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ENDOCRINOLOGY
GENERAL PHYSIOLOGY OF HORMONES
HORMONAL FEEDBACK
REGULATION OF HORMONE SECRETION
Jana Jurcovicova
ORGANIZATION OF THE ENDOCRINE SYSTEM
Evolution of multicellular organisms demanded coordinating systems to
regulate and integrate the function of the different cells. Three basic
regulatory systems developed:
1 – THE NERVOUS SYSTEM (elctrochemical signals)
2 – THE ENDOCRINE SYSTEM (chemical agents, affect target organs)
3 – THE IMMUNE SYSTEM (interleukins regulating host defense)
These 3 systems are closely interrelated:
1 – 2 NEURO-ENDOCRINE REGULATION (hypothalamo-pituitary reg.)
2 – 3 IMMUNO-ENDOCRINE REGULATION
1 – 2 – 3 IMUNO-NEURO-ENDOCRINE REGULATION
HORMON - TO STIMMULATE TO THE ACTION
classical definition of hormone by Baylis and Starling (1902)
Hormone is produced by an organ in small amounts, released into the
blood stream, and transported to a distal organ to exert action.
Nowadays this definition does not apply to all hormones:
Paracrine - action on contiguous cells
Autocrine – action on the same cell
OUT-OF-DATE FACTS OF CLASSICAL
ENDOCRINOLOGY
Hormones act distally
not true (paracrine,
autocrine actions
Hormones are produced
only in specialized glands
One hormone – one function
not true (fat tissue,
immune cells etc.)
not true (leptin,
estrogens, prolactin
cortisol, etc.
FUNCTION OF HORMONES
Regardless of their chemical nature hormones are present in the blood
stream in very low concentration 10-8 – 10-11 M
They bind to a very specific, high-affinity cellular receptors located at
CELL MEMBRANES or in the NUCLEUS.
Single hormone – various effects ( e.g. estradiol promotes granulosa cells
proliferation stimulates mammary gland, promotes growth of linear
bones and closure of epiphyseal plates.
Various hormone – single function (e.g. growth hormone, glucocorticoids
stimulate lipolysis
Hormones exert their functions in four broad physiological areas:
REPRODUCTION
GROWTH AND DEVELOPMENT
MAINTAINANCE OF INTERNAL ENVIRONMENT
REGULATION OF ENERGY BALANCE
CLASSICAL ENDOCRINE GLANDS AND
HORMONES
The endocrine glands are located in different areas of
the body that produce hormones with different functions.
Major morphological feature - they are ductless, they release
hormones directly into the blood stream, and not into the duct
system. They are richly vascularized – efficient delivery of the
secretory product into the blood circulation.
Classical view of endocrine
glands
-small glands (weighing tens of grams)
whose function is regulation,
coordination of physiological processes
such as reproduction, growth,
metabolism, energy homeostasis
CLASSICAL ENDOCRINE GLANDS AND THEIR HORMONES
NON-CLASSICAL ENDOCRINE GLANDS AND
HORMONES
• Heart (atrial natriuretic hormone)
• Gastrointestinal tract (cholecystokinin, gastrin, secretin, vasoactive
intestinal peptide, somatostatin, incretins)
• Stomach (ghrelin)
• adipocytes (leptin, adiponectin, visfatin, resistin, angiotensin,
interleukins, cortisol, catecholamins)
• Kidney (erytropoetin)
• Immune cells (interleukins, visfatin, prolactin, growth hormone,
neuropeptides, opioids)
• Tissues (growth factors)
• Endotelial cells (endotelins)
• Placenta (placental lactogen, growth factors)
• Limbic system (neuropeptides interleukins)
FAT TISSUE AS A NON-CLASSICAL ENDOCRINE ORGAN
visfatin
angiotensin
angiotensin
dfdf
dfdf
Zinc-α2glycoprotein
lipolysis
Adipocytokines implicated in energy homeostasis, insulin sensitivity (IS),insulin resistance (IR) and
atherothrombosis. Excessive production of interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α),
acylation-stimulating protein (ASP) deteriorates insulin action in muscle and/or in liver, whereas increased
angiotensin (AGE) favours hypertension,endothelial dysfunction and thrombosis. The role of resistin on
insulin resistanceis still not clear. Leptin regulates energy balance and exerts an insulin sensitizing effect.
Adiponectin increases insulin action in muscle and liver an exerts an anti atherogenic effect. Zinc-α2glycoprotein enhances lipolytic activity by sensitizing of β-adrenergic receptors
CHEMICAL NATURE OF HORMONES
Steroid, the precursor is cholesterol:
glucocorticoids, mineralocorticoids, sex steroids, calcitriol
On the basis of tyrosine:
thyroxine, triiodothyronine noradrenaline, adrenaline, dopamine
On the basis of tryptophane: melatonine
Peptide, polypeptides and proteins:
Peptides are short sequences of
aminoacids (TRH – 3 aminoacids, GHRH – 44 aminoacids). This group
represent mainly neurohormones and hormones of GIT.
Polypeptides and proteins are hormons with longer aminoacids sequences
(prolactin 198 AA). Some are only aminoacids sequences (prolactin, insulin,
parathormone), others have glucose in their structure (FSH, LH, TSH)
BIOSYNTHESIS OF STEROIDS
cholesterol
estranes
18 atoms of C
pregnanes
androstanes
21atoms of C
19 atoms of C
three main groups of steroidal structures are derived from
cyclopentanoperhydrofenantren skeleton
BIOSYNTHESIS OF
THYROID HORMONES
BIOSYNTHESIS OF
CATECHOLAMINES
3
Guyton and Hall, 2006
SYNTHESIS OF PEPTIDE AND POLYPEPTIDE
HORMONES
(first step is prehormone synthesis which contain signal peptide)
HORMONES WHICH ARE SYNTHESIZED AS
PROHORMONES
PROOPIOMELANOCORTINE A TYPICAL
MOLECULE OF PROHORMONE
prohormone convertase 1
produced by adenopituitary
prohotmone convertase 2
produced by hypothalamus
HORMONE SECRETION – EXOCYTOSIS
three stages of exocytosis
Docking – Vesicles move to plasma membrane.This process requires the
presence of actin filaments and ATP.
Priming – ATP dependent process the granules move to
space, modification of SNARE proteins.
the subplasmatic
Fusing – attachment of granule membrane to cell plasma membrane with the
help of SNARE proteins
Easom, 2000
HORMONE SECRETION – EXOCYTOSIS
Three phases: 1-docking, 2-priming, 3-fusion
docking
priming
SNARE (soluble N-etalmaleimide-sensitive factor attachment protein receptors)
SNAP-25 (synaptosomal-associated protein 25)
VAMP (vesicle-associated mebrane protein)
NSF (N-etalmaleimide sensitive factor)
-SNAP adaptor protein
TRANSPORT OF HORMONES
Water soluble proteohormones and peptides are transported in blood in free
form (short half life time - minutes)
Lipophilic steroid hormones and also hormones of the thyroid gland
(thyroxine and triiodotyronine) require specific transport proteins (TBG –
thyronine Binding Globulin, - half life time 5 days, CBG – Corticosteroid
Binding Globulin – half life time: 60 -90 minutes,
MECHANISMS OF HORMONE ACTION
Nuclear receptors :
steroid hormones (glucocorticoids, mineralocorticoids, sex steroids,
calcitriol) and thyronines
Membrane receptors:
Proteins, peptides, catecholamines
Hormone - receptor binding - first messenger
Intracellular signal - second messenger
The function of receptor is: to recognize specific hormon, to transmit
signal after the binding of hormone to its receptor.
Receptor must meet criteria of high affinity and specificity
MECHANISM OF STEROID HORMONE SIGNALING
heat shock
proteins
heat shock
proteins
MECHANISM OF THYROID HORMONE SIGNALLING
5´-DI
MCT8
3,5,3´-T3
(deiodinase)
T4
T4 / T3
RXR
DNA
mRNA
N
C
DIMERIZATION OF NUCLEAR RECEPTOR FOR T3
WITH NUCLEAR RECEPTOR FOR RETINOUD ACID
ZINC FINGERS NECESSARY FOR SPECIFIC BINDING OF THE
RECEPTOR MOLECULE WITH DNA SEQUENCE
ADENYLYL CYCLASE RECEPTOR
SIGNALING
Guyton and Hall, 2006
SELECTED HORMONES ACTING VIA cAMP
SIGNALING
Guyton and Hall, 2006
PHOPSPHOLIPASE C RECEPTOR SIGNALING
Guyton and Hall, 2006
SELECTED HORMONES ACTING VIA
PHOSPHOLIPASE C SIGNALING
TYROSINE KINASE RECEPTOR SIGNALING
Guyton and Hall, 2006
UPREGULATION OF RECEPTORS
time
DOWNREGULATION OF RECEPTORS
PATTERN OF HORMONE SECRETION
The basal secretion of hormones is not continuous process, it has
pulsatile character (minutes)
Besides the pulsatile secretion some hormones have episodic secretory
profile
Secretory episodes may appear with different periodicities
ULTRADIAN - <1 hour< 24 hours
CIRCADIAN – episodes occur at defined periods of the day (ACTH)
INFRADIAN – episodes are longer than 25 hours (menstrual cycle)
CIRCANNUAL – SEASONAL – episodes occur in relation to the seasonal
phases of the year
CIRCADIAN CHANGES OF ACTH AND CORTISOL
IN PLASMA
ACTH in plasma
cortisol in plasma [
cortisol
ACTH
08
12
16
20
24
04
08
time of day
HORMONE LEVELS - 8:00 a.m. , 8:00 p.m.
morning
evening
.
GH
Cortisol
ENDOCRINE GLANDS
hypothalamus
(TRH, GnRH, GHRH, SRIH, CRH, PrlIH-dopamine)
pineal
melatonin
pituitary
anterior lobe: TSH, GH, ACTH,
FSH, LH, prolactin
posterior lobe : oxytocin, AVP
parathyreoid: PTH
thyroid gland:T3 a T4, calcitonin)
adrenal glands: aldosterone, cortisol, androgens
adrenaline, noradrenaline, dopamine
pancreas
Insulin, glucagon, somatostatin
ovaries
estrogens, progesterone
testis
testosterone
FEEDBACK REGULATION OF HORMONE
SECRETION
Feedback regulation- closed loop system that is an essential feature of
endocrine regulation
Hypothalamo – adenopituitary- peripheral gland regulation TRH - TSH –
thyroid gland
CRH – ACTH – adrenal cortex
GnRH – LH/FSH – ovaries/testes
GHRH/Srif – GH - tissues
PRH/PIF – PRL – tissue
Hypothal.
CRH
adenopituitary
ACTH
complex feedback
CORTISOL FEEDBACK
REGULATION
adrenal gland
cortisol
liver, fat tissue, muscles,
lymph nodes
FEMALE SEX HORMONE COMPEX FEEDBACK
MECHANISMS
estrogens
ASSESSMENT OF ENDOCRINE FUNCTION
First step - measurement of hormone levels
In vivo – bioassay: Plasma extracts were injected to animals and biological
response was quantified
Radioimmunoassay- in the 70-ties of the last century Nobel prize for in vitro
measurement hormone –andibody binding.
IMMUNE – ENDOCRINE INTERACTIONS IN
NORMAL AND PATHOLOGICAL STATE
CORTISOL physiological suppressor of immune functions
GROWTH HORONE , PROLACTIN – physiological activators of
immune functions
SCHEMATIC DRAWING OF IMMUNO-NUROENDOCRINE LOOP
MECHANISMS OF IMMUNO-NEURO-ENDOKRINE
LOOP
SDFDDA
DDSDDDSD
DA
, GHRH, PRF
PRL GH
adapted from
ENDOCRINE DISRUPTORS
POLYCHLORINATED BIPHENYLS – PCB, toxic poluants of environment with
long dissapearance rate (decades) – accumulate in nature, oceans, animals,
soil
Use in industry – production of plastics, transformers, capacitors, fillings of fire
extinguishers, thinners of dyes
They affect endocrine functions - gonads, thyroid gland
Since the early 90-ties they are named
DISRUPTORS OF ENDOCRINE FUNCTIONS – ED
Definition:
Exogenous substances interfering with production, release, bindning,
transport, metabolism, action, and elimination of natural hormones
(Kavlock et al., 1996).
About 90 % are accumulated in soil and recycle into food.
They are lipophilic and are stored in fat tissue and are released into milk.
ACTIONS OF ENDOCRINE DISRUPTORS
Reversible binding to specific molecules (receptors, transport proteins,
enzymes)
Irreversible binding to target molecules (DNA, proteins)
Accumulation in fat tissue
ACTIONS OF ENDOCRINE DISRUPTORS
Carcinogenic effects
In women a correlation between mammary carcinoma and amount
of PCB in fat tissue was found
Functions of sex organs
PCB negatively affects growth and development and functions of
sex organs in men and women.
In young boys living near waste incinerator a correlation between
decrease of sperm count and amount of PCB in blood was found.
Function of thyroid gland
In workers in PCB factory a correlation between enlarged thyroid
gland and the amount of PCB in blood was found.
NEGATIVE CORRELATION OF TESTOSTERONE IN
BLOD AND CONCENTRATION OF
HEXACHLORBENZENE IN LIPID FRACTION OF
BLOOD IN YOUNG MEN
TESTOSTERONE
TESTOSTERONE
TESTOSTERÓN (ng/ml)
16
14
12
10
8
6
4
2
0
0
1000
2000
3000
4000
5000
HCB IN BLOOD (ng/g lipids)
HCB V SÉRE (ng/g lipidov)
Langer et al, 2011
TRANSGENERATION EFFECTS OF
ENDOCRINE DYSRUPTORS
Fowler et al, Mol. Cell. Endocrinol. 2012
TRANSGENERATION TRANSFER OF PCB
5000
10000
4000
3000
2000
1000
0
0
MOTHERS
20
00
40
00
MOTHERS
MOTHERS
MATKY
(ng/g)
60
00
ng/g
ng/g
CORRELATION OF PCB IN LIPID FRACTION
OF BLOOD IN MOTHERS AND UMBILICAL
CORD IN NEWBORNS
16 infants
MES. DETI (ng/g)
16 mo
12000
PUPOČNÍK (ng/g)
umbilical
cord
6000
8000
6000
4000
2000
0
0
400
0
800
0
120
00
MOTHERS
MATKY (ng/g)
CORRELTION OF PCB IN LIPID FRACTION OF
BLOOD IN MOTHERS AND BLOOD OF BREST
FED INFANTS
Langer et al, 2011