medical-notes/content/Fysiologi/Canvas/Del III/Block 13 - Hormoner, tillväxt och kroppsviktreglering/Growth.md

# Growth.pdf

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## Page 1

2024-04-26
1
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Body growth- effects by the 
hypothalamus-pituitary
PROFESSOR SUZANNE L DICKSON
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
1
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Robert Wadlow (1918-1940)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
272 cm
1936 Class Photo
2


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## Page 2

2024-04-26
2
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Body growth - general
• Body growth - endocrine regulation 
• What are the effects of the GH-IGF-1 axis?
• How is the GH-IGF-1 axis regulated?
• What are the mechanisms of action of GH and IGF-1?
• What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
3
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ø Body growth - general
• Body growth - endocrine regulation 
• What are the effects of the GH-IGF-1 axis?
• How is the GH-IGF-1 axis regulated?
• What are the mechanisms of action of GH and IGF-1?
• What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
4


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## Page 3

2024-04-26
3
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Organ growth (% of size at age 20)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Size obtained 
(as % adult size)
LYMPHOID
BRAIN & HEAD – develop early
GENERAL – eg skeleton, muscle
REPRODUCTIVE – develop late -
puberty
Age (years)
5
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Genetic – 80% of an individual’s height is 
genetically determined
• Environment: nutrition, illness, stress
- Food provides energy for growth but also vitamins 
& minerals.
- Growth is a luxury spared in times of famine.
- Injury and disease stunt growth (catabolic state).
Factors that affect growth
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 4

2024-04-26
4
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Genetic – 80% of an individual’s height is 
genetically determined
• Environment: nutrition, illness, stress
Factors that affect growth
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Hormones:
growth hormone
insulin-like growth factor 1 and 2, insulin
thyroid hormones 
androgens - estrogens
glucocorticoids – inhibitory (catabolic)
7
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Growth is not continuous – it is 
episodic
• Periods of physiological rapid 
growth
– In infancy
– In late puberty (just before 
growth stops)
Growth in humans
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
% adult height
age in years
INFANCY
CHILDHOOD
PUBERTY
5
10
15
20
100
75
50
25
8


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## Page 5

2024-04-26
5
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
“Catch-up” growth: pathophysiological after illness or 
food restriction
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Illness or
Food restriction 
A Normal Growth
B Decline in growth
C Hyperanabolic phase
D Return to normal 
growth rate
CG= catch-up growth
9
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Catch-up growth in relation 
to a population of children
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Illness
or fasting
period
Normal
Normal
5% 
95% 
Gaussian curve (any age)
50% 
Recovery
From
illness
95%
5%
10


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## Page 6

2024-04-26
6
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Growth velocity in boys and girls
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
5
10
15
20
25
0
0
2
4
6
8 10 12 14 16 18 20
Age in years
BOYS
GIRLS
Height
gain
(cm/yr)
Growth 
spurt
Why are men taller?
11
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Body growth - general
Ø Body growth - endocrine regulation 
• What are the effects of the GH-IGF-1 axis?
• How is the GH-IGF-1 axis regulated?
• What are the mechanisms of action of GH and IGF-1?
• What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
12


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## Page 7

2024-04-26
7
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Endocrine control of postnatal growth
5
10
15
20
25
0
0
2
4
6
8 10 12 14 16 18 20
Age in years
BOYS
GIRLS
Height
gain
(cm/yr)
Thyroid hormones
Growth hormone à ↑IGF-1
Gonadal steroids 
Estradiol
Testosterone à Estradiol
(à ERa à ↑ GH  à ↑ IGF-1)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
13
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Induction of growth plate closure by steroids in men 
and women
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Aromatase 
E2
TàE2
Same hormones that cause 
the growth spurt, but later!
Females: Estradiol  acts on ERa in 
growth plate.
Males:
Testosterone à Estradiol 
acts on ERa in growth plate.
14


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## Page 8

2024-04-26
8
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Responsible for the growth spurt at puberty
• Stimulate secretion of GH and IGF-1
• T is more anabolic à more pubertal growth in males.
• Body weight: T à ↑muscle mass & E à↑fat deposition.
• E more potent than T at level of growth plate
• E first stimulates the epiphyseal growth plate but then leads to its 
closure.
Patients with precocious (early) puberty have short stature.
Androgens (T) and estrogens (E)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
15
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
u Nutrients (dose response)
u Insulin – once beta cells have developed
u IGF-1 
u IGF-2
u Thyroid hormone
u Not GH.
Endocrine control of prenatal growth 
(trimester 2-3)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
16


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## Page 9

2024-04-26
9
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
anterior pituitary GH-N, GH gene (somatotrophs) – pulsatile
placenta - GH variant – continuous, 3rd trimester, secretion to mother, not fetus, 
may increase B-glucose and lipolysis in mother à more nutrients for fetus?
Growth hormone (GH)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
In addition 3 human placental 
lactogen (hPL)=
 human chorionsomatomammotropin 
  (hCG) genes
GH-N
(pit) 
GH-V
(pla-
centa) 
Mum
↑GH-Và
↓GH-N
hCG
Gene
clusters
Maternal
circulation
17
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Human GH protein (192 amino acids, 4 a-helices) 
must be injected (from GH-N gene). 
Without GH à proportional dwarf  - 110 cm.
GH tumour: Giant if not adult. 270 cm. à Wide dose 
response! (maybe also for IGF-1.)
Growth hormone therapy
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
GH structure
18


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## Page 10

2024-04-26
10
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Body growth - general
• Body growth - endocrine regulation 
Ø What are the effects of the GH-IGF-1 axis?
• How is the GH-IGF-1 axis regulated?
• What are the mechanisms of action of GH and IGF-1?
• What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
19
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
What does GH do? 
(One opnion)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
20


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## Page 11

2024-04-26
11
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
What does GH do? 
(One opnion)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
21
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH is anabolic, lipolytic and diabetogenic
Bone growth
direct
anabolic
Local IGF-1
production 
Liver-derived
IGF1
?
¯ glucose uptake
(insulin resistance)
diabetogenic
glycogenolysis
­ blood glucose
GH
anabolic
­ Protein  synthesis
­ Amino acid uptake
­ Lean body mass
FFAs
¯ fat mass
lipolytic
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
22


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## Page 12

2024-04-26
12
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
GH-deficient patient
before GH therapy
GH-deficient patient
after 26 weeks 
GH therapy
Bengtsson et al 1993 
J. Clin. Endocrinol. Metab. 76:309
GH therapy reduces visceral adiposity in GH-deficiency
23
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• hGH is banned in professional sport
• Usually taken for effects to reduce fat 
rather than to build muscle.
• Health risks similar to those of patients 
with acromegaly (see later).
• Common complaints: bloating, joint 
inflammation, joint pain, diabetes-like 
symptoms, injection site reactions, carpal 
tunnel syndrome, breast development in 
men, increased risk of cancers
GH abuse and doping in sport
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 13

2024-04-26
13
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Body growth - general
• Body growth - endocrine regulation 
• What are the effects of the GH-IGF-1 axis?
Ø How is the GH-IGF-1 axis regulated?
• What are the mechanisms of action of GH and IGF-1?
• What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
25
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Physiological control of GH secretion
GH
Exercise
Fasting
Sleep
Aging
Stress
Arginine
Lipids
GH/IGF-1
Glucose
+
+
+
+
_
_
_
_
+
Gonadal 
steroids
+
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
ghrelin +
Cortisol
_
26


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## Page 14

2024-04-26
14
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Control of GH secretion
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
27
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Nutrient control of GH secretion in relation to GH effects
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Amino acids 
(Arginine)
Lipids (FFA)
Glucose
GH
_
+
+
+
_
_
Pituitary
anabolic
lypolytic
diabetogenic
28


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## Page 15

2024-04-26
15
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Implications of pulsatile GH 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Time
GH levels
GH producing 
tumor
Normal GH
 pattern
GH deficiency
X
X
X
Single GH blood samples 
not good enough
How to distinguish?
• 24 h GH pattern
 (golden standard)
• Serum IGF-1 as marker 
of mean 24 h GH
• Stimulators or inhibitors
X
29
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Effect of arginine or insulin on plasma GH
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Arginine & insulin can
be used as 
provocactive tests 
for GH release
Arg/
insulin
hGH µg/ml
100
80
60
40
20
0
-10 0
30
60
90
120
Time (minutes)
Normal 
GH deficient
30


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## Page 16

2024-04-26
16
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Glucose tolerance test
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Glucose
0
2
4
Hours
Normal
Acromegaly (nonresponsive to glucose)
35
6
3
0
GH
mU/ml
31
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH secretion is increased by gonadal steroids during 
the growth spurt and then declines
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
32


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## Page 17

2024-04-26
17
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Clock time
SLEEP
STAGE
Plasma 
GH µg/l
Clock time
SWS
SWS = slow 
wave sleep
GH secretion during sleep
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
33
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Fasting increases GH 
secretion in man
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Effects:
•Keep B-glucose up
•Lipolysis
•Does NOT increase growth
Bergendahl et al, 1999
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## Page 18

2024-04-26
18
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH, IGF-1 and fasting
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
IGF-1 stimulated by GH and Nutrition (partly via insulin). 
FASTING 
­ 
GH
­ B-glucose
­ Lipolysis
Fasting blocks GH effects
 on body growth and IGF-1
à Appropriate response 
to fasting
¯ IGF-1 
¯ « Body growth
Needed for IGF-1 synthesis:
GH and food!
35
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Somatotrophs: GHRH and somatostatin regulate GH 
synthesis & release + cell replication
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
P
CREB
CREB
PKA
cAMP
Somatostatin
GHRH
AC
+
-
Pituitary
somatotroph
2 GH Secretion
3 Proliferation
1 GH synthesis
Pit-1
Pit-1
GH
GH
G-prot
Pit1 is a pituitary-specific 
transcription factor that is 
essential for the 
development of 
somatotrophs (& 
lactotrophs & thyrotrophs).
36


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## Page 19

2024-04-26
19
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• It is a peptide with a fatty acid group
• Ghrelin treatment stimulates GH release (and food intake)
• Most mice with disrupted ghrelin signalling are not “skinny 
dwarfs” although certain models do have a mild phenotype.
• Ghrelin is mainly produced by the empty stomach between 
meals
Ghrelin has 2 main roles: 1) ­ food intake and 2) ­ GH 
release.  
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Ghrelin receptors: In GHRH (growth) 
and NPY (food intake) neurons 
in arcuate nucleus (ARC) 
37
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Non-Hypothalamic Brain Areas
-
Taste sensation
-
Reward behaviour
-
Olfaction & sniffing
-
Learning & Memory
-
Depression
-
Sleep/wake rhythm
-
Neuroprotection
Sympathetic nervous system
- SNS activity ¯
BAT
- Thermogenesis ¯
Heart
- Cardiac output ­
- Cardiac contractility ­
- Vasodilatation ­
Stomach
- Gastric emptying­
- Gastric motility­
- Gastric acid secretion ­
Pituitary
- GH ­
Ghrelin directly stimulates 
growth hormone release from 
the anterior pituitary.
It also activates GHRH* 
neurones in the hypothalamus.
GHRH and ghrelin act 
synergistically to increase GH 
secretion.
Pituitar
Hypothalamus
- GHRH ­
*Growth hormone-releasing hormone
Physiological effects of ghrelin: GH release
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 20

2024-04-26
20
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ø Synthetic peptide and non-peptides that 
release GH e.g. GH-releasing peptide 6 
(GHRP-6), MK-0677, ipamorelin, hexarelin. 
(1980s)
Ø NOTE: These ligands are now known to be 
ghrelin mimetics. Discovered before ghrelin 
or its receptor.
Ø Amplify GH release induced by GHRH
Ø Therapeutic potential - but have not become 
prescribed drugs 
-
for treating certain forms of GH 
deficiency (when somatotrphs intact) or 
-
for enhancing GH secretion when it 
could have beneficial effects e.g. in the 
elderly? 
GH release
Placebo
0.1 ug/kg GHRP
1.0 ug/kg GHRP
1.0 ug/kg GHRH
0.1 ug/kg GHRP plus 1 ug/kg GHRH
From Bowers et al., 1990, J JCEM, 70: 975-982. 
GH secretagogues (ghrelin mimetics) – 1980s-1990s
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
39
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Veldhuis JD et al., 2008, JCEM, 93:3597-603.
Ghrelin (like GHRPs) amplifies GH secretion in healthy 
subjects
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
40


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## Page 21

2024-04-26
21
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Pantel et al., 2006, JCI, 116:760  
Loss of constitutive activity of the growth 
hormone secretagogue receptor in familial short 
stature 
Whereas several clinical studies support a role of 
ghrelin in regulation growth and height, mice lacking 
ghrelin or its receptor mostly do not have growth 
abnormalities.
We do not know the role of ghrelin in GH physiology –
it could be important to promote GH release during 
fasting (and rescue blood glucose).
Sun et al Mol Cell Biol. 2003;23:7973-81.
Pfluger et al Am J Physiol Gastrointest Liver 
Physiol. 2008;294:G610-8
Peris-Sampedro F Mol Metab 2021 13: 1301
Zhao et al., PNAS, 2010;107:7467-72
Those in 
red support 
a role 
in growth
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Not clear that ghrelin is important for growth
41
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Ghrelin mimetics tested in clinical trials
Many linked to GH release!
42


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## Page 22

2024-04-26
22
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Body growth - general
• Body growth - endocrine regulation 
• What are the effects of the GH-IGF-1 axis?
• How is the GH-IGF-1 axis regulated?
Ø What are the mechanisms of action of GH and IGF-1?
• What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
43
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Endochondral 
growth
Calcifying
Hypertrophic
Proliferative
Geminal
Chondrocytes
Epiphyseal
plate
Oestrogens induce closure 
of the growth plate via Erα, such that no further 
proliferation or hypertrophy is possible.
Growth of long bones before epiphyseal plate closure
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
44


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## Page 23

2024-04-26
23
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH actions to stimulate bone 
growth are mediated by 
insulin-like growth factor 1 
(IGF-1), produced by the liver.  
IGF-1 - previously called 
somatomedin C.
Salmon & Daughaday, 1957
GH
IGF-1
Somatomedin (IGF-1) hypothesis of GH action on bone
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
45
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH acts locally within the 
epiphyseal plate to promote 
growth. No effect via liver IGF-1 
on contralateral leg
Direct action of GH?
Locally produced IGF-1 
needed
GH
NaCl
Experiment: 
Administration of GH to growth
plate of one leg.
Olle Isakssson and coworkers, Science 1982
Challenge to the somatomedin hypothesis - 1
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
46


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## Page 24

2024-04-26
24
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH plus
IGF antiserum
NaCl
Additional  Experiment: 
IGF-1 antiserum (removes IGF-1) 
+ GH to growth plate of one leg.
Result: No increase in growth of 
injected leg.
Conclusion: GH actions require 
the presence of IGF-1.
IGF-1 may be produced locally.
Challenge to the somatomedin hypothesis - 2
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
47
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
0
10
20
30
40
50
0
8
12
16
20
24
Liver IGF-1 knockout
Control
Days after induction of knockout
Body
Weight
(g)
Normal body growth 
in liver-specific IGF-
1-knockout mice. 
àLiver-derived IGF-1 
may not be 
important for growth.
Sjögren K, Ohlsson C 
et al, PNAS 1999
Challenge to the somatomedin hypothesis - 3
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
48


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## Page 25

2024-04-26
25
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
The local 
actions of 
GH within 
the growth 
plate 
require the 
presence of 
IGF-1
Green et al, 1985
Maturing 
chondrocytes
IGF1
IGF1
Clonal expansion
Early chondrocyte
IGF1 mRNA
Epiphyseal
growth
plate
GH
GH-R
Differentiation
Prechondrocyte
GH
Long bone
Needed for growth:
1. Direct GH effect.
and 
2. IGF-1 (liver or local)
IGF-1 cannot replace 
GH if GH deficient.
GH no effect in IGF-1 
knockout mice.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Modified somatomedin (IGF-1) hypothesis
49
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH actions to stimulate 
bone growth are direct on 
the bone.
The effects are partly 
mediated by local IGF-1.  
GH
IGF-1
GH
IGF-1
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Revised GH action on bone
50


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## Page 26

2024-04-26
26
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH receptor dimerization for biological effect
1
2
inactive
1
2
active
1
2
GH antagonist
(pegvisomant, 
No proper dimerisation)
inactive
1
2
GH
GH
receptor
inactive
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
51
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH Receptor signaling: active STAT dimer to nucleus 
P
1
2
1
2
GH
GH
receptor
P
JAK2
P
Nucleus
Nucleus
STAT5b
P
Phosphotyrosine
binding domain
STAT : signal transducer and
activator of transcription
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
52


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## Page 27

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27
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Serum IGF-1 levels determine sizes of dog breeds
Polymorphism near IGF-I 
gene associated with body 
size of dog breeds 
IGF-I
IGF-I
IGF-I
IGF-I
IGF-I
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
53
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Derek LeRoith NEJM 1997
Scavenger receptor?
The ligands bind mainly 
to their own receptors , 
but also to others with
lower affinity
Insulin- and IGF-I receptors
à Biological signaling
IGF-II Receptors 
à Scavenging of ligand
INSULIN
IGF-1
IGF-2
Metabolic
Actions
Growth &
Differentiation
?
Insulin receptor
IGF-1 receptor
Scavenger rec?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Comparisons between IGF-1, IGF-2, and insulin
54


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## Page 28

2024-04-26
28
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
IGF-IIR
IGF-IR
Insulin-R
insulin
IGF-I
IGF-II
P
P
P
P
P
P
P
P
IGFBP-2
IGFBP-1
IGFBP-4
IGFBP-6
IGFBP-3
ALS
IGFBP-5
ALS
" "
IGFBP proteases
Courtesy of Dr Ricarda Granata
IGFBP-3 – ALS (acid-labile 
subunit) binds most of all 
IGF-1 in serum.
These ”chop up” 
binding proteins and 
release IGF-1
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
The insulin-like growth factor (IGF) system
55
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
IGF-1
ALS
IGF-BP3
IGF-1 
Rec
ALS: “acid labile subunit”
(old term)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Interactions between IGF-1, IGF-BP3, ALS and BP3 
protease
BP3 protease
56


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## Page 29

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29
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
IGF-1 stimulates proliferation
IGF-1 inhibits apoptosis.
In epidemiologic studies: High S-IGF-1 predictor 
of breast cancer, prostate cancer, colon cancer…
Low S-IGF-BP3 – independent predictor of cancer.
PSA (IGF BP3 protease) a clinical marker of prostate cancer
On the other hand: IGF-1R blockers (e g teprotumumab) do not 
decrease cancer.
IGF-1 is approved by FDA to increase growth in 
small children, irrespective of cause. Caution. 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Beware of IGF-1? 1) Tumors
57
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
1/3 ↓ food
 intake
↓GH effect 
↓ IGF-1 &
 insulin
?
Animals with ↓IGF-1 all live longer (15-30%!)
u
Partly starved animals (not monkeys?) 
u
Growth mutants (GHRH-/- (Little) mice, ames dwarf 
mice, GHR-/-, IGF-1+/- etc.)
Genetic
growth 
defects
↑ Longevity
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Beware of IGF-1? 2) Longevity
58


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## Page 30

2024-04-26
30
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Body weight
Longevity
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Smaller dogs live longer – IGF-1 involved?
59
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Body growth - general
• Body growth - endocrine regulation 
• What are the effects of the GH-IGF-1 axis?
• How is the GH-IGF-1 axis regulated?
• What are the mechanisms of action of GH and IGF-1?
Ø What can go wrong with GH- IGF-1?
Content
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
60


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## Page 31

2024-04-26
31
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Excessive GH production
in childhood, or before the 
epiphyseal growth plates 
have fused 
Dose-response 110-270 cm!
Cause: 
Pituitary tumour
that starts from a 
somatotrophic cell.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Gigantism
61
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Excessive GH production
in adulthood after the 
epiphyseal growth plates 
have fused. Growth of 
“the tips of the body”.
Cause: 
Pituitary tumor that 
starts from a 
somatotrophic cell.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Acromegaly
62


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## Page 32

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32
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Large nose
Thick lips
Growth of 
mandible
Prominent
cheek bones
Osteoarthritic
vertabral changes
Enlarged
hand &
feet
Visual field 
defects
(bitemporal 
hemianopia)
Hirsutism
Barrel chest
Excessive
sweating
Often caused by
Lack of GTPase
activity in G-protein
(see next slide) 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Clinical features of acromegaly
63
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Arg201 in G-protein changed à
 No dephosphorylisation  by GTPase à No signal termination à
  1 GH production,  2 GH release,  3 Somatotroph proliferation 
Gs-
GTP
Gs-
GDP
GDP
GTP
P
GHRH receptor
X
Adenylate
cyclase
­cAMP
Active
Inactive
+
40% of acromegaly 
in Europeans.
GTPase
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Molecular causes of Acromegaly in a somatotroph
64


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## Page 33

2024-04-26
33
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Pit-1 defect. Snell (dw/dw)  Don’t get development of GH, TSH, PRL-
producing cells 
• Prop-1 ”Prophet of Pit” defect. Ames (df/df): GH, TSH, PRL +LH +FSH 
Pit-1 and Prop-1: master genes. Also in man. ­ Longevity?? 
• GHRH receptor gene defect ”little” mouse.  Identified 
   families in Bangladesh, South America.
• GH gene defect. Antibodies against GH unfortunately
       
……. Continued on next slide
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Known genetic defects with growth defects in which 
the body remains in proportion - I
65
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• GH receptor gene defect. Laron dwarfism.  
   IGF-1 treatment partially effective. Have low IGF-1.
• STAT5b gene defect. IGF-1 treatment partially effective.
• IGF-1 gene defect. Mental retardation, deaf. IGF-1 treatment
• IGF-1 receptor gene defect. As for IGF-1 defect. No IGF-1 
treatment
• (Fibroblast growth factor-receptor 3 (FGFR3) gene defect. 
Achondroplasia, short arms and legs; body not in proportion. 
Not linked to GH-IGF-1 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Known genetic defects with growth defects in which 
the body remains in proportion - II
66


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## Page 34

2024-04-26
34
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH
somatostatin
IGF-1
Target organs
¯ IGF-1 
synthesis & release
Defective GH gene
IGF1-R mutations
IGF1-R
GH-R
GH-R
Mutation
Laron Dwarfism
GHRH-R
Ghrelin-R
Mutation?
GHRH-R
Mutation
Defective development
of somatotrophs
“Little”
Dwarfism
Ghrelin-R
GHRH
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Monogenic causes of dwarfism; defective GH axis
67
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Prop-1
Defect:
Ames Dwarf mice
Human dwarfs 
(Krk)
Pit-1
Defect: 
Snell Dwarf mice
Human dwarfs
GH
PRL
TSH
LH, FSH
Stem cell
Stem cell
Pit-1 :
1. Mediator of GHRH effect 
on GH production postnatally
2. Inducer of pituitary 
development prenatally
Defect earlier in development,
(e g Prop-1 instead of Pit-1)
à More hormones lacking.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Dwarf mice and human equivalents: defective pituitary 
master genes during development
68


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## Page 35

2024-04-26
35
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Evidence that the GHRH-receptor, and not down-stream 
pathways, is nonfunctional in dwarf  “little” mice
40
30
20
10
GH secretion 
(% of cell 
content)
Little mice
Wild type
Control
dbcAMP
Forskolin
Cholera toxin
GHRH
cAMP
GHRH
AC
GH   Secretion
G-prot
Forskolin
Cholera 
toxin
GH secretion from pituitaries of Little mice is decreased after GHRH compared to Wild type mice.
In contrast, stimulation of the down stream G-protein –adenylate cyclase (AC) – cAMP signal pathway by cholera 
toxin, forskolin or dbcAMP can all stimulate GH secretion in little mice  
(Adapted from Jansson JO et al Science 1986)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Little mice
wildtype mice
69
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Dwarfism due to mutations
of  human GHRH receptor
Effect of Sindh
Mutation (AlaàGlu)
Brazil (intron 1 splice donor)
Leu
D
E
I
I Y
H G V T
S I S
L A V I
F
A
V
L
T I
I
V A L
R
R L H C P
R
K
D
W
L
C S V
T
T
F
V
G
W
L
F
G
P
G A
W L V
A
W
L
V
T
S
R
W
Y
Q
S
Q
T
H
R
I
L
V
R
K
L
E
P
A
Q G S L
N
C
L
L
A S T S P
S
R
R
A
A
F
L
F
H
S
D D T D H
C
S
A
L
K
D
F
E
I A C W
T
D
D
L
D
N
L
A
G L G I R
P
L
G
E L G
L
Q
L
F
A
C
L
G
V
S
I F
I
F
Y
Q
N
K
E
R
V
T
E
I
S
R
K
W
H
G
H
D
P
E
L
P
W A
L
R
T
R
A
K
W
T
T
P
S
R
S
A
A
K
L V
S
M
T
C
I
V
Y
Y WW
I
G K
I
P
V
G V S L
N F
F L G
N I
I
L
A K
LV
T
L F
G R V
L
T F L
H
Q
N
Y
V
T
S
F
Y
S
E
E
E
A
L
L
E
L
P V P C A V P Y P P F P E S W G T I
T C D R K V A
G S
S
E
S F H S F F D P C P L T V W
G
G
S
A
T
P
W
C
L
L
G
W
T
A
P
C
G
L
T
T
N
P
M
E
E
A
A
Q
L
C
A
S
E
D
E
R
L
Q
T
I
F
D
C
E
P H M H
C
L
K
S
T
L
V S V
Y
N
H
A A
F A
L
V
A E A
F
T S
W L
M
S
S
T F I
S
P
K
S
L
F
L
F
L
L
N
I
I Y
G I H
F L P
F
I
T S
P
D
NH2
COOH
Sindh
His
Glu
Ala
Cys
Phe
Spain
Pakistan
USA
USA
D 4
Japan
Gly
Asp
Stop
Glu
Little mouse
little mouse 
-/- and -/+ littermates
Little mouse 
AspàGlu
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
GHRH receptor
70


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## Page 36

2024-04-26
36
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GH receptor deficiency 
(Laron dwarfism)
1
2
GH
GH
receptor
inactive
X X
•  GH treatment ineffective
•  IGF-1 only small effect
 (lack of cells with IGF-1 rec 
in growth plate when no GH?)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
71
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
IGF-1 and IGF-1 receptor deficiency 
IGF-1 gene defect
IGF-1 receptor  gene defect
Chernausek  S et al NEJM 2003
Woods KA et al NEJM 1996
Intrauterine
growth defect
Chernausek  S et al NEJM 2003
Woods KA et al NEJM 1996
Intrauterine
growth defect
autosomal
recessive
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
72


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## Page 37

2024-04-26
37
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Causes of dwarfism unrelated to GH-IGF axis
Thyroid hormone deficiency in childhood (Cretinism).
Retardation of mental development & growth.
Thyroid hormones are permissive for growth.
Excess glucocorticoids - stunts growth.
Glucocorticoids are permissive for growth, but inhibitory in 
high doses.
Genetic diseases:
Pygmy mouse, HMGA2 (high-mobility group A2), a transcription factor 
for e g cycline A. 
Human SNP 0.5 cm height.

Achondroplasia (next slide)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
73
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Achondroplasia: Selective shortening of long bones in dogs & humans
Hypothesis: Gain of function mutation in fibroblast growth factor receptor-3  
(FGFR-3). FGFR3 prevents stem cell proliferation and differentiation.  
Gain of function à Autosomal dominant disease. 80% new mutations. 
Diego Velázquez (1599-1660). 
Museo del Prado, Madrid 
(Achondroplasia “No chondrocyte proliferation” 
Not responsive to GH or IGF-1 treatment.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
74


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## Page 38

2024-04-26
38
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Summary
•
Prenatal, postnatal and pubertal body growth is regulated by different 
hormones. 
•
Postnatal longitudinal body growth is regulated by a hypothalamus – pituitary 
– liver – bone axis. 
•
GH is diabetogenic and lipolytic in addition to growth promoting.
•
GH- IGF-1 axis is regulated by feeding, amino acids, lipids and glucose. 
•
GH- IGF-1 in relation to tumour growth is a concern, but few alarming data 
at present. 
•
Dwarfism can be due to defects of various hormones and receptors in the 
GHRH - GH- IGF-1 – FGFR3 axis. Diagnos for right treatment.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
75


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