An Introduction to the Endocrine System
An Introduction to the Endocrine System
An Introduction to the Endocrine System
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Chapter 17<br />
<strong>An</strong> <strong>Introduction</strong> <strong>to</strong> <strong>the</strong><br />
<strong>Endocrine</strong> <strong>System</strong>
Overview of Cell Communications<br />
• Internal communication between cells is necessary<br />
<strong>to</strong> coordination cellular activities.<br />
• four principal mechanisms of communication exist<br />
between cells<br />
– gap junctions<br />
• pores in cell membrane allow signaling<br />
molecules, nutrients, and electrolytes <strong>to</strong> move<br />
from cell <strong>to</strong> cell<br />
– neurotransmitters<br />
• released from neurons <strong>to</strong> travel across synaptic<br />
cleft <strong>to</strong> second cell<br />
– paracrine (local) hormones<br />
• secreted in<strong>to</strong> tissue fluids <strong>to</strong> affect nearby cells<br />
– hormones<br />
• chemical messengers that travel in <strong>the</strong><br />
bloodstream <strong>to</strong> o<strong>the</strong>r tissues and organs<br />
• <strong>the</strong> endocrine system
<strong>Endocrine</strong> <strong>System</strong> Components<br />
• endocrine system - glands,<br />
tissues, and cells that secrete<br />
hormones<br />
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<strong>Endocrine</strong><br />
cells<br />
Target cells<br />
• endocrine glands – organs<br />
that are traditional sources of<br />
hormones<br />
(b) <strong>Endocrine</strong> system<br />
Hormone in<br />
bloodstream<br />
• hormones<br />
chemical messengers that are<br />
transported by <strong>the</strong> bloodstream<br />
and stimulate physiological<br />
responses in cells of ano<strong>the</strong>r<br />
tissue or organ, often a<br />
considerable distance away<br />
• endocrinology – <strong>the</strong> study of<br />
this system and <strong>the</strong> diagnosis<br />
and treatment of its disorders<br />
Key Steps:<br />
1. Hormone syn<strong>the</strong>sized by<br />
tissue.<br />
2. Hormone released in<strong>to</strong> blood.<br />
3. Hormone circulates within<br />
cardiovascular system<br />
4. Hormone leaves blood, diffuse<br />
<strong>to</strong> target tissue’s recep<strong>to</strong>r.<br />
5. Hormone binds <strong>to</strong> recep<strong>to</strong>r.<br />
6. Hormone changes metabolism<br />
of target tissue.
Comparison of <strong>Endocrine</strong> and Exocrine Glands<br />
• exocrine glands<br />
– have ducts carry secretion <strong>to</strong> an epi<strong>the</strong>lial surface or <strong>the</strong><br />
mucosa of <strong>the</strong> digestive tract – ‘external secretions’<br />
– extracellular effects (food digestion)<br />
• endocrine glands<br />
– no ducts<br />
– contain dense, fenestrated capillary networks which allows<br />
easy uptake of hormones in<strong>to</strong> bloodstream<br />
– ‘internal secretions’<br />
– intracellular effects such as altering target cell metabolism<br />
• Pancreas<br />
– Exocrine – digestive enzymes<br />
– <strong>Endocrine</strong> – insulin / glucagon<br />
• Hepa<strong>to</strong>cytes (liver cells) defy rigid classification<br />
– releases hormones<br />
– releases bile in<strong>to</strong> ducts<br />
– releases albumin and blood-clotting fac<strong>to</strong>rs in<strong>to</strong> blood (not<br />
hormones)
Comparison of Nervous and <strong>Endocrine</strong> <strong>System</strong>s<br />
(Differences)<br />
• both serve for internal communication<br />
– nervous - both electrical and chemical<br />
– endocrine - only chemical<br />
• speed and persistence of response<br />
– nervous - reacts quickly (1-10 msec), s<strong>to</strong>ps quickly<br />
– endocrine - reacts slowly (hormone release in<br />
seconds or days), effect may continue for weeks<br />
• adaptation <strong>to</strong> long-term stimuli<br />
– nervous - response declines (adapts quickly)<br />
– endocrine - response persists (adapts slowly)<br />
• area of effect<br />
– nervous - targeted and specific (one organ)<br />
– endocrine - general, widespread effects (many<br />
organs)
Comparison of Nervous and <strong>Endocrine</strong> <strong>System</strong>s<br />
(Similarities)<br />
• several chemicals function as both hormones<br />
and neurotransmitters<br />
– norepinephrine, cholecys<strong>to</strong>kinin, thyrotropin-releasing<br />
hormone, dopamine and antidiuretic hormone<br />
• some hormones secreted by neuroendocrine<br />
cells (neurons) that release <strong>the</strong>ir secretion in<strong>to</strong> <strong>the</strong><br />
bloodstream<br />
– oxy<strong>to</strong>cin and catecholamines<br />
• both systems with overlapping effects on same<br />
target cells<br />
– norepinephrine and glucagon cause glycogen<br />
hydrolysis in liver<br />
• systems regulate each o<strong>the</strong>r<br />
– neurons trigger hormone secretion<br />
– hormones stimulate or inhibit neurons<br />
• target organs or cells – those organs or cells that have<br />
recep<strong>to</strong>rs<br />
for a hormone and can respond <strong>to</strong> it.
Communication by <strong>the</strong> Nervous<br />
and <strong>Endocrine</strong> <strong>System</strong>s<br />
Neurotransmitter<br />
Nerve impulse<br />
(a) Nervous system<br />
Neuron<br />
Target cells<br />
<strong>Endocrine</strong><br />
cells<br />
Target cells<br />
(b) <strong>Endocrine</strong> system<br />
Hormone in<br />
bloodstream
Major <strong>Endocrine</strong> Organs<br />
Pineal gland<br />
Hypothalamus<br />
Pituitary gland<br />
Thyroid gland<br />
Thymus<br />
Adrenal gland<br />
Pancreas<br />
Parathyroid<br />
glands<br />
Posterior<br />
view<br />
Trachea<br />
Gonads:<br />
Ovary (female)<br />
Testis (male)<br />
organs of endocrine system
• Next, we will continue our<br />
discussion of <strong>the</strong> endocrine<br />
system by looking at <strong>the</strong><br />
hormone chemistry.
• Three Chemical Classes<br />
– steroids<br />
• derived from cholesterol<br />
• secreted by gonads and adrenal<br />
glands<br />
• estrogens, progesterone,<br />
tes<strong>to</strong>sterone, cortisol, corticosterone,<br />
aldosterone, DHEA, and calcitriol<br />
– peptides (and glycoproteins)<br />
• created from chains of amino acids<br />
• secreted by pituitary and<br />
hypothalamus<br />
• oxy<strong>to</strong>cin, antidiuretic hormone,<br />
releasing and inhibiting hormones,<br />
and anterior pituitary hormones<br />
– monoamines (biogenic amines)<br />
• derived from amino acids<br />
• secreted by adrenal, pineal, and<br />
thyroid glands<br />
• epinephrine, norepinephrine,<br />
mela<strong>to</strong>nin, and thyroid hormone<br />
• Note: all hormones are made from ei<strong>the</strong>r<br />
cholesterol or amino acids with carbohydrate<br />
added <strong>to</strong> make glycoproteins.<br />
O<br />
HO<br />
(a) Steroids<br />
(c) Peptides<br />
Hormone<br />
Chemistry<br />
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CH 3<br />
<strong>An</strong>giotensin II<br />
Tes<strong>to</strong>sterone<br />
Estradiol<br />
Insulin<br />
CH 3<br />
OH<br />
H 2 N<br />
OH<br />
CH 3<br />
I<br />
I<br />
OH<br />
Thyroxine<br />
OH<br />
HO<br />
CH CH 2<br />
HO<br />
(b) Monoamines<br />
I<br />
H<br />
C<br />
CH 2<br />
O<br />
Epinephrine<br />
S<br />
S<br />
S<br />
COOH<br />
Pro Thr Tyr Asn<br />
Phe Cys Tyr Asn Glu<br />
Lys<br />
Phe<br />
Leu<br />
S<br />
Gln<br />
Thr<br />
Gly<br />
Gly<br />
Tyr<br />
Arg<br />
Leu<br />
lle<br />
Glu<br />
S<br />
Ser<br />
Val<br />
Gly<br />
Cys<br />
Glu<br />
Cys<br />
Gln<br />
Val<br />
lle<br />
Cys<br />
Ser<br />
Thr Cys<br />
Leu<br />
Tyr<br />
Arg Val Tyr<br />
Leu<br />
Asp<br />
lle<br />
Ala<br />
His<br />
Glu<br />
Val<br />
Pro Phe<br />
Leu His Ser Gly Cys Leu<br />
His<br />
Gln<br />
Asn<br />
Val<br />
Phe<br />
S<br />
I<br />
NH<br />
CH 2
Hormone Syn<strong>the</strong>sis: Steroid Hormones<br />
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CH 3<br />
CH 3<br />
HO<br />
Cholesterol<br />
CH 3<br />
CH 3<br />
CH 3<br />
C O<br />
CH 3<br />
CH 3<br />
C<br />
O<br />
Progesterone<br />
CH 2 OH<br />
OH<br />
C O<br />
CH 3<br />
HO<br />
CH 3 OH<br />
HO<br />
CH<br />
O 2 OH<br />
O<br />
HC<br />
CH 3<br />
CH 3<br />
CH 3<br />
CH 3<br />
O<br />
Tes<strong>to</strong>sterone<br />
O<br />
Cortisol (hydrocortisone)<br />
O<br />
Aldosterone<br />
OH<br />
HO<br />
Estradiol<br />
• syn<strong>the</strong>sized from cholesterol – differs in functional<br />
groups attached <strong>to</strong> 4-ringed steroid backbone
Peptides<br />
• syn<strong>the</strong>sized in same way as any<br />
protein<br />
• at first is an inactive pre-prohormone<br />
• first several amino acids is a signal<br />
peptide that guides it in<strong>to</strong> cisterna of<br />
rough endoplasmic reticulum<br />
• signal peptide removed <strong>to</strong> form<br />
prohormone<br />
• Golgi does final transformation <strong>to</strong><br />
hormone packaged for secretion
Hormone Syn<strong>the</strong>sis: Insulin<br />
• begins as preproinsulin,<br />
<strong>the</strong>n<br />
becomes proinsulin<br />
• when connecting<br />
peptide is removed,<br />
two polypeptide chains<br />
are formed that make<br />
up insulin<br />
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C peptide<br />
Proinsulin<br />
Insulin
Monoamines<br />
• Syn<strong>the</strong>sized from amino acid<br />
• mela<strong>to</strong>nin is syn<strong>the</strong>sized from<br />
amino acid tryp<strong>to</strong>phan<br />
• thyroid hormone is composed<br />
of 2 tyrosines
Thyroid Hormone Syn<strong>the</strong>sis<br />
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Thyroid follicle<br />
Blood capillary<br />
Transport<br />
proteins<br />
I −<br />
Iodide<br />
1 Iodide absorption and oxidation<br />
5<br />
1<br />
Follicle cell<br />
2 Thyroglobulin syn<strong>the</strong>sis and secretion<br />
T 3<br />
T 4<br />
3 Iodine added <strong>to</strong> tyrosines of thyroglobulin<br />
4<br />
Thyroglobulin uptake and hydrolysis<br />
Lysosome<br />
4<br />
I –<br />
2<br />
Thyroglobulin<br />
5 Release of T 4 and a small amount of T 3 in<strong>to</strong><br />
<strong>the</strong> blood<br />
I *<br />
Iodine<br />
S<strong>to</strong>red<br />
thyroglobulin<br />
3
T 3 and T 4 Syn<strong>the</strong>sis<br />
• follicular cells<br />
– absorb iodide (I - ) ions from blood and s<strong>to</strong>re in<br />
lumen as a reactive form of iodine<br />
– syn<strong>the</strong>size thyroglobulin and s<strong>to</strong>re in lumen<br />
• forms colloid<br />
• contains lots of tyrosine<br />
– tyrosine and iodine combine <strong>to</strong> form thyroxine (T 4 )<br />
bound <strong>to</strong> thyroglobulin<br />
– s<strong>to</strong>red in follicle<br />
• TSH<br />
– stimulates follicular cells <strong>to</strong> remove T 4 from<br />
thyroglobulin for release in<strong>to</strong> plasma<br />
– most T 3 is produced in liver or by target cells<br />
removing an iodine from circulating T 4<br />
– 95% T 4 and 5% T 3
Chemistry of Thyroid Hormone<br />
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Thyroglobulin<br />
CH 2<br />
CH 2<br />
Tyrosine<br />
OH<br />
DIT<br />
l<br />
l<br />
OH<br />
+<br />
1<br />
Addition of iodine <strong>to</strong><br />
tyrosine <strong>to</strong> form MIT<br />
DIT<br />
l<br />
l<br />
OH<br />
3 Two DITs<br />
combine <strong>to</strong><br />
form thyroxine (T4)<br />
CH 2<br />
MIT<br />
CH 2<br />
I<br />
OH<br />
l<br />
l<br />
O<br />
OH<br />
l<br />
l<br />
2<br />
Addition of ano<strong>the</strong>r<br />
iodine <strong>to</strong> form DIT<br />
H 2 N<br />
H<br />
C<br />
4<br />
CH 2<br />
Thyroxine<br />
released from<br />
thyroglobulin<br />
COOH<br />
CH 2<br />
DIT<br />
Figure 17.19<br />
l<br />
l<br />
OH<br />
MIT contains one iodine a<strong>to</strong>m, DIT has two<br />
T 3 - combination of MIT plus DIT<br />
T 4 - combination of two DITs<br />
l<br />
l<br />
O<br />
l<br />
l<br />
OH
Hormone Transport<br />
• most monoamines and peptides are hydrophilic<br />
– mix easily with blood plasma<br />
• steroids and thyroid hormone are hydrophobic<br />
– bind <strong>to</strong> transport proteins (albumins and globulins syn<strong>the</strong>sized by<br />
<strong>the</strong> liver)<br />
– <strong>the</strong>se hormones are “bound hormones”<br />
– have longer half-life<br />
– protected from liver enzymes and kidney filtration<br />
– transport proteins protect circulating hormones<br />
– being broken down by enzymes in <strong>the</strong> plasma and liver<br />
– being filtered out of <strong>the</strong> blood by <strong>the</strong> kidneys<br />
– only unbound hormone leaves capillaries <strong>to</strong> reach target cell<br />
• thyroid hormone binds <strong>to</strong> three transport proteins in <strong>the</strong> plasma<br />
– albumin, thyretin and TGB (thyroxine-binding globulin)<br />
– more than 99% of circulating TH is protein bound<br />
• steroid hormones bind <strong>to</strong> globulins<br />
– transcortin – <strong>the</strong> transport protein for cortisol<br />
• aldosterone - short half-life<br />
– 85% unbound<br />
– 15% binds weakly <strong>to</strong> albumin and o<strong>the</strong>rs
Hormone Recep<strong>to</strong>rs<br />
• hormones stimulate only those cells that have<br />
recep<strong>to</strong>rs for <strong>the</strong>m<br />
• recep<strong>to</strong>rs are protein or glycoprotein molecules:<br />
– on plasma membrane, in <strong>the</strong> cy<strong>to</strong>plasm, or in <strong>the</strong><br />
nucleus<br />
• recep<strong>to</strong>rs act like switches turning on metabolic<br />
pathways when hormone binds <strong>to</strong> <strong>the</strong>m<br />
• usually each target cell has a few thousand<br />
recep<strong>to</strong>rs for a given hormone<br />
• recep<strong>to</strong>r-hormone interactions exhibit specificity<br />
and saturation<br />
– specific recep<strong>to</strong>r for each hormone<br />
– saturated when all recep<strong>to</strong>r molecules are occupied by<br />
hormone molecules
Hormone Mode of Action<br />
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Transport<br />
protein<br />
Free<br />
hormones<br />
Bound<br />
hormone<br />
Blood<br />
Hydrophilic<br />
hormone<br />
Recep<strong>to</strong>r in<br />
plasma<br />
membrane<br />
Secondmessenger<br />
activation<br />
Hydrophobic<br />
hormone<br />
Recep<strong>to</strong>r in<br />
Tissue fluid<br />
nucleus<br />
Target<br />
cell<br />
• hydrophobic hormones<br />
– penetrate plasma<br />
membrane and enter<br />
nucleus<br />
– act directly on <strong>the</strong> genes<br />
changing target cell<br />
physiology<br />
– estrogen, progesterone,<br />
thyroid hormone act on<br />
nuclear recep<strong>to</strong>rs<br />
– take several hours <strong>to</strong> days<br />
<strong>to</strong> show effect due <strong>to</strong> lag<br />
for protein syn<strong>the</strong>sis<br />
• hydrophilic hormones<br />
– cannot penetrate in<strong>to</strong><br />
target cell<br />
– must stimulate<br />
physiology indirectly
Thyroid Hormone<br />
TBG<br />
• thyroid hormone enters target<br />
cell by diffusion – mostly as T 4<br />
with little metabolic effect<br />
Various<br />
metabolic effects<br />
• within target cell, T 4<br />
is<br />
converted <strong>to</strong> more potent T 3<br />
Protein<br />
syn<strong>the</strong>sis<br />
mRNA<br />
• T 3<br />
enters target cells and binds<br />
<strong>to</strong> recep<strong>to</strong>rs in chromatin<br />
T 3<br />
T 4<br />
T 4<br />
T 3<br />
I<br />
DNA<br />
• activates genes<br />
– make a muscle protein<br />
(myosin) enhancing cardiac<br />
muscle response <strong>to</strong><br />
sympa<strong>the</strong>tic stimulation<br />
– streng<strong>the</strong>ning heartbeat<br />
Blood<br />
Tissue fluid<br />
Target cell
Peptides and Catecholamines: Hydrophilic<br />
1<br />
Recep<strong>to</strong>r<br />
G<br />
GTP<br />
ACTH<br />
FSH<br />
LH<br />
PTH<br />
TSH<br />
Glucagon<br />
Calci<strong>to</strong>nin<br />
Catecholamines<br />
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Hormone<br />
G protein<br />
GDP<br />
+<br />
P<br />
i<br />
2<br />
Adenylate<br />
cyclase<br />
G<br />
ATP cAMP + PP<br />
3 i<br />
4<br />
Inactive protein<br />
kinase<br />
Inactive<br />
enzymes<br />
Activated protein<br />
kinase<br />
5<br />
6<br />
Enzyme<br />
substrates<br />
Activated<br />
enzymes<br />
Enzyme<br />
products<br />
Various<br />
metabolic<br />
effects<br />
1<br />
2 G protein activates adenylate cyclase.<br />
3 Adenylate cyclase produces cAMP.<br />
4 cAMP activates protein kinases.<br />
5<br />
6<br />
Hormone–recep<strong>to</strong>r binding<br />
activates a G protein.<br />
Protein kinases phosphorylate enzymes.<br />
This activates some enzymes and<br />
deactivates o<strong>the</strong>rs.<br />
Activated enzymes catalyze metabolic<br />
reactions with a wide range of possible<br />
effects on <strong>the</strong> cell.<br />
• hormone binds <strong>to</strong> cell-surface<br />
recep<strong>to</strong>r<br />
• recep<strong>to</strong>r linked <strong>to</strong> second<br />
messenger system on o<strong>the</strong>r<br />
side of <strong>the</strong> membrane<br />
• activates G protein which<br />
• activates adenylate cyclase<br />
• produces cAMP<br />
• activates or inhibits enzymes<br />
• possible metabolic reactions:<br />
– syn<strong>the</strong>sis<br />
– secretion<br />
– change membrane potentials
O<strong>the</strong>r Second Messengers<br />
Diacylglycerol (DAG) pathway<br />
Inosi<strong>to</strong>l triphosphate (IP 3 ) pathway<br />
1<br />
Hormone<br />
Ca 2+ -gated<br />
ion channel<br />
Ca 2+<br />
IP 3 -gated Ca 2+ channeI<br />
Hormone<br />
1<br />
Recep<strong>to</strong>r<br />
Phospholipase<br />
Phospholipase<br />
Recep<strong>to</strong>r<br />
3<br />
DAG<br />
G<br />
IP G<br />
3<br />
G<br />
4 6<br />
2 2<br />
Inactive Activated<br />
8<br />
5<br />
PK<br />
PK<br />
G<br />
Various<br />
metabolic<br />
effects<br />
Enzyme<br />
Activated<br />
PK<br />
9<br />
10<br />
Calmodulin<br />
Ca 2+<br />
IP 3<br />
IP 3<br />
7<br />
Hormones<br />
ADH<br />
TRH<br />
OT<br />
LHRH<br />
Catecholamines<br />
Key<br />
DAG<br />
G<br />
IP 3<br />
PK<br />
Diacylglycerol<br />
G protein<br />
Inosi<strong>to</strong>l triphosphate<br />
Protein kinase<br />
Inactive<br />
PK<br />
Smooth<br />
ER<br />
• diacylglycerol (diglyceride) second-messenger system<br />
• inosi<strong>to</strong>l triphosphate second-messenger system<br />
• act on cell metabolism in a variety of ways
Enzyme Amplification<br />
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Small stimulus<br />
Hormone<br />
cAMP and<br />
protein kinase<br />
Activated enzymes<br />
Metabolic product<br />
Great effect<br />
Reaction cascade (time)<br />
• hormones are<br />
extraordinarily potent<br />
chemicals<br />
• one hormone<br />
molecule can trigger<br />
<strong>the</strong> syn<strong>the</strong>sis of many<br />
enzyme molecules.<br />
• very small stimulus<br />
can produce very<br />
large effect<br />
• circulating<br />
concentrations very<br />
low
Modulation of Target Cell Sensitivity<br />
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Hormone<br />
Recep<strong>to</strong>r<br />
Low recep<strong>to</strong>r density<br />
Weak response<br />
(a ) Up-regulation<br />
High recep<strong>to</strong>r density<br />
Strong response<br />
(b ) Down-regulation<br />
Increased recep<strong>to</strong>r density<br />
Increased sensitivity<br />
Reduced recep<strong>to</strong>r density<br />
Reduced sensitivity<br />
Response<br />
Stronger response<br />
Response<br />
Diminished response<br />
• target cell sensitivity<br />
adjusted by changing <strong>the</strong><br />
number of recep<strong>to</strong>rs<br />
• up-regulation means<br />
number of recep<strong>to</strong>rs is<br />
increased<br />
– sensitivity is increased<br />
• down-regulation reduces<br />
number of recep<strong>to</strong>rs<br />
– cell less sensitive <strong>to</strong> hormone<br />
– happens with long-term<br />
exposure <strong>to</strong> high hormone<br />
concentrations<br />
• bind <strong>to</strong> o<strong>the</strong>r recep<strong>to</strong>rs<br />
• converted <strong>to</strong> different hormone
Hormone Interactions<br />
• most cells sensitive <strong>to</strong> more than one<br />
hormone and exhibit interactive effects<br />
• synergistic effects<br />
– multiple hormones act <strong>to</strong>ge<strong>the</strong>r for greater effect<br />
• synergism between FSH and tes<strong>to</strong>sterone on sperm<br />
production<br />
• permissive effects<br />
– one hormone enhances <strong>the</strong> target organ’s<br />
response <strong>to</strong> a second later hormone<br />
• estrogen prepares uterus for action of progesterone<br />
• antagonistic effects<br />
– one hormone opposes <strong>the</strong> action of ano<strong>the</strong>r<br />
• insulin lowers blood glucose and glycogen raises it
Hormone Clearance<br />
• hormone signals must be turned off<br />
when <strong>the</strong>y have served <strong>the</strong>ir purpose<br />
• most hormones are taken up and<br />
degraded by liver and kidney<br />
– excreted in bile or urine<br />
• metabolic clearance rate (MCR)<br />
– rate of hormone removal from <strong>the</strong> blood<br />
– half-life - time required <strong>to</strong> clear 50% of<br />
hormone from <strong>the</strong> blood<br />
– faster <strong>the</strong> MCF, <strong>the</strong> shorter is <strong>the</strong> half-life