (and sometimes the cytoplasm)
of the target cell.
 Because these hormones can diffuse through the
lipid bilayer of the plasma membrane, their
receptors are located on the interior of the target cell
Ho rmones and their
recepto rs
Hormone Class of Location
hormone

Amine Water-soluble Cell surface


(epinephrine)

Amine (thyroid Lipid soluble Intracellular


hormone)

Peptide/protein Water soluble Cell surface

Steroids and Lipid Soluble Intracellular


Vitamin D
Se cond me ssenger
syst ems
 Receptors for the water soluble
hormones are found on the surface of the
target cell, on the plasma membrane.
These types of receptors are coupled to
various second messenger systems
which mediate the action of the hormone
in the target cell
Se cond m esse ngers f or
cell- su rface receptors
 Second messenger systems include:
 Adenylate cyclase which catalyzes the conversion of
ATP to cyclic AMP;
 Guanylate cyclase which catalyzes the conversion
of GMP to cyclic GMP (cyclic AMP and cyclic GMP
are known collectively as cyclic nucleotides);
 Calcium and calmodulin; phospholipase C which
catalyzes phosphoinositide turnover producing
inositol phosphates and diacyl glycerol.
Typ es of r eceptors
Se cond m esse nger
syst ems
 Each of these second messenger systems
activates a specific protein kinase enzyme.
 These include cyclic nucleotide-dependent protein
kinases
 Calcium/calmodulin-dependent protein kinase, and
protein kinase C which depends on diacyl glycerol
binding for activation.
 Protein kinase C activity is further increased by calcium
which is released by the action of inositol phosphates.
Se cond me ssenger
syst ems
 The generation of second messengers and
activation of specific protein kinases results in
changes in the activity of the target cell which
characterizes the response that the hormone
evokes.
 Changes evoked by the actions of second
messengers are usually rapid
Si gnal transducti on
mechani sms of hor mones
Activation of Inhibition of Increased Tyrosine kinase
adenylate adenylate phospho- activation
cyclase cyclase inositide
turnover
β-adrenergic α2-adrenergic α1-adgrenergic Insulin

LH, FSH, TSH, Opioid Angiotensin II Growth factors


hCG (PDGF, EGF,
FGF, IGF-1
Glucagon Muscarinic Muscarinic Growth hormone
cholinergic – M2 cholinergic – M3

Vasopressin- V2 Vasopressin –V1 Prolactin

ACTH
Cell s urfa ce r eceptor actio n
G-p rotein c ouple d
recepto rs
Adenylate cyclase, cAMP and PKA
Amplification
via 2nd
messenger
Tr ansme mbrane
kin ase -li nked
recepto rs
 Certain receptors have intrinsic kinase activity.
These include receptors for growth factors, insulin
etc.

 Other tyrosine-kinase associated receptor, such as


those for Growth Hormone, Prolactin and the
cytokines, do not have intrinsic kinase activity, but
activate soluble, intracellular kinases such as the
Jak kinases.

 In addition, a newly described class of receptors


have intrinsic serine/threonine kinase activity—this
class includes receptors for inhibin, activin, TGFβ,
and Mullerian Inhibitory Factor (MIF).
Protei n tyros ine ki nase
recepto rs
Re ceptors for l ip id -
so lu ble hormo nes
resid e within t he c ell
 These hormones can diffuse through the lipid bilayer of
the plasma membrane, their receptors are located on
the interior of the target cell.
 Diffuses into the cell and binds to the receptor which
undergoes a conformational change. The receptor-
hormone complex is then binds to specific DNA
sequences called response elements.
 These DNA sequences are in the regulatory regions of
genes.
Re ceptors for l ip id -
so lu ble h ormo nes
resid e with in t he c ell
 The receptor-hormone complex binds to the regulatory
region of the gene and changes the expression of that
gene.
 In most cases binding of receptor-hormone complex to
the gene stimulating the transcription of messenger
RNA.
 The messenger RNA travels to the cytoplasm where it
is translated into protein. The translated proteins that
are produced participate in the response that is evoked
by the hormone in the target cell
 Responses evoked by lipid soluble hormones are
usually SLOW, requiring transcription/translation
to evoke physiological responses.
Me chanism
of lipid
sol uble
hormo ne
action
Re ceptor control
mechanism s
 Hormonally induced negative regulation of receptors is
referred to as homologous-desensitization
 This homeostatic mechanism protects from toxic
effects of hormone excess.
 Heterologous desensitization occurs when exposure of
the cell to one agonist reduces the responsiveness of
the cell any other agonist that acts through a different
receptor.
 This most commonly occurs through receptors that act
through the adenylyl cyclase system.
Me chanisms of
endocrine dise ase
 Endocrine disorders result from hormone
deficiency, hormone excess or hormone
resistance
 Almost without exception, hormone
deficiency causes disease
 One notable exception is calcitonin
deficiency
Me chanism s of
endocrine dise ase
 Deficiency usually is due to destructive
process occurring at gland in which
hormone is produced—infection,
infarction, physical compression by tumor
growth, autoimmune attack

Type I Diabetes
Me chanism s of
endocrine dise ase
 Deficiency can also arise from genetic
defects in hormone production—gene
deletion or mutation, failure to cleave
precursor, specific enzymatic defect
(steroid or thyroid hormones)

Congenital Adrenal Hyperplasia


Me chanism s of
endocrine dise ase
 Inactivating mutations of receptors can
cause hormone deficiency

Testicular Feminization Syndrome


Me chanism s of
endocrine dise ase
 Hormone excess usually results in
disease
 Hormone may be overproduced by gland
that normally secretes it, or by a tissue
that is not an endocrine organ.
 Endocrine gland tumors produce
hormone in an unregulated manner.
Cushing’s Syndrome
Me chanism s of
endocrine dise ase
 Exogenous ingestion
of hormone is the
cause of hormone
excess—for
example,
glucocorticoid
excess or anabolic
steroid abuse
Me chanism s of
endocrine dise ase
 Malignant transformation of non-
endocrine tissue causes
dedifferentiation and ectopic
production of hormones
 Anti-receptor antibodies stimulate
receptor instead of block it, as in the
case of the common form of
hyperthyroidism.

Grave’s Disease
Me chanism s of
endocrine dise ase
 Alterations in receptor number and
function result in endocrine disorders
 Most commonly, an irregular increase in
the level of a specific hormone will cause
a decrease in available receptors

Type II diabetes
Various types of abnormal secretion of a target organ hormone (TOH), which is
normally regulated by a tropic hormone (TH) from the anterior pituitary. Bold and
broken lines depict greater and less than normal rates of secretion, respectively. Cross-
hatching indicates the location of the defect. Simulation and inhibition are indicated by
(+) and (-), respectively.
Hy pot hal am us
and P itu it ar y
Hyp oth ala mu s and
Pitu itary
 The hypothalamus-pituitary unit is the
most dominant portion of the entire
endocrine system.
 The output of the hypothalamus-pituitary
unit regulates the function of the thyroid,
adrenal and reproductive glands and also
controls somatic growth, lactation, milk
secretion and water metabolism.
Hypothal amus and
pi tui tary gl and
Hypothal amus and
pi tui tary gl and
Hypothala mu s and
Pit uitary
 Pituitary function depends on the
hypothalamus and the anatomical organization
of the hypothalamus-pituitary unit reflects this
relationship.
 The pituitary gland lies in a pocket of bone at
the base of the brain, just below the
hypothalamus to which it is connected by a
stalk containing nerve fibers and blood vessels.
The pituitary is composed to two lobes--
anterior and posterior
Po st erio r Pituita ry:
neuro hyp ophysis
 Posterior pituitary: an outgrowth of the
hypothalamus composed of neural
tissue.
 Hypothalamic neurons pass through the
neural stalk and end in the posterior
pituitary.
 The upper portion of the neural stalk
extends into the hypothalamus and is
called the median eminence.
Hypothal amus
and posteri or
pi tui tary
Midsagital view
illustrates that
magnocellular
neurons
paraventricular and
supraoptic nuclei
secrete oxytocin and
vasopressin directly
into capillaries in the
posterior lobe
An terio r pituit ary:
adenohyp ophysis
 Anterior pituitary: connected to the
hypothalamus by the superior hypophyseal
artery.
 The antererior pituitary is an amalgam of
hormone producing glandular cells.
 The anterior pituitary produces six peptide
hormones:
prolactin, (PRL)
growth hormone (GH),
thyroid stimulating hormone (TSH),
adrenocorticotropic hormone (ACTH),
follicle-stimulating hormone (FSH),
and luteinizing hormone (LH).
Hypothal amu
s and
anteri or
pi tui tary
neurosecretory
cells secrete
releasing factors
into capillaries of
the pituitary portal
system at the
median eminence
which are then
transported to the
TSH
anterior pituitary
gland to regulate
LH
the secretion of
FSH
pituitary
hormones.
Anatomi cal and
functi onal or ga niz ati on
neocortex

Reticular
Thalamus Limbic

Regula tion
activating Optical
substance system system
pain Emotion, fright,
Sleep/ rage, smell vision

of
wake

Heat regulation Energy Autonomic

Hyp othalam
(temperature) regulation regulation
(hunger, (blood pressure
BMI) etc)

us
Water balance (blood
Metabolic rate, stress
volume, intake--thirst,
response, growth,
output—urine volume)
reproduction, lactation)

Anterior
pituitary
posterior hormones
pituitary
hormones
Hypot halamus/ Pi
tu itary Axis
Posterior Pituitary
Hyp othalamic releas ing
factor s fo r anter ior pit uit ary
hormo nes

 Travel to adenohypophysis via hypophyseal-


portal circulation
 Travel to specific cells in anterior pituitary to
stimulate synthesis and secretion of trophic
hormones
Hypothal ami c rel easi ng
hormones
Hypothalamic releasing Effect on pituitary
hormone
Corticotropin releasing hormone Stimulates ACTH secretion
(CRH)
Thyrotropin releasing hormone Stimulates TSH and Prolactin
(TRH) secretion
Growth hormone releasing Stimulates GH secretion
hormone (GHRH)
Somatostatin Inhibits GH (and other hormone)
secretion
Gonadotropin releasing hormone Stimulates LH and FSH
(GnRH) a.k.a LHRH secretion
Prolactin releasing hormone (PRH) Stimulates PRL secretion

Prolactin inhibiting hormone Inhibits PRL secretion


(dopamine)
Characteri sti cs of
hypot halam ic rel easi ng
horm ones
 Secretion in pulses
 Act on specific membrane receptor
 Transduce signals via second messengers
 Stimulate release of stored pituitary hormones
 Stimulate synthesis of pituitary hormones
 Stimulates hyperplasia and hypertophy of
target cells
 Regulates its own receptor
Hypot hal am
us and
anteri or
pi tui tary
Anterior pituitary
 Anterior pituitary: connected to the
hypothalamus by hypothalmoanterior pituitary
portal vessels.
 The anterior pituitary produces six peptide
hormones:
 prolactin, growth hormone (GH),
 thyroid stimulating hormone (TSH),
 adrenocorticotropic hormone (ACTH),
 follicle-stimulating hormone (FSH),
 luteinizing hormone (LH).
Anteri or pi tui tary cel ls
and hormones
Cell type Pituitary Product Target
population
Corticotroph 15-20% ACTH Adrenal gland
β-lipotropin Adipocytes
Melanocytes
Thyrotroph 3-5% TSH Thyroid gland
Gonadotroph 10-15% LH, FSH Gonads
Somatotroph 40-50% GH All tissues,
liver
Lactotroph 10-15% PRL Breasts
gonads
An terio r pituit ary
hormones