Download L 1 Characters_Mechanisms_Pituitary Final

Endocrine System
Lecture 1
Characters and mechanisms of actions of
hormones
Pituitary hormones
Asso. Professor Dr Than Kyaw
17 September 2012
What is endocrinology?
Endocrinology
Study of:
- Intercellular Chemical Communication
- about communication systems & information
transfer.
Hormones
Definition (classical)
- Chemical substances produced by specialized
ductless glands
- Released into the blood
- Carried to other parts of the body
- Produce specific regulatory effects.
Is that definition true?
PGF2α - produced by most of the body cells, transmitted
by diffusion in interstitial fluid rather than by
circulation in the blood.
Pheromones – transmission through olfaction (smell)
-- outside the body
Modes of transmission
Hormone transmission restricted only to blood – incorrect
1. Epicrine transmission
- Hormones pass through gap junctions of adjacent
cells without entering extracellular fluid.
2. Neurocrine transmission
- Hormones diffuse through synaptic clefts between
neurons. Neural – through neurons (neurotransmitters)
Gap junctions
- Pores connecting adjacent cells. Small molecules
and electrical signals in one cell can pass through the
gap junctions to adjacent cells.
Synaptic cleft
- Between a neuron and a muscle fiber or
- Between 2 neurons
- Acetylcholine
Mode of transmission
3. Paracrine transmission
- Hormones diffuse through interstitial fluid - PGF2α
4. Endocrine transmission
- Hormones are transported through blood circulation.
- Typical of most hormones
5. Exocrine transmission
- Hormones are secreted to the exterior of the body.
E.g - Somatostatin secreted into the lumen of GI tract
(and inhibit intestinal motility and absorption)
- Pheromones
Endocrine Functions
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Maintain Internal Homeostasis
Support Cell Growth
Coordinate Development
Coordinate Reproduction
Facilitate Responses to External Stimuli
Elements of an endocrine system
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Sender = Sending Cell (where hormone is produced)
Signal = Hormone
Nondestructive Medium = Serum & Hormone Binders
Selective Receiver = Receptor Protein (Target cells)
Transducer = Transducer Proteins & 2º Messengers
Amplifier = Transducer/Effector Enzymes
Effector = Effector Proteins
Response = Cellular Response
What are transducers?
Transducers
- proteins that convert the information in hormonal signals
into chemical signals understood by cellular machinery.
- They change their shape & activity when they interact
directly with protein-hormone complexes.
- Usually enzymes or nucleotide binding proteins, they
produce 2nd messengers, or change the activity of other
proteins by covalently modifying them (adding or removing
phosphate, lipid groups, acetate, or methyl groups), or they
interact with other proteins that do these things.
- They begin amplifying the energy content of the original
hormone signals.
Classes of hormone
1. Amine hormones
- thyroid hormones, catecholamines
- all derived from single amino acids
- thyroid hormones - from tyrosine
- catecholamines
- from tyrosine
- melatonin - from tryptophan
Classes of hormone
2. Peptide hormones
- Peptides, polypeptides and proteins
- Hydrophilic/Lipophobic
- short half life
- hormones of hypothalmus (releasing and inhibiting)
- pituitary hormones
- Insulin, glucagon
Classes of hormone
3. Steroid hormones
- adrenocortical and reproductive hormones
- derived from cholesterol
- Hydrophobic/lipophilic
- long half life
- travel with a protein carrier
- bind to cytoplasmic/nuclear receptor
Classes of hormone
4. Eicosanoids (Lipid hormones)
- produced from 20 carbon fatty acids (arachidonic
acid)
- produced in all cells except RBCs
- prostaglandin, leukotrienes (smooth m/s contraction
in trachea), thromboxanes
Hormone Interactions
Responsivenss of a target cell to a hormone depends on:
- The hormone concentration
- The abundance of the target cell’s hormone receptors
- influences exerted by other hormones
1. Permissive effect: when the action of a hormone on
target cells requires a simultaneous or recent exposure to
a second hormone.
- e.g: Epinephrine – alone, weakly stimulates lipolysis
but presence of a small amounts of thyroid
hormones - the same amount of epinephrine
stimulates lipolysis much more powerfully.
Hormone Interactions
2. Synergistic effects
when the effect of two hormones acting together is
greater or more extensive than the sum of each hormone
acting alone
3. Antagonistic effects
when one hormone opposes the activation of another
hormone.
E.g, Insulin promotes glycogen synthesis by the liver
cells and glucagon stimulates glycogen breakdown
Enzyme amplification
- One hormone molecule does not trigger
- the synthesis of just one enzyme molecule
- It activates thousands of enzyme molecules through a
cascade of called enzyme amplification
- This enables a very small stimulus to produce a very
large effect
- Hormones are therefore needed in very small quantities
- circulating concentration very low compared to
other blood substances: on order of nanograms per
deciliter of blood
- Because of amplification target cells do not need a great
number of hormone receptors
Hormone clearance
- Hormone signals, like nervous signals, must be turned off
when they have served their purpose
- Most hormones are taken up and degraded by the liver
and kidneys and then excreted in bile or urine
- Some are degraded by the target cells
- Rate of hormone removal (metabolic clearance rate – MCR)
- Halflife – the length of time required to clear 50% of the
hormone from the blood
- the faster the MCR – the shorter half life
Metabolic Clearance Rate or
Half-life of some hormones
Hormone
Half-life
Amines
2-3 min
Thyroid hormones: T4
T3
6.7 days
0.75 days
Polypeptides
4-40 min
Proteins
15-170 min
Steroids
4-120 min
Modulation of target cell sensitivity
- Hormones affect only target cells
- cells that carry specific receptors that bind the
recognized hormone
- Down regulation: when receptor quantity decrease
when hormone is in excess
- Decreases responsiveness to hormone
for example, in response to obesity when cells become
less sensitive to insulin.
- Up regulation: when receptor quantity increases when
hormone is deficient
- Make target cell more sensitive to hormone
for example, in response to regular exercise when cells
become more sensitive to insulin.
Hormone receptors
(Cell surface receptor, membrane receptors,
transmembrane receptors)
- Cellular proteins that bind with high affinity to
hormones & are altered in shape & function by
binding.
- exist in limited numbers.
- Binding to hormone is noncovalent & reversible.
- Hormone binding will alter binding to other cellular
proteins & may activate any receptor protein enzyme
actions.
Hormone & Receptor in General
Hormone receptors
- Specialized integral membrane proteins
- Communication between the cell and the outside world.
- Extracellular signalling molecules (usually hormones, neurotransmitters,
cytokines, growth factors or cell recognition molecules)
- Attach to the receptor, trigger changes in the function of the cell.
- This process is called signal transduction: The binding initiates a
chemical change on the intracellular side of the membrane. In this way
the receptors play a unique and important role in cellular
communications and signal transduction.
G Protein
Any of a class of cell membrane proteins that function as
intermediaries between hormone receptors and effector enzymes
and enable the cell to regulate its metabolism in response to
hormonal changes.
2 Types -- Stimulatory (GS)
-- Inhibitory (GI)
Surface Hormone Receptors
4 types or 4 domains of Surface hormone receptors
1. Seven-transmembrane domain receptors
- β adrenergic
- Parathyroid hormones (PTH)
- Luteinizing hormone (LH)
- Thyroid-stimulating hormone (TSH)
- Growth hormone-releasing hormone (GHRH)
- Thyrotropin releasing hormone (TRH)
- Adrenocorticotropic hormone (ACTH)
- MSH (melanocyte-stimulating hormone)
Surface Hormone Receptors
2. Single transmembrane receptors
- Insulin
- Insulin like growth factor I (IGF I)
- Epidermal growth factor (EGF)
- Platelet derived growth factor (PDGF)
3. Cytokine receptor super family
- GH, Prolactin,
- Erythropoietin
- Interleukin
- Leptin
4. Guanyl cyclase –linked receptor
- Natriuretic peptide
1. A seven-transmembrane
domain receptor
2. A single-ransmembrane
domain receptor with
kinase activity typical of
many growth factors
3. Receptors with no intrinsic
tyrosine kinase activity but
activation by soluble
transducer molecules.
4. Receptors dependent on
guanylyl cyclase or adenylyl
cyclase and synthesis of cGMP
and cAMP.
G protein-linked hormone
mechanism
Activation of receptor
induced by binding of
the hormone (1st
messenger).
Cytoplasmic tail of
receptor activates
G protein
The activated G protein complex links to
2nd messenger which is responsible for the
effect associated with hormone action
Second messenger systems
cyclic AMP
- Hormone travels in blood plasma
- Hormone binds to its receptor in the plasma membrane
GPCR (G-protein coupled receptor)
- Hormone-receptor binding activates a G protein (in plasma
membrane)
- Activated G protein in turn activates the enzyme adenyl cyclase
- Adenyl cyclase causes ATP to lose two P, becoming cAMP
(cyclic AMP [adenosine monophosphate])
- cAMP activates protein kinases (enzymes that activate other
proteins/enzymes), producing the hormonal effect
Hormones and their receptors
by classifying water soluble and lipid soluble
Hormone
Class of
hormone
Location
Amine
(epinephrine)
Water-soluble
Cell surface
Amine (thyroid
hormone)
Lipid soluble
Intracellular
Peptide/protein
Water soluble
Cell surface
Steroids and
Vitamin D
Lipid Soluble
Intracellular
Endocrine glands of animals
Hypothalamus
and
Pituitary gland
(hypophysis cerebri)
Hypothalamic releasing hormones
Hypothalamic releasing hormone
Effect on pituitary
Corticotropin releasing hormone
(CRH)
Thyrotropin releasing hormone
(TRH)
Growth hormone releasing hormone
(GHRH)
Somatostatin
Stimulates ACTH secretion
Gonadotropin releasing hormone
(GnRH) a.k.a LHRH
Prolactin releasing hormone (PRH)
Prolactin inhibiting hormone
(dopamine)
Stimulates TSH and Prolactin
secretion
Stimulates GH secretion
Inhibits GH (and other hormone)
secretion
Stimulates LH and FSH secretion
Stimulates PRL secretion
Inhibits PRL secretion
Putuitary gland = Master gland
- Because pituitary gland produces many hormones –k/s
master gland
- Pituitary extracts – obtained from pituitary glands from
slaughter houses
- Laborious and low yields
- 340 g/100 cattle; 30 g/100 pigs
- Pituitary extracts are used for research or commercial
purposes
Pituitary gland (hypophysis cerebri)
- Anterior lobe (adenohypophysis)
- Posterior lobe (neurohypophysis)
Location of the pituitary gland
- Just below the hypothalmus
- Provide direct delivery of releasing and inhibiting
hormones from the hypothalmus to the anterior lobe
- direct entry of secretory neurons from the
hypothalmus to posterior lobe
- Hypophysioportal circulation
The venous blood drained from the hypothalmus is
redistributed by another capillary system within the
anterior lobe. Shortages of hormones in arterial blood
are directed by specific cells within the hypothalmus,
which are stimulated to secrete releasing hormones.
The hormones produced are distributed by the second
capillary bed to their appropriate cells in the anterior
lobe.
Anterior Pituitary
Hormone
A
c
r
o
n
y
m
Hypop
hysial
Cell
Type
Hypothalamic Regulator(s)
Hormonal Function(s)
Corticotropin
,
Adrenocortic
otropin
A
C
T
H
Cortic
otrope
+Corticotropin Releasing Hormone,
Corticoliberin (CRH); + Interleukin 1 ; Glucocortical Steroids (via CRH); +
Vasopressin
Stimulates glucocorticoid production by
adrenal fasiculata & reticularis
Thyrotropin,
Thyroid
Stimulating
Hormone
T
S
H
Thyrot
rope
-Thyroxine (T4); +Thyroid Releasing
Hormone, Thyroliberin (TRH); -Somatostatin
(SS)
Stimulates thyroxine production by thyroid
Prolactin,
Mammotropi
n,
Luteotropin
P
R
L
-Dopamine; + TRH; - SS; + Estrogens; +
Oxytocin
Stimulates milk synthesis by secretory
epithelium of breast; supports corpus luteum
function
Somatotropin
, Growth
Hormone
G
H
Lactot
rope;
Mam
motro
pe
Somat
otrope
+ Growth Hormone Releasing Hormone,
Somatoliberin (GHRH); - SS
Stimulates somatic growth, supports
intermediary metabolism
Follitropin,
Follicle
Stimulating
Hormone
F
S
H
Gona
dotro
pe
+ Gonadotropin Releasing Hormone,
Luteinizing Hormone Releasing Hormone,
Gonadoliberin (GnRH, LHRH); - Inhibin; - Sex
steroids (via LHRH)
Supports growth of ovarian follicles &
estradiol production; Supports Sertoli cell
function & spermatogenesis
Lutropin,
Luteinizing
Hormone
L
H
Gona
dotro
pe
+ GnRH (LHRH); - Sex steroids (via LHRH); +
Estradiol in near midcycle
Supports late follicular development,
ovulation, & corpus luteum function
(especially progesterone synthesis); Supports
testosterone synthesis, Leydig cell
Melanotropin,
Melanocyte
Stimulating
Hormone
M Melan
S otrope
H
+ CRH
Supports dispersal & synthesis of pigment in
melanocytes; may alter adrenal response to
ACTH
STIMULUS
Hypothalamus
Releasing Hormone
(Release-Inhibiting Hormone)
Pituitary
Stimulating Hormone
Gland
Hormone
Target
Anterior Putuitary Hormones
Regulated by:
Releasing Hormones and Inhibiting hormones of hypothalmus
Cells of anterior pituitary and hormones
5 cell type; 7 hormones
1. Somatotrope cells (Growth ormone)
2. Corticotrope cells (adrenocorticotropic hormone and
beta-lipotropin hormone)
3. Mammotrope cells (prolactin)
4. Thyrotrope cells (thyroid stimulating hormone)
5. Gonadotrope cells (Follicle stimulating hormone and
luteinizing hormone)
Nature of anterior pituitary hormones
- Polypeptides to large proteins
- Different structures among species
- Replacement therapy from one spp to another not
uniformly successful
Growth hormone (GH)
-
Somatotropic hormone (STH)
Stimulatory effect of increase in body size
Growth of all tissues of the body
Both cell numbers and cell size
Epiphyseal bone plates are more sensitive to GH
Increases mitotic activity
Stimulate the liver to form several small proteins,
somatomedins (Insulin-like growth factors 1 and 2,
IGF 1 and IGF2)
- Somatomedins act on cartilage and bone growth.
Therefore bone and cartilage are not stimulated
directly by GH but indirectly by this intermediate
compound.
GH
- Several specific metabolic effects
- because of this, GH is necessary throughout life
Metabolic effects
- Increases
- rate of protein synthesis in all body cells
- mobilization of fatty acids from fat
- use of fatty acids for energy
- Decreased rate of glucose uptake throughout the body
- Use of fats for energy conserves glucose and
promotes glycogen storage – the heart can endure
emergency contraction more effectively whereby
glycogen stored in the heart is converted to glucose.
GH
Milk production
- Increasing milk yield in lactating cows by growth
hormone is not stimulation on mammary gland but by
partitioning of available nutrients from body tissues
towards milk synthesis
Abnormal GH production
Excessive production of GH
Before puberty:
– increase growth of long bones (prolonged proliferation
of growth plate chondrocytes)
After puberty – closure of epiphyseal plates
- acromegaly
- enlargement of extremities and facial bones
Gigantism – frequently seen in human
Failure to produce sufficient GH
– stunted growth
- dwarfism
Adrenocorticotrophic hormone (ACTH)
- Increase activity of the adrenal cortex
- Glucocorticoids and mineralocorticoids
(aldosterone ) secretion
- Similar effects of somatotropic hormone (STH)
- ↑protein synthesis
- ↑fatty acid uptake
- ↓ glucose uptake
Thyroid stimulating hormone (TSH)
- Stimulate
- Synthesis of colloids by thyroid gland
- Release of thyroid hormone
- Associate functions
- accumulation of iodine
- organic binding of iodine
- formation of thyroxine within the thyroid gland
- No extrathyroid activity as for STH and ACTH.
Gonadotropic hormones and prolactin
- Follicle stimulating hormone (FSH) and luteinizing
hormone (LH) have specific roles in male and female
reproduction
- FSH stimulates oogenesis and spermatogenesis
- LH assists ovulation and development of functioning
corpus luteum in female
- LH stimulates secretion of testerone in male
- Prolactin helps to initiate and maintain lactation after
pregnancy
- Maintenance of CL in ewe
Beta-lipoprotein hormone (β-LPH)
- Secreted by adrenocorticotropic cells
- Exact physiologic role unknown
- Assumed to be involved in the pain relief and response
to stress.
Posterior Pituitary
Posterior pituitary and its hormones
- An outgrowth of hypothalmus
- Contains terminal axons from two pairs of nuclei
- supraoptic nucleus and paraventricular nucleus
- These nuclei synthesize
- Antidiuretic hormone (ADH)
- Oxytocin
Neurosecretions
- Transported to axon terminals in the posterior pituitary, stored
in secretary granules
- An action potential generated by the need for each of stored
hormones causes the release of the hormone and subsequent
absorption into the blood – distributed to the receptor cells
- Both hormones – peptides (nona-peptides – nine amino acids)
Antidiuretic hormone (Vasopressin)
- Normally outloaded water of the body – excreted by diuresis
(increased output of dilute urine)
- Diuresis can be prevented by administration of ADH
Dehydration
(osmoconcentration)
↓
osmoreceptors
↓
Posterior putuitary
Release of ADH
↓
↓
Target cells
(collecting tubules &
Collecting ducts of
kidney)
Retention of water
Oxytocin
- Function related to the reproductive processes
- Includes in parturition and laction
- Neuroendocrine reflexes
- Suckling by young or similar teat stimulation
- Release of oxytocin
- Milk letdown
- Myometrial contraction at parturition
- Transport of sperm in the oviduct at copulation
Intermediate Lobe of Putuitary
 During development a
transitional zone between the
neurally derived posterior
lobe & the epithelially derived
anterior lobe forms.
 It is lost in adults of some
species like humans but
persists in others.
 It makes melanocortin (MSH).
Negative
Feedback
Mechanism
Simple
example
NEGATIVE FEEDBACK MECHANISM
Decreased hormone concentration
In the blood (e.g. Thyroxine)
Pituitary gland
Release of stimulating hormone (e.g. TSH)
Stimulation of target organs to produce &
(e.g.
release hormone
Thyroid gland release of Thyroxine)
Return of the normal
Concentration of hormone
• Most hormonal regulatory systems work via
negative feed back
• Occasionally, a positive feed back system
contributes of regulation
- E.g. At parturition, where oxytocin
stimulates contractions of the uterus and the
uterus in turn stimulates more oxytocin
release.
Thyroid Gland and
Thyroid Hormones
Thyroid glands
Located -
on the trachea just caudal to the larynx
2 laterally placed, flattened lobes joined by isthmus
No isthmus in dog and cat
pig has a large medial lobe instead of isthmus
Thyroid gland
- composed of numerous follicles lined by simple
cuboidal epithelial cells filled with fluids (colloids)
Colloids - gel-like substances
- consists of a protein–iodine complex, thyroglobulins
- hormones T3 and T4 are stored in the colloids
Bovine thyroid gland
Thyroid hormones
T3 = tri-iodothyronine; T4 = tetra-iodothyronine
Regulation of secretion
 Thyrotropin-releasing hormone
(TRH) from hypothalmus
controls the secretion of
thyroid stimulating hormone
(TSH) from the anterior
pituitary
 TSH stimulates the synthesis of
thyroxine (T4) and
triiodothyroxine (T3)
 T4 and T3 inhibit TRH by
negative feedback
 There is no thyrotropin
inhibiting hormone
Regulation of secretion
Thyroid hormones: Synthesis and release
-
Iodine containing compounds
Belong to the amine classification of hormones
derived from tyrosine
Iodine trapping and iodination are unique features of the
thyroid gland
Synthesis of thyroglobulin
Iodination of tyrosine
Coupling of T1 and T2 to form T3 and T4
T3 and T4 are attached to the thyroglobulin in the colloids
- Lysosomes - release proteolytic enzymes that separate T3
and T4 from the thyroglobulin
Thyroid hormones: Synthesis and release
- About 90% of thyroid hormones released is T4
- Released T3 and T4 immediately combined with plasma
protein (mainly thyroxine binding globulin – TBG) for
transport in the blood
- TBG – greater affinity to T3 than T4
- Therefore, T3 is released more to the tissues
- Once in the tissues, T3 is more potent than T4 but short
duration of action
Functions of thyroid hormones
- Increase internal heat
- increased rate of O2 consumption
- Stimulate metabolic activities of most tissues of the body
except brain, lungs, retina, testes and spleen
- Increased metabolic activity and O2 consumption are through
activation and stimulation of key enzymes
- alpha glycerophosphate dehydrogenase
- hexokinase
- diphosphoglycerate mutase
- cytochrome b and c
- Thyroid hormones also markedly potentiate lipolytic effect of
epinphrine
- It is suggested that heat generated is secondary to protein
synthesis stimulated by thyroid hormones
Thyroid deficiency and antithyroid compounds
Typical deficiency
- Result from iodine deficiency and consequently inability of
the thyroid gland to produce T3 and T4
- Lack of circulating hormones causes feedback mechanisms so
that TSH is produced
- This causes thyroglobulin accumulation without effective
output of T3 and T4
- Thyroid gland enlarges because of colloid accumulation
- a condition k/s goiter
Thyroid enlargement (goiter) may be caused by
- Hypothyroidism (iodine deficiency) or
- Hyperthyroidism (increased thyroxine demands, tumour)
- Goiter caused by iodine deficiency – rare in animals
- Other causes of thyroid disfunction
– relatively low in sheep, cattle and swine
Hyperthyroidism
– common in dogs and cats
- Signs of hyperthyroidism
- Fatigue
- weight loss
- Hunger
- nervousness
- sensitivity to heat
- Signs of hypothyroidism
- lack of activity (lethargy)
- hair loss, dry and dull hair
- cold sensitivity
- anaemia
Antithyroid compounds
Goitrogens
- Natural substances – inhibit thyroid function
- Thyroxine is not produced in sufficient amounts and TSH continues
to be secreted -- thyroglobulin accumulation
Goitrin
- Produced in the intestinal tract after ingestion of progoitrin
containing plants (cabbage, turnip)
Thiocyanate
- Another goitrogen in some plants; it interferes with iodine trapping
- This can be overcome by feeding excess iodine
Antithyroid compounds are used in the treatment of hyperthyroidism
- thiourea, thiouracil, sulphonamides, chlorpromazine
- propylthiouracil or methimazole
Hyperthyroidism in man
Signs and symptoms
- Increased heart rate
- More forceful heartbeat or contractions
- Increased blood pressure
- Anxiety
- Weight loss
- Difficult sleeping
- Tremors in the hands
- Weakness
- Bulging eyes (exophthalmos)
Remember - Hyperthyroidism rare in animals except old cats
and dogs
Hypothyroidism in man
Signs and symptoms
-
Weight gain
Dry skin and puffy skin
Constipation
Cold intolerance
Hair loss
Fatigue and
Menstrual irregularity in women.
Cretinism
- Congenital lack of thyroid hormone
- Characterized by arrested physical and mental development
Calcitonin
- Produced by C cells (parafollicular cells) of thyroid gland
- Peptide hormone
- Lowers blood calcium level inhibiting the action of osteoclasts
- Calcitonin release
– Hypercalcemia (lesser degree by hypermagnesemia)
– directly regulated by negative feedback of serum
calcium concentration on C cells, NOT by TSH
- physiological importance in overall regulation of calcium conc
is minimal compared with the role of parathyroid hormones
1. Presentations
8 groups of students, each with 5 students
Presentation on Week 13
1.
2.
3.
4.
5.
6.
7.
8.
Hormone receptors and their regulations (G2)
Hyperthyroidism and hypothyroidism (G3)
Hyper- and hypo-secretion of Growth Hormone (G6)
Parathyroid gland and calcium metabolism (G1)
Factors that affect urine concentration (G8)
Renal function tests (G7)
Thyroid function test (G4)
Hormonal influence on the various stages of estrous cycle
(G5)
2. One Assignment
Diabetes in animals before midterm break