52. Principles of endocrine control systems.b, biosynthesis c, secretion c, transport d, metabolism 5., Signal transduction 6., Interaction with other systems 7., Pathological conditions

2020.02.19.

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52. Principles of endocrine control

systems.

Physiology lecture 2.

2019/2020. 2nd semester

Pharmacology, Dentist students

Alexandra Büki

Department of Physiology

52. Principles of endocrine control systems.

Give the definitions of hormone and hormonal control.

Describe the classification of hormones based on their chemical structure (e.g. amino

acid derivatives, biogenic amines, peptides, proteins, steroids) and also the

classification of hormone receptors (membrane receptors and intracellular receptors)

and describe their signaling pathways. Give 1-1 examples from each group.

Explain the types of hormonal effects using 1-1 example (stimulatory, inhibitory,

permissive effects).

Understand the effects of plasma hormone binding proteins on access of thyroid

hormones and steroid hormones to their sites of action and degradation and on the

regulation of hormone secretion.

Explain the importance of patterns of hormone secretion, such as pulsatile, diurnal,

and menstrual. Give examples.

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1., Definition of hormone and hormonal regulation and its functions

2., Forms of chemical signaling

3., Hormone secreting cells

a, localization

b, functioning system

c, principles of regulation

4., Hormones

a, chemical structure

b, biosynthesis

c, secretion

c, transport

d, metabolism

5., Signal transduction

6., Interaction with other systems

7., Pathological conditions in the regulation




a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism




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1. Definition of hormone and hormonal regulation and its

functions

Hormones are chemical substances and serve to communicate

between organs and tissues for physiological regulation and behavioral

activities. It is part of the homeostatic response to an altered environment,

whether external or internal.

Endocrine Exocrine

Secretion into the

interstitium/blood by internal

glands/cells.

The secreted product called

hormone.

Exocrine glands are glands that secrete

substances onto an epithelial surface by

way of a duct. E.g. sweat (skin), bile and

pancreatic juice (gastrointestinal tract )

Characteristics:

• No ducts – epithelial cell groups

• Hormone secretion

• Secretion into the interstitium � blood (rich blood supply)

• Influence at another location in the body (mainly)

• Homeostatic (regulatory) functions

• Large effects in small amount

Functions regulated by hormones:

• Metabolism

• Adaptation to the environment (e.g. stress)

• Sexual functions

• Growth

1. Definition of hormone and hormonal regulation and its functions

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a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism




Hormone, cytokines,

neurotransmitters have very

similar mechanism to act on

the target cells!


Neurotransmitters are released

by an axon terminal into a

synaptic cleft (act locally, on

neighboring cells, e.g. Ach)

Hormones are released by

endocrine glands/cells and

secreted directly into the

circulating blood (target cells are

another location of the body) e.g.

cortisol

Neurohormones are released by

neurons into the circulating

blood (target cells are another

location of the body) e.g. ADH

Cytokines are peptides secreted

by cells into the extracellular

fluid (part of the immune

system) e.g. interleukins,

lymphokines

Effector

cell

Macrophage

Effector

cell

T-helper

B-lymphocyte

Synapse

T-helper

Endocrine system Immune system Nervous system

AU

TO

CR

INE

PA

RA

CR

INE

EN

DO

CR

INE

+ intracrine effect

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a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism




Belsőelválasztású

mirigyek


a, localization

Diffuse endocrine system

Non-endocrine organs with

endocrine function

E.g. kidney (exretion, filtration,

metabolism)

+ erythropoietin �

red blood cells production


mirigyek

Pancreas

Insulin

Ovaries

estrogens

Testes Testosteron

Central nervous system

(Hypothalamus)

Thymus tymosin

Atrium of the

heart ANP

Stomach

Gastrin, secretin…

Fat tissue

Leptin, adiponectin,

Gastrointestinal tract

cholecystokinin…

Kidney

Erythropoietin,

calcitriol

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mirigyek


a, localization

„Classic” endocrine cells

forms well defined glands/organs


mirigyek

Central nervous system

(Hypothalamus) TRH,

CRH…Adenohypophysis

ACTH, TSH, FSH,

LH, GH, PRL

Tyroid gland

Calcitonin, T3/T4

Pineal gland melatonin

Parathyroid gland

parathormone

Adrenal cortex

aldosteron, cortisol…

The hypothalamus-hypophysis system forms a hierarchical feedback-control

system to regulate and control various body functions and activity of the endocrine

cells/glands of the system.

Hypothalamus (releasing and inhibiting factors) and anterior hypophysis

/anterior pituitary gland (hormones, trophormones) have the major role!



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Median eminence

ENDOCRINE

CELL

INTEGRATED

STIMULUS

HORMONE

RESPONSE

DIRECT

NEGATIVE

FEEDBACK

ENDOCRINE

CELL

INTEGRATED

STIMULUS

HORMONE

RESPONSE

POSITIVE

FEEDBACK

General principles of feedback regulations



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A

B

C

Hormone A

Hormone B

Hormone C

DIRECT

NEGATIVE

FEEDBACK

INDIRECT

NEGATIVE

FEEDBACK

SHORT

NEGATIVE

FEEDBACK

(-) (-)

(-)

ENDOCRINE

CELL

INTEGRATED

STIMULUS

HORMONE

RESPONSE

DIRECT

NEGATIVE

FEEDBACK

General principle of negative

feedback regulation


c, principles of regulationNegative feedback loops

involving three endocrine

glands

Negative feedback

Stimulus

Hypothalamus

Adenohypophysis

Endocrine

organ

X

Target cell

XTH

Dir

ect

neg

ati

ve

feed

ba

ck /

Ind

irec

t n

ega

tive

feed

ba

ck

Sh

ort

lo

op

/ D

irec

t n

ega

tive

feed

ba

ck

Ult

ra-s

hort

loop

Lo

ng

lo

op

XRH

Stimulus

Hypothalamus

Adenohypophysis

Adrenal cortex

Cardiovascular function,

metabolism, bones,

connective tissues,

immune cells….

ACTH

Dir

ect

neg

ati

ve

feed

ba

ck /

Ind

irec

t n

ega

tive

feed

ba

ck

Sh

ort

lo

op

/ D

irec

t n

ega

tive

feed

ba

ck

Ult

ra-s

hort

loop

Lo

ng

lo

op

CRH

cortisol

3., Hormone secreting cells c, principles of regulation

CRH: corticotropin releasing hormone

ACTH: adrenocorticotropic hormone

XRH: releasing hormone X

XIH: inhibiting hormone X

XTH: tropic hormone X

XIH

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days

Pozitive feedback

3., Hormone secreting cells c, principles of regulation

Months

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior

pituitary gland




a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism




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4., Hormones a, Chemical structures

1) Derivatives of aminoacids

2) Peptides, proteins

(glycoproteins)

3) Steroids

1) Derivatives of aminoacids

� Derived from tyrosine

• Catecholamines (adrenaline, noradrenaline, dopamine)

• Thyroid hormones (thyroxine, triiodothyronine)

� Derived from tryptophan

• Melatonin


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2) Peptides and proteins

� Oligopeptides (2-20 aminoacids)• TRH (3AA), ADH (9 AA), Oxytocin (9AA), GnRH (10 AA), MSH (13 AA),

Somatostatin (14-18 AA)

� Polipeptides (20-50 aminoacids)• glucagon (29 AA), calcitonin (32 AA), ACTH (39 AA), CRH (41 AA), GHRH (44 AA)

� Proteins (50 < aminoacids)• Insulin (51 AA), IGF-1 (70 AA), GH (~200 AA), PRL (~200 AA), PTH (84 AA)

� Glycoproteins• FSH, HCG, LH, TSH HCG: Human chorion gonadotropin

LH: luteinizing hormone

MSH: Melanocyte-stimulating

hormone

PRL: Prolactin

PTH: Parathormone

TRH: Thyroid-releasing hormon

TSH: Thyroid-stimulating hormon


AA: amino acid

ACTH: Adrenocorticotropic hormone

ADH: vasopressin

CRH: Corticotropin-releasing hormone

FSH: Folliculus-stimulating hormone

GH: Growth hormone

GHRH: Growth hormone-releasing hormone

GnRH: Gonadotropin-releasing hormon

IGF- 1: Insulin-like growth factor

3) Steroids

� Adrenal cortex:

• aldosterone,

• cortisol,

• androgens:

� Dehydroepiandrosterone

(DHEA)

� Dehydroepiandrosterone

sulphate (DHEAS)

� Reproductive glands

• testosterone

• estrogens

• progesteron

� 1,25-dihydroxicholecalciferol

(Vitamin D)


aldosterone

cortisol

androgens

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STEROIDS hormones

Types:

• C21:

• Aldosterone

• Cortisol

• Corticosterone

• Progesterone

• C19: Androgens

• Testosterone

• DHEA

• DHEAS

• Androstendion

• C18: Estrogens

• estradiol

• estriol

• estrone

• C27

aldosterone

testosterone

progesterone cortisol corticosterone

androstendione DHEAS: dehydroepiandrosterone-

sulphate

estradiol estriol estrone

• Vitamin D

1,25-dihydroxicholecalciferol

Solubility of hormones

Water-soluble hormones: peptides, proteins and catecholamines

Lipid-soluble hormones: steroid hormones, thyroid hormones

Solubility of hormones determines their biological

characteristics


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PEPTIDE HORMONES biosynthesis

Following the general principles of protein synthesis4., Hormones b, Biosynthesis

• Preprohormone � prohormone � hormone

nucleus

Endoplasmic

reticulum

ribosomes

cisterns

Golgi

apparatus

Granulum

Membrane

DNA

Preprohormone

Prohormone

Hormone↑Ca2+

↑cAMP

Stimulus

Biosynthesis of steroid hormones

Derived from cholesterol

Lipid-soluble

Synthesis:

� Smooth endoplasmic reticulum

� Mitochondria

Enzymes:

� Cytochrome P450

� Hydroxysteroid dehydrogenases

4., Hormones b, Biosynthesis

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plasma LDLsynthesis

4., Hormones b, Biosynthesis

Zona glomerulosa Zona fasciculata Zona reticulosa

Adrenal cortex

4., Hormones c, secretion

STORAGE � secretion

• Proteins and peptides hormones, catecholamines: – They are stored in vesicles, exocytosis results in expulsion of vesicle

contents.

• Lipophilic hormones:– They are synthesised on demand. Their release into the bloodstream is

the consequence of the passive diffusion through the lipid membrane.

– Cholesterol can be esterified and stored intracellularly in lipid droplets.

– Thyroid hormones are stored in colloid.

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4., Hormones c, secretion Rhythm of hormone secretion

Minutes

Hours

Circadian rhythm

sleep

Weeksovulation

Lifespan

years

days

men

stru

ati

on

minutes

hours

24 hours

Estradiol

Est

rad

iol

GnRH: Gonadotropin releasing hormone

STH: (somatotropin, Growth hormone)

The secreted hormones are MAINLY biologically active.

But certain hormones „become active” in the peripherial tissues

• Thyroid hormones: Thyroxine (T4) Triiodothyronine (T3)

Testosterone 5α-Dihydrotestosterone

Transport of hormones in the circulation

Water-soluble hormones: generally in a free form

Lipid-soluble hormones: free + protein-bound form

Transport-proteins:

• prealbumin, albumin, globulin (specific to type of the hormones)

4., Hormones d, transport

Only free hormones are biologically active, but bound and free

fractions are in equilibrium.

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The half-life of a hormone in blood is

defined as that period of time needed for

its concentration to be reduced by half.

Bound to

transportproteins%

Hormone Half-life in

minutes

Hormone concentrations in the blood:

unstable ≈ 10-9 – 10-12 mol/l

It depends on the rate of production,

secretion and degradation.

4., Hormones d, transport

4., Hormones e, metabolism

Inactivation of hormones /metabolism

• Metabolic destruction by the tissues/plasma

• Binding with the tissues: endocytosis

• Excretion by the liver into the bile

• Excretion by the kidneys into the urine

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a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism

5., Mechanism of action of hormones -Signal transduction



Receptors of hormones

BUT:• 1 hormone – more receptors (ADH – V1,V2)

• 1 receptor - more hormones (Mineralocorticoid receptor type I can bind aldosterone and cortisol

• Autoantibodies (Basedow/Graves disease� antibodies against TSH receptors)

5., Mechanisms of action of hormones

Locations of receptors:• In the cell membrane (peptides, cathecolamines, melatonin)

• In the cytoplasm (steroids)

• In the nucleus (T3,T4)

Regulation of the number and sensitivity of receptors:

• Down-regulation: • Receptor inactivation

• IC signal inactivation

• Receptor endocytosis, breakdown

• Decreased synthesis of receptors

• Up-regulation

• Receptor: protein, specific sensitivity for single hormone

• Receptor-binding

• Response: cell specific

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Hormone receptors:

1) Membrane-receptors (Peptide and protein hormones)

- extracellular domain

- membrane-spanning section

- intracellular domain

5., Mechanisms of action of hormonesAction – hormone receptors – intracellular signal transduction

Tyrosine kinase

receptorG protein coupled receptors

Tyrosine kinase-

coupled receptor

Guanylate cyclase-

coupled receptor

Enzyme linked receptors

Gs/Gi Gq

Parathormone Vasopressin (V1)

Atrial natriuretic

peptid (ANP)Insulin Growth hormone

Gs/ Gi

Adenylate cyclase system

Serkentő v. gátló• CRH ↑

• (Nor)adrenaline, α2 ↓,β1,2,3↑

• Dopamine (D1, D5: ↑;

D2-4: ↓)

• ACTH ↑�melanocortin receptor-2 (MCR2)• FSH ↑• LH ↑• PTH ↑• TSH ↑• Vasopressin V2 (epithelial cell: kidney ) ↑• α-MSH � melanocortin receptor-1(MCR1)

• melatonin (MT1) ↓

• calcitonin ↑

• Angiotensin II AT2 [epithelial cell: kidney ] ↑

• somatostatin ↓

• glucagon ↑• HCG ↑


G protein coupled receptors

CREB: cAMP response element binding protein

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• TRH• GnRH• GHRH

• oxytocin• vasopressin

(V1:vascular smooth muscle)

• melatonin (MT2)

• Angiotensin II (AT1: vascular smooth muscle)

• catecholamines (α1-receptors)


G protein coupled receptors

Gq

PLC system

Receptor tyrosine kinase• 1 transmembrane structure

• extracellular transmitter-

binding site

• Intracellular

catalytic/enzyme-binding

site

Receptor tyrosine kinase

• Insulin

• Insulin-like growth factor

I (IGF-I)

Tyrosine-kinase-associated

receptors

• GH

• Prolactin

• (Leptin)

Tyrosine-kinase-associated

receptors

5., Mechanisms of action of hormones Enzyme-linked receptors

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InsulinPancreas ß-cells �

Lowering blood sugar level


Receptor tyrosine kinase

LeptinFat cells �

Regulation of appetite

and energy balance

Tyrosine-kinase-associated receptors


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Hormone receptors:

2) Intracellular receptors of lipid soluble hormones)

+ membrane receptors!5., Mechanisms of action of hormones

Typ I: in the cytoplasm (glucocorticoids, mineralocorticoids, androgens, progesterone)

Typ II: in the nucleus (thyroid hormones, calcitriol, estrogen)

Steroids

HRE: hormon response element


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a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism




6, Interaction in the regulation

with other systems

Autonomic innervation:

- direct

- regulation of blood flow

Neurosecretion:

hypothalamus, adrenal medulla

Neural activity of the

oxytocin secreting

neurons

Increase in pressure in the

ducts

Permissive effect:

e.g. requirement of glucocorticoids/tyroid hormones to be present for

catecholamines to exert their effects.

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a, localization



4., Hormones


b, biosynthesis

c, secretion

c, transport

d, metabolism




7. Pathophysiology of hormone secretion

Hypofunction

Hormone or receptor ?

Hyperfunction

- tumor

- stimulating autoantibodies

- disturbances of feedback regulation

Hormone therapy

Hormone replacement

Treatment

Glucocorticoids: anti-inflammatory and immunosuppressive agents

Estrogens, gestagens: hormonal contraception

Doping (growth hormone, androgens) side effects!

Documents

52. Principles of endocrine control systems.b, biosynthesis c, secretion c, transport d, metabolism 5., Signal transduction 6., Interaction with other systems 7., Pathological conditions