Chapter 9

Growth Hormones and

the Somatomedins

Nam Deuk Kim, Ph.D.

1

1. Endocrine Control of Growth

• Growth depends on growth hormone but is

influenced by other factors as well

– Genetic determination of an individual’s

maximum growth capacity

– An adequate diet

– Freedom from chronic disease and stressful

environmental conditions

– Normal levels of growth-influencing hormones

2

Growth Rate

• Not continuous

• Factors responsible for promoting growth

are not the same throughout growth period

• Fetal growth

– Promoted largely by hormones from placenta

– GH plays no role in fetal development

• Postnatal growth spurt

– Displayed during first two years of life

• Pubertal growth spurt

– Occurs during adolescence

3

Normal Growth Curve

4

2. Growth Hormone and the Somatomedins • Primarily promotes growth indirectly by stimulating liver’s

production of somatomedins

– Primary somatomedin is insulin-like growth factor (IGF-1)

• 70 amino acids

• Acts directly on bone and soft tissues to bring about most

growth-promoting actions

• Stimulates protein synthesis, cell division, and lengthening

and thickening of bones

• IGF-2: 67 amino acids polypeptide with less well known

function

• Exerts metabolic effects not related to growth

– Increases fatty acid levels in blood by enhancing breakdown

of triglyceride fat stored in adipose tissue

– Increases blood glucose levels by decreasing glucose uptake

by muscles

5

Fig. 12-2. Primary structure of human IGF-1 (70 aa). The amino acids

in black circles denote those in identical position in the A and B chain

of human insulin. 6

INSULIN-LIKE GROWTH FACTOR 1 (IGF-1)

Synthesized mainly by liver in response to GH - somatomedin

Mediates effects of GH on bone and cartilage

85% homology with proinsulin

Continuous peptide chain unlike insulin

Starvation or illness blocks IGF-1 formation in response to GH –

growth ceases during severe illness

Does it make sense that starvation activates GHRH release?

YES – in starvation GH exerts glucagon-like effects

but its ability to promote IGF-I synthesis and secretion is blocked

7

Relative

GH

receptor

mRNA

levels

Tissue distribution of GH receptor mRNA. *Tissues with

high levels of IGF-1 receptor. Muscle contains GH and

IGF-1; bone and cartilage only IGF-1

8

Summary of GH and IGF-1 effects

Direct effects of GH include

Muscle amino acid uptake resulting in protein synthesis

Glucose use peripherally (anti-insulin)

Glucose output from liver (anti-insulin)

Fat mobilization (anti-insulin) Ketogenesis in liver (anti-insulin)

IGF-I release from liver

Direct effects of IGF-1 include

Cartilage/bone growth

Muscle growth/proliferation

9

IGF-1 mechanism of action – similar to insulin in that

signaling is via receptor tyrosine kinase

Insulin and IGF-1 bind to each other’s receptors but only at

high concentration

IGF-1 receptor mainly mediates mitogenic/growth effects

Different physiological roles of insulin and IGF-1 accounted

for by cellular distribution of their receptors

IGF-1 vs. INSULIN

10

Comparison of insulin, GH and IGF-1 hormone

receptor distribution

Receptor location Response Receptor location

ADIPOSE: LIVER:

GH Metabolic GH

Insulin Metabolic Insulin

MUSCLE: CARTILAGE/BONE:

GH Growth

IGF-1 Growth IGF-1

Insulin Metabolic

11

Fig. 12-3. The insulin and IGF-1 receptors are structurally related

heterotetrameric glycoproteins consisting of two and two subunits.

The subunits lie entirely extracellularly, contain cysteine-rich

regions, and bind the ligands. The transmembrane subunits are

joined to the subunits by disulfide bonds and contain a tyrosine

kinase domain in their cytoplasmic portion. The level of amino acid

similarity between these two receptors is particularly high (85%) in the

tyrosine kinase domains [26]. 12

Control of growth hormone

secretion

13

Fig. 12-5. Model for the control of

GH secretion by growth hormone-

inhibiting hormone [(GHIH, or

somatostatin (SST)] and growth

hormone-releasing hormone

(GHRH, or somatocrinin).

(IGF-1)

14

Anatomy and growth of long bones

15

Fig. 12-4. Model of the dual-effector hypothesis of GH action. 16

Fig. 12-6. Summary

scheme of the direct and

indirect actions of growth

hormone on growth and

metabolism.

17

Targeting IGF-1R Pathway in Cancer

• 키 클수록 소득 높다

• 키 클수록 암 발생 위험도 함께 커진다.

• 남성: 5cm 커질수록 5%씩 증가

• 여성: 5cm 커질수록 7%씩 증가

• 베르그만(Bergmann) 법칙: 항온동물의 경우 같은 종이라도 추운 곳에 사는 것이 더운 곳에 사는 것보다 몸집이 더 크다는 법칙. 더운 곳에서는 몸의 열을 발산해야 하지만 추운 곳에서는 체온 유지를 위해 몸 표면적을 줄여 열 손실을 막아야 한다. 몸의 길이가 두배가 되면 표면적은 4배(22)로, 부피는 8배(23)로 늘어난다. 몸집이 커지면서 부피에 대한 표면적의 비율이 줄어드는 것이다. 사람도 북유럽인이 남유럽인 보다 더 크다.

• AMGEN Oncology - 2009

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Fig. 12-7. Serum immunoreactive (IR) IGF-1 and -2 levels in

normal adults, acromegalic patients, and patients with isolated GH

deficiency.

19

Fig. 12-8. Serum concentrations of IGF-1 and IGF-2 in controls,

hypopituitary dwarfism, and Pygmies. IGF-1 and IGF-2 were

measured in the same adult controls. Lines and bars denote means

± SEM. Note that only one Pygmy has an IGF-1 value within the

lower normal range, whereas all but one have IGF-2 values within

the normal range. All values are corrected for cross-reactivity. 20

Fig. 12-9. Growth hormone signal transduction pathway. GH brings about receptor dimerization by

binding first to the extracellular domain (ECD) of one receptor molecule and then to that of another

receptor molecule. The signal of GH-binding is probably transmitted via the transmembrane

domain (TMD) to bring about conformational changes in the intracellular domain (ICD). This results

in the recruitment and binding of the cytoplasmic tyrosine kinase, JAK2, to the receptor. JAK2

undergoes autophosphorylation and activation, which in turn phosphorylates the receptor.

Phosphorylated tyrosines on the receptor then function as docking sites for STAT transcription

factors, which bind through the SH2 domain and are phosphorylated. The activated STATs

dimerize, translocate to the nucleus, and bind enhancer regions in GH target genes to regulate

their transcription.

21

Laron syndrome

• Laron-type dwarfism, is

an autosomal recessive

disorder characterized by

an insensitivity to growth

hormone (GH), caused by

a variant of the growth

hormone receptor.

• Defect in the GH receptor

• It causes short stature and

a resistance to diabetes

and cancer.

22

23

LARON-TYPE DWARFS

• GH receptor defective

• Unresponsive to hGH treatment

• Leads to metabolic problems as

well – hypoglycemia, TG

(Triglyceride) storage

• Responsive to IGF-1 treatment

A group of villagers in Ecuador with the Laron-

type mutation with Dr. Jaime Guevara-Aguirre,

an Ecuadorean physician and diabetes

specialist. Image credited to npr.com

A gene that prevents cancer and diabetes, and

makes humans grow to only 3 and a half feet

tall is the key apparently.

AFRICAN PYGMIES

• Normal GH and IGF-I binding

• Defect is post-receptor

• Tissue resistance to IGF-1 leads to short stature

24

(a) Normal

Growth

Fig. 12-11. Various endocrine disorders relating to the overproduction

or underproduction of pituitary GH or to inadequate hepatic or

peripheral tissue response to GH or somatomedins. 25

3. Other Hormones for Growth

• Other hormones besides growth hormone are essential for normal growth

– Thyroid hormone

• Growth severely stunted in hypothyroid children

• Hypersecretion does not cause excessive growth

– Insulin

• Deficiency often blocks growth

• Hyperinsulinism often spurs excessive growth

– Androgens

• Play role in pubertal growth spurt, stimulate protein synthesis in many organs

• Effects depend on presence of GH

– Estrogens

• Effects of estrogen on growth prior to bone maturation are not well understood poorly

26

4. Growth Hormone Abnormalities • Growth hormone deficiency

– Due to pituitary defect or hypothalamic dysfunction

– Hyposecretion of GH in child is one cause of dwarfism

– Deficiency in adults produces relatively few symptoms

• Growth hormone excess

– Most often caused by tumor of GH-producing cells of anterior

pituitary

– Symptoms depend on age of individual when abnormal

secretion begins

• Gigantism

– Caused by overproduction of GH in childhood before epiphyseal

plates close

• Acromegaly

– Occurs when GH hypersecretion occurs after adolescence

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Hypopituitarism-mild

28

Hypopituitarism-moderate

29

Hypopituitarism-severe

30

Hypopituitarism-panhypopituitarism

31

Chromophobe

Adenoma

• Compressing the optic chiasm

• Cushing’s syndrome

• Active acromegaly

• Virilizing adrenal hyperplasia

• Galactorrhea

32

Postpartum pituitary

Necrosis

Sheehan’s syndrome

33

Anorexia nervosa

Simmonds’ disease

= extreme insufficiency

of the adenohypophysis

34

Dwarfism • Targets of GH therapy: 20%

• 10~15% of dwarfism is effective

on GH therapy

35

그림 18-18 36

Hyperpituitrism

GH secreted in excess causing acromegaly, gigantism

PRL secreted in excess causing galactorrhea

ACTH secreted in excess causing Cushing's syndrome

TSH secreted in excess causing hyperthyroidism

37

Acidophil adenoma

Hyperfunction of

the acidophil cells

of the adenohypophysis

Acromegaly

Gigantism

38

Acromegaly

Typical symptoms of acromegaly

• coarsening of facial features

• enlarged hands and feet

• thickening of the soft tissue in the

palms and soles of the feet

• carpal tunnel syndrome (tingling

feeling or pains in the hands)

• excessive sweating and oily skin

• headaches

• vision disturbance

• sleep apnoea

• general tiredness

• (amenorrhoea) - adult females

• impotence - adult males

• reduced fertility

39

40

Gigantism

41

Fig. 12-12. Hypothetical scheme

for the evolution of growth

hormone, prolactin, and placental

lactogen.

5. Other Hormones Essential to Normal Body Growth

1) Prolatin:

- Important role in milk synthesis

- Essential for ductile branching

during mammary gland

development

- Directly affects the growth and

function of the ovaries and testes

2) Placental Lactogen (PL)

- Essential for cartilage maturation

- Stimulates growth and induction of

milk protein synthesis

- Testes development and

maturation

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3) Neurotropic growth factors

• Several peptide growth factors regulate the differentiation and

growth of both CNS and PNS.

• Nerve growth factor (NGF) promotes survival of peripheral

sympathetic and spinal neurons during development.

- NGF is one member of a family of neurotropins.

- NGF is a small secreted protein that is important for the growth,

maintenance, and survival of certain target neurons (nerve cells).

- It also functions as a signaling molecule.

- Other members of the neurotrophin family that are well

recognized include Brain-Derived Neurotrophic Factor (BDNF),

Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5).

43

4) Hematopoietic GFs

- Erythropoietin enhances the

formation of new red blood cells

Fig. 12-14. Scheme for the biogenesis

and actions of erythropoietin.

44

Fig. 12-13. Semilogarithmic

presentation of the exponential increase

in serum erythropoietin with the degree

of anemia in 63 subjects with intact

kidneys (normal persons and patients

with primary hemapoietic disorders;

black triangles) and lack of this increase

in 22 patients with chronic renal failure

(open squares).

Fig. 12-17. Primary structure of bovine thymosin 1.

5) Thymic hormones stimulate maturation of T lymphocytes

• Thymosins are small proteins present in many animal tissues.

• They are named thymosins because they were originally isolated

from the thymus, but most are now known to be present in many

other tissues.

• Thymosins have diverse biological activities, and two in particular,

thymosins α1 and β4, have potentially important uses in medicine,

some of which have already progressed from the laboratory to the

clinic.

• In relation to diseases, thymosins have been categorized as

biological response modifiers.

45

Fig. 12-18. Primary structure of bovine thymosin 4. Residues

31–43 are aligned with residues 18–30 to indicate regions of

internal duplication.

46

6) Platelet-derived growth factor (PDGF) acts locally on injured

blood vessels.

• Platelet-derived growth factor (PDGF) is one of the numerous growth

factors, or proteins that regulate cell growth and division.

• In particular, it plays a significant role in blood vessel formation

(angiogenesis), the growth of blood vessels from already-existing blood

vessel tissue. Uncontrolled angiogenesis is a characteristic of cancer.

• In chemical terms, platelet-derived growth factor is dimeric glycoprotein

composed of two A (PDGF-AA) or two B (PDGF-BB) chains or a

combination of the two (PDGF-AB).

• PDGF is a potent mitogen for cells of mesenchymal origin, including

smooth muscle cells and glial cells.

• In both mouse and human, the PDGF signaling network consists of four

ligands, PDGFA-D, and two receptors, PDGFR-α and PDGFR-β.

• All PDGFs function as secreted, disulphide-linked homodimers, but only

PDGFA and B can form functional heterodimers.

47

7) Epidermal growth factor (EGF) stimulates

proliferation and keratinization of epidermal tissue.

• EGF is a growth factor that

plays an important role in the

regulation of cell growth,

proliferation, and differentiation

by binding to its receptor EGFR.

• Human EGF is a 6,045-Da

protein with 53 amino acid

residues and three

intramolecular disulfide bonds.

• EGF can be found in human

platelets, macrophages, urine,

saliva, milk, and plasma.

Fig. 12-19. Primary structure of

mouse epidermal growth factor

(EGF).

48

• EGF acts by binding with high affinity to epidermal

growth factor receptor (EGFR) on the cell surface

and stimulating the intrinsic protein-tyrosine kinase

activity of the receptor (see the diagram).

• The tyrosine kinase activity, in turn, initiates a

signal transduction cascade that results in a variety

of biochemical changes within the cell - a rise in

intracellular calcium levels, increased glycolysis

and protein synthesis, and increases in the

expression of certain genes including the gene for

EGFR - that ultimately lead to DNA synthesis and

cell proliferation.

49

• EGF is the founding member of the EGF-

family of proteins.

• Members of this protein family have

highly similar structural and functional

characteristics.

• Besides EGF itself other family

members include:

- Heparin-binding EGF-like growth factor

(HB-EGF)

- transforming growth factor-α (TGF-α)

- Amphiregulin (AR)

- Epiregulin (EPR)

- Epigen

- Betacellulin (BTC)

- neuregulin-1 (NRG1)

- neuregulin-2 (NRG2)

- neuregulin-3 (NRG3)

- neuregulin-4 (NRG4).

• All family members contain one or

more repeats of the conserved amino

acid sequence:

• CX7CX4-5CX10-13CXCX8GXRC

• Where X represents any amino acid.

• This sequence contains 6 cysteine

residues that form three intramolecular

disulfide bonds.

• Disulfide bond formation generates

three structural loops that are essential

for high-affinity binding between

members of the EGF-family and their

cell-surface receptors.

50

• EGF therapy:

• Because of the increased risk of cancer by EGF, inhibiting it

decreases cancer risk.

• Such medications are so far mainly based on inhibiting the EGF

receptor. Monoclonal antibodies are potential substances for this

purpose.

• Gefitinib (INN) (trade name Iressa) is a drug used in the treatment

of certain types of cancer.

• Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts

signaling through the epidermal growth factor receptor in target

cells.

• It is marketed by AstraZeneca and Teva.

51

8) Fibroblast Growth Factors

• Fibroblast growth factors, or FGFs, are a family of

growth factors involved in angiogenesis, wound healing,

and embryonic development.

• The FGFs are heparin-binding proteins and interactions

with cell-surface associated heparan sulfate

proteoglycans have been shown to be essential for FGF

signal transduction.

• FGFs are key players in the processes of proliferation

and differentiation of wide variety of cells and tissues.

52

FGF Family • In humans, 22 members of the FGF family have been identified, all of

which are structurally related signaling molecules:

• Members FGF1 through FGF10 all bind fibroblast growth factor receptors

(FGFRs). FGF1 is also known as acidic, and FGF2 is also known as basic

fibroblast growth factor.

• Members FGF11, FGF12, FGF13, and FGF14, also known as FGF

homologous factors 1-4 (FHF1-FHF4), have been shown to have distinct

functional differences compared to the FGFs. Although these factors

possess remarkably similar sequence homology, they do not bind FGFRs

and are involved in intracellular processes unrelated to the FGFs. This

group is also known as "iFGF”.

• Members FGF16 through FGF23 are newer and not as well characterized.

FGF15 is the mouse ortholog of human FGF19 (hence there is no human

FGF15).

• Human FGF20 was identified based on its homology to Xenopus FGF-20

(XFGF-20).

• In contrast to the local activity of the other FGFs, FGF15/FGF19, FGF21

and FGF23 have more systemic effects. 53

9) Transforming Growth Factors

• Transforming growth factor (sometimes referred to as

Tumor growth factor, or TGF) is used to describe two

classes of polypeptide growth factors, TGFα and TGFβ.

• The name "Transforming Growth Factor" is somewhat

arbitrary, since the two classes of TGFs are not structurally

or genetically related to one another, and they act through

different receptor mechanisms.

• Furthermore, they do not always induce cellular

transformation, and are not the only growth factors that

induce cellular transformation.

54

Types of TGF

TGFα is upregulated in some human cancers. It is

produced in macrophages, brain cells, and keratinocytes,

and induces epithelial development.

TGFβ exists in three known subtypes in humans, TGFβ1,

TGFβ2, and TGFβ3.

- These are upregulated in Marfan's syndrome and some

human cancers, and play crucial roles in tissue

regeneration, cell differentiation, embryonic development,

and regulation of the immune system.

- Isoforms of transforming growth factor-beta (TGF-β1) are

also thought to be involved in the pathogenesis of pre-

eclampsia.

- TGFβ receptors are single pass serine/threonine kinase

receptors.

55

Function of TGF

• These proteins were originally characterized by their

capacity to induce oncogenic transformation in a

specific cell culture system, rat kidney fibroblasts.

• Application of the transforming growth factors to

normal rat kidney fibroblasts induces the cultured cells

to proliferate and overgrow, no longer subject to the

normal inhibition caused by contact between cells.

56