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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 />

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.<br />

<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 />

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.<br />

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 />

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.<br />

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

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