Normal growth and Clinical aspects

Question 1

What factors regulate growth? (7)

Answer 1

Growth hormone

Thyroid hormones

Insulin

Sex steroids (esp. at puberty)

Availability of nutrients

Stress

Genetics

Question 2

What is growth hormone?

Answer 2

A peptide hormone produced by the anterior pituitary

Release is controlled by Growth hormone inhibiting hormone (GHIH) and Growth hormone releasing hormone (GHRH)

Question 3

What are the two broad actions of growth hormone?

Answer 3

Growth and development (indirect action)

Regulation of metablism (direct action)

Question 4

When does GH become important in growth and development timescale? And what does GH require for stimulation of growth?

Answer 4

GH is necessary for growth and development of the child but only really after 8-10 months of life - before this nutritional intake has a more dominant influence.

GH requires permissive action of thyroid and insulin before it will stimulate growth - this is why children with untreated hypothyroidism or poorly controlled diabetes have stunted growth despite normal GH levels

Question 5

What is growth in the foetal period and first 8-10 months of life largely controlled by?

Answer 5

nutritional intake

Question 6

Growth-promoting effect of GH is mediated through stimulation of what?

Answer 6

cell size (hypertrophy)

cell division (hyperplasia) in its many target tissues

Question 7

Describe Growth and development and the indirect effect GH has on it

Answer 7

The effect of GH on growth is almost entirely indirect, being achieved through the action of an intermediate known as insulin-like growth factor-I (IGF-1) aka somatomedin C as it mediates the action of GH.

IGF-I is secreted by the liver, and many other cell types, in response to GH release, and IGF-1 controls GH release through a negative feedback loop.

GH and IGF-I are peptide hormones - they are transported in the blood bound to carrier proteins. ~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 from excretion in the urine.

Question 8

What is IGF-II

Answer 8

IGF-II = other growth factor that exists but it’s functional importance appears to limited to the foetus and neonate.

Question 9

How does IGF exhibit negative feedback on GH release?

Answer 9

via inhibiting GHRH and stimulating GHIH

Question 10

GH/IGF-I effects on bone growth

Answer 10

GH stimulates chondrocyte precursor cells (prechondrocytes) in the epiphyseal plates to differentiate into chondrocytes.

During the differentiation, the cells begin to secrete IGF-I and to become responsive to IGF-I

IGF-I then acts as an autocrine or paracrine agent to stimulate the differentiating chondrocytes to undergo cell division and produce cartilage, the foundation for bone growth.

Question 11

Why do epiphyseal plates close during adolescence?

Answer 11

influence of sex steroid hormones - longitudinal bone growth is no longer possible when they close

Question 12

How does GH regulate metabolism?

Answer 12

Increases gluconeogenesis by the liver.

Reduces the ability of insulin to stimulate glucose uptake by muscle and adipose tissue.

Makes adipocytes more sensitive to lipolytic stimuli

In all of these GH is releasing energy stores to support growth

Also increases amino acid uptake and protein synthesis in almost all cells - anabolic effect

Question 13

What does bone not require for growth?

Answer 13

Insulin

Question 14

Summary of Direct effect of GH

Answer 14

Mobilises glucose stores to increase blood [glucose]

Inhibits the action of insulin (by reducing the number of insulin receptors on muscle and adipose tissue) thus augmenting the increased blood [glucose]

Promotes lipolysis, providing a source of energy for most cells of the body, sparing glucose and again augmenting increased blood [glucose]

Promotes amino acid uptake to cells, supporting protein synthesis

1-3 might seem strange given that GH is anabolic and concerned with GROWTH, but remember that only muscle and adipose tissue are insulin sensitive. Other tissues do not require insulin for glucose uptake, so bone and brain development are hugely supported by the actions of GH, as is muscle development due to effect on aa uptake.

Question 15

Secretion rate of GH

Answer 15

Undergoes rapid spontaneous fluctuations as well as increase or decreases in response to specific stimuli

Majority of GH released during first 2 hours of sleep (deep delta sleep). 20X increase in GH secretion in children during this period.

GH release during waking hours is low.

Question 16

What controls Growth hormone secretion?

Answer 16

heavily influenced by nutritional status

Nutritional control of GH release is mainly mediated via modulation of control of GHRH/GHIH release from the hypothalamus.

Question 17

Stimuli that increase GHRH secretion (5)

Answer 17

Actual or potential decrease in energy supply to cells

Increased amounts of amino acids in the plasma

stressful stimuli - infection, psychological stress

delta sleep

oestrogen and testosterone

Question 18

Stimuli that increase GHIH (Somatostatin secretion) (decrease GH)? (4)

Answer 18

Glucose

Free FA’s

REM sleep

Cortisol

Question 19

3 factors affecting growth

Answer 19

hormones

nutrition

genetics

Question 20

Which hormones affect growth? (6)

Answer 20

GH

IGF-1

Thyroid hormones

Sex hormones (minor influence until puberty)

Glucocorticoids

Insulin

Question 21

Discuss Thyroid Hormones

Answer 21

Essential for normal growth, particularly important for development of the N.S in utero and early childhood.

Effects are permissive to GH/IGF-1

Have widespread effects on ossification of cartilage and teeth maturation as well as the contours of the face and the proportions of the body.

Question 22

What is cretinism?

Answer 22

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.

GH levels are normal

Question 23

When are the 2 periods of rapid growth in humans?

Answer 23

Infancy

Puberty

Question 24

What is growth like in puberty?

Answer 24

Due to androgens and oestrogens - produce spikes in GH secretion that increase IGF-1 which increases growth

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 25

What is growth like during infancy?

Answer 25

Growth spurts of 2.5cm in a few days and then nothing ie episodic, mechanism unknown

Question 26

Gigantism

Answer 26

excess GH due to a pituitary tumour before epiphyseal plates of long bones closes causes excessive growth, may be more than 7ft tall (210cm), called pituitary giants.

Question 27

Acromegaly - hypersecretion of GH

Answer 27

Excess 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 and the characteristic features are enlarged hands and feet.

Question 28

What is a classic sign of acromegaly?

Answer 28

In adults feet should NOT get bigger but they do in acromegaly so this is a classic sign

normal height but enlarged hands and feet and facial features

Question 29

How do you treat acromegaly?

Answer 29

surgery to remove tumour or somatostatin analogues