Download Lect E3 - Endocrine growth (K K DEV)

Lect E3 - Endocrine growth
Growth, Metabolism & Calcium
Endocrine System
Summary Lect # 3
Growth & Metabolism
1.
Growth Hormone & Somatomedins (IGF’s)
Prof Kumlesh K. Dev
D
Department
off Physiology
Ph i l
2.
Thyroid hormones (T3 & T4)
3.
Oestrogens & Testosterone
4.
Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids
5.
Insulin & Glucagon
6.
Calcitonin, PTH & Vit D
CRH
TRH
PRH
PIH
GnRH
dopamine
(LH releasing
hormome LHRH)
CorticotropinReleasing
hormone
ThyrotropinReleasing
hormone
Prolactinreleasing
hormone
Prolactininhibiting
hormone
Gonadotropinreleasing
hormone
GHRH
GHIH
somatostatin
Growthhormone
inhibiting
hormone
Growthhormone
releasing
hormone
ACTH
TSH
Prolactin
FSH
LH
GH
AdrenoAdrenocorticotropic
hormone
Thyroid
stimulating
hormone
(non(non-tropic)
FollicleFolliclestimulating
hormone
Luteinising
hormone
Growth
Hormone
Adrenal
cortex
Thyroid
gland
mammary
glands
cortisol
Thyroid
Hormone
(T3.T4)
breast
growth, milk
secretion
Chapter 4 Principles of Neural and Hormonal Communication
Human Physiology by Lauralee Sherwood ©2007 Brooks/Cole-Thomson Learning
many
target
organs
Ovaries
/Testes
progesterone
& estrogen
ovulation &
luteinisation
estrogen
(develop
ovarian
follicles)
testosterone
sperm
production
growth,
anabolic
actions
y
The Glands
Growth Factors & Hormones
Summary
Growth Hormone
• Growth hormone & Somatomedins (IGFs)
– from anterior pituitary gland
– essential for normal growth
– GH releases somatomedins (insulin like growth factors – IGF’s alter
growth)
• Thyroid hormone (Triiodothyronine – T3)
– permissive for GH
• Androgens/Estrogens (Oestrogns/Testosterone)
– growth in puberty, stimulate protein synthesis in organs
– effects
ff t depend
d
d on presence off GH
• Insulin
– promotes protein synthesis, deficiency blocks growth
– hyper-insulin spurs excessive growth
• Calcitonin, PTH and Vit D
1
Lect E3 - Endocrine growth
Other Growth Factors
Growth Rate
Growth Hormone
Growth Hormone
• Epidermal Growth Factor
─ polypeptide with mitogenic activity
• Not continuous
• different factors responsible for
growth at different periods
g
• Platelet Derived Growth Factor
─ each human platelet contains ~1000 molecules, stimulates
fibroblasts and glial cell growth
Fetal growth
• Promoted by placenta hormones
• GH plays no role in fetal growth
• Nerve Growth Factor
─ important for maintaining viability and promoting
diff
differentiation
ti ti and
d synaptic
ti out-growth
t
th ffrom sensory and
d
sympathetic ganglionic neurones
Postnatal growth spurt
• first two years of life
• Fibroblast Growth Factor
─ stimulates bone cell proliferation and collagen synthesis
Growth Hormone
Puberty growth spurt
• Male: Androgens (testes) promote
protein synthesis and bone growth
• Female: Androgens (adrenal glands,
less potent) promote protein
synthesis and bone growth
Related Growth Hormones & Receptors
Growth Hormone
─ Also called somatotropin
─ Peptide hormone 191
amino acid
─ Mol wt approx. 20 kDa
─ 500µg made per day
((circulating
g 0-30 ng/ml,
g ,
t1/2 ~20min)
─ GH is encoded on
chromosome 17
Normal Growth Curve
Growth Hormone
─ Other members of GH family:
─ Placental Lactogens (somato-mammotropins) are 85% identical
t GH
to
─ Prolactin, less closely related to GH
─ evolved from a common ancestral gene
─ GH, Prolactin and PL can cross activate their receptors:
─ Growth hormone has weak prolactin-like, lactogenic activity
─ Prolactin has lactogenic activity, but no growth-promoting activity
─ Placental lactogen has weak growth-promoting activity
2
Lect E3 - Endocrine growth
GH Release
GHRH Receptor Signalling
Growth Hormone
Pulsed release
─
─
─
─
released from anterior pituitary in several daily
bursts
peak secretion early morning before awakening
and lowest in day
secretion stimulated during deep sleep
rhythm linked to sleep-wake not light/dark
surges in first 2 hr sleep at night
Deviation from 24h m
mean
(%)
─
Growth Hormone
Diurnal variation in
serum GH
Growth Hormone
150
100
50
─ terminated by somatostatin
0
-50
-100
Number/magnitude pulses depend on age
─ increased pulses during puberty
─ declines in adults
─ absent at 50yr+
─ GH bursts initiated by bursting
secretion of growth hormone
releasing
l
i h
hormone (GHRH)
0
6
12
18
Time (hr
24
─ GHRH and somatostatin
produced by hypothalamic
neurons
─ GHRH receptor is a 7
transmembrane domain
G-protein coupled receptor
Age-related decrease in GH release
─ change in muscle:fat ratio
─ decreased bone density
─ GH sold as “anti-ageing” therapy? (but may
actually speed ageing)……..
─ GHRH stimulates GH
synthesis and secretion
Stimuli that regulate GH secretion
Long term metabolic effects of GH
Growth Hormone
Stimulants
Inhibitors
¾ low energy substrate
¾ REM sleep
¾ hypoglycemia
¾ hyperglycemia
¾ exercise and fasting
¾ cortisol
¾ increase in blood levels
of certain amino acids
(e.g. Arg, Leu)
¾ free fatty acids
¾ glucagon
¾ hypothyroidism
¾ stress
¾ aging
¾ deep sleep
¾ dopamine receptor
agonists
Growth Hormone
Carbohydrates
─
─
─
─
increases blood glucose
decreases peripheral insulin sensitivity
increases hepatic glucose output
increases serum insulin levels
Proteins
─
─
─
─
increases tissue amino acid uptake
increases incorporation into proteins
decreases urea production
produces positive nitrogen balance
¾ growth hormone
(feedback)
Lipids
IGF
─ is lipolytic - activates hormone sensitive lipase
─ stimulates IGF production
─ stimulates growth
─ mitogenic
3
Lect E3 - Endocrine growth
Injection of GH into animals causes
…….also don’t believe this
Growth Hormone
─ Stimulation of bone growth
─ Stimulation of protein synthesis in many tissues
Growth Hormone
protein-building activity
of GH does not promote
athletic ability…..
ability
GH will not enlarge your…..
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─ Stimulation of erythropoesis
─ Anti-insulin activity
─ increases hepatic glucose output
─ promotes lipolysis in adipocytes
IGF-1A
SAY NO TO STEROIDS
─ decreased glucose uptake by muscle
GH releases IGF-1
IGF is on the
streets right
now…..
AT LAST A SAFE ALTERNATIVE TO
GROWTH HORMONE
Accelerates bodies production of GH
“..IGF-1 is out there on the streets right now….it’s the
most wonderful stuff in the world for gaining muscle and
losing fat.. Many athletes are comparing IGF-1A to
Anabolic Steroids”. Quote From A Major Muscle
Magazine
GH mediates actions via IGFs
Growth Hormone
• GH stimulates
– Liver production of
somatomedins (insulin-like
growth factor; IGF-1)
IGF 1)
– Acts on bone & soft tissues to
promote growth
– Stimulates protein synthesis, cell
division (of condrocytes),
lengthening, thickening of bones
• metabolic effects
– increases fatty acid levels in blood
(enhances breakdown of
triglyceride fat in adipose tissue)
– increases blood glucose levels
(decreases glucose uptake by
muscles)
Growth Hormone
─ main function of GH is to promote IGF-l production
─ GH stimulates liver to make IGF- 1
─ GH requires
i
IGF
IGF-1
1 tto promote
t growth
th
─ Mice genetically lacking GH are dwarfed; IGF-l gene
overcomes GH defects
─ IGFs are structurally related to insulin
─ Insulin has weak somatomedin-like activity on some cells
─ Two different genes encode IGF- 1 and IGF-2
─ IGF
IGF- 1 stimulates
ti l t b
bone growth
th and
d cellll proliferation
lif ti lleading
di tto
soft tissue growth
─ In some forms of dwarfism, GH production is normal, but IGF-I
production is subnormal
─ African Pigmies lack pubertal surge of IGF-I
4
Lect E3 - Endocrine growth
Pituitary Gigantism
Acromegaly
Growth Hormone
Growth Hormone
• GH hypersecretion after adolescence
causes acromegaly
• certain benign tumors (adenomas) in
pituitary gland produces excess GH
─ GH excess caused by
tumour cells of anterior
pituitary producing GH
Progression of acromegaly
A - Age 9 (normal)
B - Age 16 (coarsening features)
C - Age 33 (established acromegaly)
D - Age 52 (severe acromegaly)
• Features include
– Excessive thickening of bones
– Coarsened facial features
─ in children this leads to
gigantism
• Brow/lower jaw protrusion (enlarge jaw)
• Teeth spacing increase
─ in adults acromegaly
results (growth in stature
does not occur because
adult long bones are
unable to lengthen)
– Soft tissue swelling of hands and feet
• Enlarged hands & feet
• Arthritis and carpal tunnel syndrome
– Heart failure (major problem)
– Vision loss (compressed optic chiasm)
• Medication reduce GH secretion/tumor
Robert Wadlow the
“Alton Giant”
He was 8 feet, 11
inches tall and
weighed 475 pounds
at the age of 22
– Bromocriptine (DA receptor agonist)
– somatostatin, to stop GH production
– GH receptor antagonists are emerging
Dwarfism
Feedback Loops of GH
Growth Hormone
Growth Hormone
GH deficiency
• treated by replacing GH
• GH was extracted from human
pituitary glands at autopsy
• now made by recombinant tech
Hypothalamus
GHRH
GHRH
Hereditary
• underproduction of GHRH
• incapable of manufacturing GH
Laron dwarf
• circulating GH levels ok but GH
receptors unable to bind
Long Loop
GrowthGrowth
hormone
inhibiting
hormone
Ant. Pituitary
GH
Growth
Hormone
GH
The Dwarf
Sebastian de
Morra
The Dwarf
Francisco Lezcano,
Called "El Nino de
Vallecas“
many
target
organs
Short
Loop
African Pygmy
• unresponsiveness to IGF
• defect in IGF1 receptor
GHIH
somatostatin
Growthhormone
releasing
hormone
Liver
growth,
anabolic
actions
IGF-I
5
Lect E3 - Endocrine growth
Growth, Metabolism & Calcium
The Glands
Summary Summary
1.
Growth Hormone & Somatomedins (IGF’s)
2.
Thyroid hormones (T3 & T4)
3.
Oestrogens & Testosterone
4.
Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids
5.
Insulin & Glucagon
6.
Calcitonin, PTH & Vit D
CRH
TRH
PRH
PIH
GnRH
dopamine
(LH releasing
hormome LHRH)
CorticotropinReleasing
hormone
ThyrotropinReleasing
hormone
Prolactinreleasing
hormone
Prolactininhibiting
hormone
Gonadotropinreleasing
hormone
GHRH
GHIH
somatostatin
Growthhormone
inhibiting
hormone
Growthhormone
releasing
hormone
ACTH
TSH
Prolactin
FSH
LH
GH
AdrenoAdrenocorticotropic
hormone
Thyroid
stimulating
hormone
(non(non-tropic)
FollicleFolliclestimulating
hormone
Luteinising
hormone
Growth
Hormone
Adrenal
cortex
Thyroid
gland
mammary
glands
cortisol
Thyroid
Hormone
(T3.T4)
breast
growth, milk
secretion
many
target
organs
Ovaries
/Testes
progesterone
& estrogen
ovulation &
luteinisation
estrogen
(develop
ovarian
follicles)
testosterone
sperm
production
growth,
anabolic
actions
y
Thyroid Gland
T3 and T4 Hormones
Thyroid
Thyroid Gland
• front of upper part of trachea
• encapsulaed
p
by
y a fiborous capsule
p
• develops from epithelial outgrowth of tongue
TRACHEA
Types of thyroid hormones
• Thyroxine (T4) (t1/2 ~7 days) in follicles
• Triiodotyronine (T3) (t1/2 ~1.5 days) in follicles
• Calcitonin by C cells
Function of T3 and T4
• T3 and T4 accelerate metabolism
• increase carbohydrate, fat and protein turnover
• increase oxygen consumption & heat production
• important during development, essential between
wk 11 and birth
Thyroid
Thyroxine (T4)
Structure of T3 and T4
• T4 & T3 are tyrosine-based hormones
• T3 has 3 iodine atoms,, T4 contains 4
• T3 more effective, but T4 more abundant
Levels of T3 and T4
• levels controlled by anterior pituitary TSH
• negative feed back loop operates for T3 and T4
secretion
• transported in blood,
blood bound to thyroxine-binding
globulin (TBG)
• only made by follicular cells when iodide available
• iodide actively absorbed from blood to thyroid
follicles
• deficiency dietary iodine, thyroid enlarges to trap
more iodine, i.e. goitre
I
T3
I
-O-
HO-
-CH2-CH-COOH
NH2
I
I
I
rT3
-O-
HO-
-CH2-CH-COOH
NH2
I
6
Lect E3 - Endocrine growth
Goiter & Hashimoto’s disease
Hypothyroidism
Thyroid
Thyroid
Hypothyrodism - Infants
• stunted growth
• bone formation
• skeletal abnormalities
• severe mental retardation
Goiter - low idoine uptake
─ no T3/T4 made because not enough
i did iingested
iodides
t d
─ "iodide pump" of thyroid gland is very
effective, i.e. 30% of ingested iodide may
be taken up by thyroid
─ when dietary iodide insufficient to produce
thyroxine, efficiency of iodide uptake
increases due to thyroid cell proliferation
─ normall h
human th
thyroid
id gland
l d off 25 g may
grow to 250 g during goiter
Hypothyrodism - Adults
• low metabolic rate & decreased
energy
• always cold, cold sensitivity,
tolerance
• excess sleep, sluggishness, fatigue,
tired, cant finish tasks, weight gain
• constipation, dry skin
Hashimoto’s - autoimmune disease
─ autoimmune (autoantibodies destroy
follicular cells)
Hyperthyroidism
Feedback Loops of Thyroid Hormone
Thyroid
Symptoms
• high metabolic rate
• protruding eyes
• hyperactivity, insomnia, palpitations,
nervousness, tremor, can’t concentrate
• heat sensitivity, heat intolerance, weight
loss, always hot, warm, smooth, moist skin
Thyroid Hypothalamus
TRH
TRH
Long Loop
Ant. Pituitary
TSH
Grave’s disease
• hyperthyroidism due autoimmune problem
(TSH is mimicked by autoantibodies)
• Treatments
– Beta blockers help some symptoms
– Anti-thyroid medications
– Radioactive iodine treatment destroys
overactive thyroid cells
– Surgery thyroidectomy
Thyrotropiny
p
Releasing
hormone
Thyroid
stimulating
hormone
TSH
Thyroid
gland
Short
Loop
Thyroid
Thyroid
Hormone
(T3.T4)
Thyroid Hormone
7
Lect E3 - Endocrine growth
Growth, Metabolism & Calcium
Summary 1.
Growth Hormone & Somatomedins (IGF’s)
2.
Thyroid hormones (T3 & T4)
3.
Oestrogens & Testosterone
4.
Mineral- (Aldosterone) & Gluco- (Cortisol) corticoids
5.
Insulin & Glucagon
6.
Calcitonin, PTH & Vit D
CRH
TRH
PRH
PIH
GnRH
dopamine
(LH releasing
hormome LHRH)
CorticotropinReleasing
hormone
ThyrotropinReleasing
hormone
Prolactinreleasing
hormone
Prolactininhibiting
hormone
Gonadotropinreleasing
hormone
GHRH
GHIH
somatostatin
Growthhormone
inhibiting
hormone
Growthhormone
releasing
hormone
ACTH
TSH
Prolactin
FSH
LH
GH
AdrenoAdrenocorticotropic
hormone
Thyroid
stimulating
hormone
(non(non-tropic)
FollicleFolliclestimulating
hormone
Luteinising
hormone
Growth
Hormone
Adrenal
cortex
Thyroid
gland
mammary
glands
cortisol
Thyroid
Hormone
(T3.T4)
breast
growth, milk
secretion
many
target
organs
Ovaries
/Testes
progesterone
& estrogen
ovulation &
luteinisation
estrogen
(develop
ovarian
follicles)
testosterone
sperm
production
growth,
anabolic
actions
y
8