Normal Growth and Clinical Aspects

Question 1

Summarise schematically the routes involved in the secretion and target effects of GH.

Answer 1

a

Question 2

Define the term ‘somatotropin’.

Answer 2

(“trop” relating to growth)

AKA Growth hormone is released from the anterior pituitary. It helps to regulate growth.

Question 3

Define the term ‘somatostatin’.

Answer 3

(“statin” relating to stasis)

AKA Growth hormone inhibiting hormone is one of two hypothalamic neurohormones, which control the release of GH.

Question 4

Define the term ‘somatomedin’ and how it is similar to insulin.

Answer 4

Somatomedin C AKA insulin-like growth factor-1 (IGF-I) is a hormone that mediates the action of GH.

• Has a similar structure to proinsulin
• Binds to receptors similar to the insulin receptor
• Has hypoglycaemic qualities (limited to glucose uptake in muscle, liver/adipose tissue have few IGF receptors)

Question 5

State the factors that regulate growth.

Answer 5

Growth hormone;

• Released from anterior pituitary
• Is regulated by balance of GRGH vs GHIH released from hypothalamus
• Thyroid hormones
• Insulin
• Sex steroids (especially at puberty)
• Availability of nutrients
• Stress
• Genetics

Question 6

Besides GHIH, what other hormone helps to control GH release?

Answer 6

Growth hormone releasing hormone (GHRH), a hypothalamic neurohormone.

Question 7

Describe the actions of GH.

Answer 7

GH has a wide spectrum of biological activity that can be defined by two broad categories;

• Growth and development (indirect action)
• Regulation of metabolism (direct action)

Question 8

Describe the action of GH on growth and development.

Answer 8

GH is necessary for growth and development of the child. Growth in the foetal period and the first 8-10 months of life is largely controlled by nutritional intake, but thereafter GH becomes the dominant influence on the rate at which children grow.

Question 9

What does GH require to stimulate growth?

Answer 9

GH requires permissive action of thyroid hormones and insulin before it will stimulate growth. Children with untreated hypothyroidism, or poorly controlled diabetes, have stunted growth despite normal GH levels.

Question 10

Does GH secretion continue throughout adult life?

Answer 10

Yes - GH secretion continues throughout adult life as it is continues to be essential in the maintenance and repair of tissue.

Question 11

What two things mediate the growth-promoting effect of GH?

Answer 11

Through stimulation of both;
- Cell size (hypertrophy)
- Cell division (hyperplasia)
in its many target tissues.

Question 12

Explain why the effect of GH on growth is almost entirely indirect.

Answer 12

As it is achieved through the action of an intermediate known as insulin-like growth factor-I (IGF-I), AKA somatomedin C, as it mediates the action of GH.

Question 13

Describe the secretion of IGF-I and its control of GH.

Answer 13

• Secreted by the liver and may other cell types in response to GH release
• Control GH release through a negative feedback loop/

Question 14

IGF-II exists. True or false?

Answer 14

True, however its functional importance appears to be limited to the foetus and neonates.

Question 15

What type of hormones are GH and IGF-I?

Answer 15

Peptide hormones but like steroid and thyroid hormones, they are transported in the blood bound to carrier proteins.

Approx. 50% of GH is in the bound form. This helps to provide a “reservoir” of GH in the blood, which helps to smooth out the effects of the erratic pattern of secretion and extends half life by protecting it from excretion in the urine.

Question 16

Describe the IGF-I negative feedback loop on GH release.

Answer 16

IGF-I exhibits negative feedback on GH release both via inhibiting GHRH and stimulating GHIH.

Additional negative feedback loop of GH on GH release from somatotrophs in pituitary.

Question 17

Describe GH/IGF-I effects on bone growth.

Answer 17

1. GH stimulates chondrocyte precursor cells (prechondrocytes) in the epiphyseal plates to differentiate into chondrocytes.
2. During the differentiation, the cells begin to secrete IGF-I and become responsive to IGF-I.
3. IGF-I then acts as an auto/paracrine agent to stimulate the differentiating chondrocytes to undergo cell division and produce cartilage, the foundation for bone growth.

Question 18

Describe the action of GH on the regulation of metabolism.

Answer 18

1. Increases gluconeogenesis by the liver.
2. Reduces the ability of insulin to stimulate glucose uptake by muscle and adipose tissue.
3. Makes adipocytes more sensitive to lipolytic stimuli.

However, unlike cortisol and just like insulin, GH:
4. Increases amino acid uptake and protein synthesis in almost all cells = anabolic effect (cortisol stimulates protein catabolism).

Question 19

Describe the action of GH on the regulation of metabolism.

Answer 19

1. Increases gluconeogenesis by the liver.
2. Reduces the ability of insulin to stimulate glucose uptake by muscle and adipose tissue.
3. Makes adipocytes more sensitive to lipolytic stimuli.

In all of these actions, GH is releasing energy stores to support growth. (Remember only fat and muscle require insulin for glucose uptake – bone does not). It is having an “anti-insulin” effect and synergises with cortisol in this respect.
GH is therefore said to be diabetogenic (increases blood glucose) when present in XS.

However, unlike cortisol and just like insulin, GH:
4. Increases amino acid uptake and protein synthesis in almost all cells = anabolic effect (cortisol stimulates protein catabolism).

Question 20

Insulin and GH are anabolic hormones. Describe their effect on aa uptake, protein synthesis and glucose uptake.

Answer 20

Insulin;

• Increased aa uptake
• Increased protein synthesis
• Increased glucose uptake

GH;

• Increased aa uptake
• Increased protein synthesis
• NO EFFECT ON glucose uptake

Question 21

Describe the daily changes in GH secretion.

Answer 21

• Majority of GH released during first 2 hours of sleep (deep delta sleep)
• 20x increase in GH secretion in children during this period
• General energy requirements low so energy diverted to growth
• GHRH may have sleep inducing qualities
• GH release during waking hours is low
• Despite GH spikes, [IGF-I] in plasma remain relatively constant suggesting IGF-I buffers the pulsatile variance in GH levels.

Question 22

Describe the control of GH secretion.

Answer 22

Control of GH secretion is heavily influenced by nutritional status, as expected given the role of GH in regulating metabolism. Nutritional control of GH release is mainly mediated via modulation of control of GHRH/GHIH release from the hypothalamus.

Question 23

Describe how GH is diabetogenic.

Answer 23

During its regulation of metabolism, GH is releasing energy stores to support growth. (Remember only fat and muscle require insulin for glucose uptake – bone does not). It is having an “anti-insulin” effect and synergises with cortisol in this respect.
GH is therefore said to be diabetogenic (increases blood glucose) when present in XS.

Question 24

Explain how an actual or potential decrease in energy supply to cells increases GHRH secretion.

Answer 24

As well as growth and development, GH is needed for maintenance of tissues and their energy supply.
Fasting and hypoglycaemia = decrease in substrate supply.
In exercise and in the cold = increase demand for energy. All stimulate increase in GH.

Question 25

Explain how increased amounts of aa’s in the plasma increase GHRH secretion.

Answer 25

GH promotes amino acid transport and protein synthesis by muscle and liver.

Question 26

How do stressful stimuli e.g. infection, psychological stress, affect GH secretion?

Answer 26

Increases GH secretion.

Question 27

Explain how delta sleep increases GHRH secretion.

Answer 27

Increase in GH in delta sleep may be related to growth spurts in children and adolescents and tissue repair in adults.

Question 28

Explain how oestrogen and testosterone increase GHRH secretion.

Answer 28

Stimulate GH release from the pituitary directly as well as decreasing IGF mediated negative feedback. Responsible for growth spurt in puberty.

Question 29

Name the five stimuli that increase GHRH secretion.

Answer 29

1. Actual/potential decrease in energy supply to cells.
2. Increased amounts of aa’s in plasma.
3. Stressful stimuli.
4. Delta sleep.
5. Oestrogen and testosterone.

Question 30

Name the four stimuli that increase GHIH secretion.

Answer 30

1. Glucose.
2. FFA.
3. REM sleep (Subjects deprived of REM sleep have increased GH secretion)
4. Cortisol (although inhibitory effect on growth may be more to do with increase in protein catabolism than stimulating GHIH release)

Question 31

What 3 factors affect the physiology of growth.

Answer 31

1. Hormones.
2. Nutrition.
3. Genetics.

Question 32

How do hormones affect the physiology of growth. Give examples (of these hormones).

Answer 32

e.g. GH, IGF-I, thyroid hormones, sex steroids, glucocorticoids, insulin.

Different periods of growth are dominated by different hormones.

Sex hormone influence is minor until puberty when they dominate the growth spurt.

GH influence is also minor during foetal life. Babies born deficient in GH and IGF-1 are of normal size. Insulin and IGF-II may dominate intrauterine growth.

Question 33

Describe how thyroid hormones affect the physiology of growth.

Answer 33

Thyroid hormones are essential for normal growth, particularly important for development of the nervous system in utero and early childhood.

Effects are permissive to GH/IGF-I.

Cause;

• Ossification of cartilage
• Maturation of teeth
• Contours of face
• Proportions of the body

Question 34

Define ‘cretinism’,

Answer 34

Cretinism is a condition where children are hypothyroid from birth. They have retarded growth because of the loss of TH’s permissive action on GH. They retain infantile facial features = hypothyroid dwarf. However, GH levels are normal.

Question 35

How does nutrition affect the physiology of growth.

Answer 35

Adequate diet in terms of; - Protein content
- Essential vitamins & minerals is just as important as enough calories.

Important in utero and during development.

Injury and disease stunt growth because they increase protein catabolism (glucocorticoid effects).

Question 36

How do genetic factors affect the physiology of growth.

Answer 36

Helps determine maximum growth.

Interaction between genetic factors and nutrition.

Question 37

Describe the two period of rapid growth in humans.

Answer 37

1. Infancy
   - Amazing growth spurts 2.5cm in a few days and then nothing
   - Episodic
   - Mechanism not known
2. Puberty
   - Due to androgens and oestrogens
   - Produce spikes in GH secretion that increase IGF-I, increasing growth
   - The same sex steroids also terminate growth by causing the epiphyses of the long bones to fuse

So, in normal puberty, before the epiphyseal plates fuse, GH/IGF-I promote bone elongation and increased height, weight and body mass.

Sex hormones in the later stages of puberty act to close the epiphyses and hence stop bone elongation.

Question 38

Describe gigantism.

Answer 38

• XS GH due to a pituitary tumour before epiphyseal plates of long bones close
• Excessive growth
• May be more than 7ft tall
• Called pituitary giants

Surgery to remove tumour or somatostatin analogues to treat.

Question 39

Describe acromegaly.

Answer 39

• XS GH due to a pituitary tumour after epiphyseal plates have sealed
• Long bones cannot increase so there is no longitudinal growth and no increase in height
• However, can still grow in other directions
• Characteristic features: enlarged hands and feet

In adults feet should NOT get bigger = classic sign of ACROMEGALY.

Surgery to remove tumour or somatostatin analogues to treat.

Question 40

List signs of acromegaly.

Answer 40

• Enlarged feet and hands
• Osteoarthritic vertebral changes
• Visual field changes (bitemporal hemianopia)
• Prognathism and acromegalic facies
• Hirsutism
• Gynaecomastia and lactation