Normal Growth and Clinical Aspects

Question 1

growth is regulated by a number of factors

what are they?

Answer 1

1. Growth hormone release from anterior pituitary – which in turn is regulated by the balance of GHRH vs GHIH release from the hypothalamus. Doesnt cause much growth on its own, better supported when there is insulin and thyroid hormone
2. Thyroid hormones
3. I nsulin
4. Sex steroids (esp. at puberty) - more growth around puberty
5. Availability of nutrients - nutrients provide substrates for growth
6. Stress - Stress has a complicated effect on growth – increased release of GH but also cortisol which is catabolic so breaks down things
7. Genetics

Question 2

What type of hormone is GH?

Where is it release and by what cells?

What is it also known as?

Answer 2

GH is a peptide hormone

released from the anterior pituitary

Aka somatotropin

Released from somatotroph cells (“troph” relating to growth)

Question 3

What is the release of GH controlled by?

Answer 3

GH release is controlled via the release of two hypothalamic neurohormones with opposing action

Question 4

GH release is controlled via the release of two hypothalamic neurohormones with opposing action

what are they?

Answer 4

Growth Hormone Inhibiting Hormone (GHIH) (aka Somatostatin (“statin” relating to stasis = static/stopped))

and

Growth Hormone Releasing Hormone (GHRH)

The balance of GHRH : GHIH is determined by the myriad of factors that impinge on the hypothalamus

Question 5

GH has a wide spectrum of biological activity that can be definied by two broad categories:

what are they?

Answer 5

1. Growth and development (indirect action) - Stimulates another hormone that causes elongation of long bones
2. Regulation of metabolism (direct action) - direct action on regulating metabolism and influences metabolism of cells

Question 6

What recpetors do GH bind to?

Answer 6

Binds to tyrosine receptor like insulin, switches intracellular proteins on and off

Question 7

When does GH affect growth and development of a child?

Answer 7

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

Growth hormone doesn’t really kick in till end of first year of life

Little role in growing the very young child

Question 8

what does GH require in order to cause growth and development?

Answer 8

GH requires permissive action of thyroid hormones and insulin before it will stimulate growth

Question 9

How does hypothyroidism, or poorly controlled diabetes affect the growth of a child?

Answer 9

Children with untreated hypothyroidism, or poorly controlled diabetes, have stunted growth despite normal GH levels

This is because they would not have the permissive effect of thyroid or insulin on GH

Question 10

Does GH secretion happen in adults, if so why?

Answer 10

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

Question 11

What effect does GH have on cells allowing growth?

Answer 11

Growth-promoting effect of GH is mediated through stimulation of both cell size (hypertrophy) and cell division (hyperplasia) in its many target tissues

Question 12

The effect of GH on growth is almost entirely ________

Answer 12

indirect

Question 13

The effect of GH on growth is almost entirely indirect, so how is growth achieved?

Answer 13

it is 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

Question 14

IGF-1 has structure very similar to _________

Answer 14

pro-insulin

Question 15

What receptors doe IGF-1 bind to and what effects does it cause?

Answer 15

binds to receptors very similar to the insulin receptor

has hypoglycaemic qualities (hence “insulin-like”) although action is limited to glucose uptake in muscle

Liver and adipose tissue have few IGF receptors

Question 16

WHat secretes IGF-1, when is it released and what is its effect on GH?

Answer 16

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.

Question 17

What is IGF-II

Answer 17

IGF-II also exists but it’s functional importance appears to limited to the foetus and neonate

Question 18

How is GH and IGF-1 transported in the blood?

Answer 18

GH and IGF-I are peptide hormones, but like steroid and thyroid hormones, they are transported in the blood bound to carrier proteins

~50% of GH is in the bound form

Question 19

What is the benefit of GH and IGF-1 being boudn to carrier proteins in the blood

Answer 19

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 20

How does IGF cause engative feedback on GH?

Answer 20

IGF exhibits negative feedback on GH release both via inhibiting GHRH and stimulating GHIH (somatostatin)

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

Question 21

why does GH increase BG

Answer 21

as it blocks insulin

Question 22

What are the effects of GH/IGF-I on bone growth?

Answer 22

1. GH stimulates chondrocyte precursor cells (prechondrocytes) in the epiphyseal plates to differentiate into chondrocytes (a cell which has secreted the matrix of cartilage and become embedded in it)
2. During the differentiation, the cells begin to secrete IGF-I and to become responsive to IGF-I
3. 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 23

When does longitudinal bone growth end?

Answer 23

Epiphyseal plates close during adolescence under the influence of sex steroid hormones then no further longitudinal growth is possible

Question 24

how does GH cause regulation of metabolism (direct effects of GH)?

Answer 24

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

Question 25

However, unlike cortisol and just like insulin, how does GH affect metabolism?

Answer 25

Increases amino acid uptake and protein synthesis in almost all cells = anabolic effect (cortisol stimulates protein catabolism) (Cortisol is catabolic – increase plasma glucose and free fatty acid levels)

Question 26

Answer 26

Question 27

what is th eonly thing to increase glucose uptake?

Answer 27

insulin

Question 28

\_\_, like insulin and glucagon, has significant impact on ________ \_\_\_\_\_\_\_\_\_\_\_\_

Answer 28

**_GH_**, like insulin and glucagon, has significant impact on **_glucose metabolism_**

Question 29

In short, what are the direct effects of GH?

Answer 29

1. Mobilises glucose stores, to increase blood [glucose] 2. Inhibits the action of insulin (by reducing the number of insulin receptors on muscle and adipose tissue) thus augmenting the increased blood [glucose] 3. Promotes lipolysis, providing a source of energy for most cells of the body, sparing glucose and again augmenting increased blood [glucose] 4. 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 30

Where is GH secreted from? and at what age?

Answer 30

Large quantities of GH are present in pituitaries of both adults and children, with highest rates of secretion occurring in teenage years

Question 31

when throughout the day is GH released?

Answer 31

Majority of GH released during first 2 hours of sleep (deep delta sleep). 20X ­increased 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

Question 32

what is this image showing?

Answer 32

Fluctuation in level of growth hormone (GH) in a 7 year old child Repeated measurements over 24 hours are essential when evaluating GH release, in order to get a true picture of hormone status Despite GH spikes, plamsa levels of IGF-1 remain relatively constant suggesting IGF-1 buffers the pulsatile variance in GH levels

Question 33

contorl of GH secretion is heavily influenced by what?

Answer 33

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 34

What stimuli increase GHRH secretion (­increased GH)?

Answer 34

1. **Actual or potential decrease in energy supply to cells**. As well as growth and development GH needed for maintenance of tissues and their energy supply. In fasting and hypoglycaemia this leads to a decrease in substrate supply. In exercise and in the cold, increased­ demand for energy. Decrease in energy supply then we mobilise our energy stores available to growing tissue. All stimulate ­increased GH. 2. **Increased amounts of amino acids in the plasma**, eg protein meal. GH promotes amino acid transport and protein synthesis by muscle and liver. 3. **Physical stress and illness** although growth may actually be stunted due to catabolic action of cortisol 4. **Delta sleep.** increase­ in GH in delta sleep may be related to growth spurts in children and adolescents and tissue repair in adults. 5. **Oestrogen and testosterone** stimulate GH release from the pituitary directly as well as decreasing IGF mediated negative feedback. Responsible for growth spurt in puberty.

Question 35

What stimuli increase GHIH (Somatostatin secretion) (decrease GH)?

Answer 35

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 ­increased protein catabolism than stimulating GHIH release)

Question 36

The physiology of growth is a very complex phenomenon and is affected by what 3 factors?

Answer 36

1. hormones 2. nutrition 3. genetics

Question 37

what hormones are important for growth?

Answer 37

GH, IGF-I, thyroid hormones, sex steroids, glucocorticoids and insulin

Question 38

How does the influence of different hormones change throughout life?

Answer 38

Different periods of growth are dominated by different hormones Sex hormones 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 intrauteriene growth

Question 39

WHat develops growth of the brain and what heepsn if it isnt present?

Answer 39

Thyroid hormones develop growth of brain so if deficient then may have a cognitive impairment If hypothyroid and treated then they will develop normally but if it isn’t identified early then severe cognitive impairment as you need them for normal brain development

Question 40

Thyroid hormones are essential for normal growth, particularly important for development of the ________ \_\_\_\_\_\_\_\_\_\_\_\_ in utero and early childhood

Answer 40

nervous system

Question 41

How does thyroid hormone effect GH/IGF-I?

Answer 41

Effects are permissive to GH/IGF-I

Question 42

What is congenital hypothyroidism and what effects does it have?

Answer 42

Congenital hypothyroidism is a condition where children are deficient in TH in utero They have retarded growth because of the loss of TH’s permissive action on GH. They retain infantile facial features. GH levels are normal Reflects maternal iodine deficiency during pregnancy. Found in regions of endemic iodine deficiency

Question 43

describe child growth in this picture

Answer 43

Hypothyroid children retain infantile proportions, whereas children deficient in GH are proportionally normal, just small

Question 44

WHat sort of diet provides the correct nutrition for growth?

Answer 44

Adequate diet in terms of protein content and essential vitamins and minerals is just as important as enough calories Important in utero and during development

Question 45

How does injury or disease affect growth? and what happens after the injury or disease?

Answer 45

Injury and disease stunt growth because it causes increased ­protein catabolism (glucocorticoid effects) period of catch up where the child returns to normal height

Question 46

hwo do genetic factors affect growth?

Answer 46

Helps determine maximum growth Interaction between genetic factors and nutrition

Question 47

In humans there are 2 periods of rapid growth, what are they?

Answer 47

infancy puberty

Question 48

What rapid growth occurs in infancy?

Answer 48

amazing growth spurts 2.5cm in a few days and then nothing i.e. episodic, mechanism not known

Question 49

what rapid growth occurs in puberty?

Answer 49

due to androgens and oestrogens, produce spikes in GH secretion that increased­ IGF-I which leads to increased 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 50

what is the usual cause of GH hypersecretion?

Answer 50

tumours

Question 51

what things can hypersecretion of GH cause?

Answer 51

Gigantism Acromegaly

Question 52

how is gigantism caused?

Answer 52

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

Question 53

how is agromegaly caused?

Answer 53

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 and the characteristic features are enlarged hands and feet. In adults feet should NOT get bigger = classic sign of ACROMEGALY

Question 54

how do you treat hypersecretion of GH?

Answer 54

Surgery to remove tumour or somatostatin analogues to treat

Question 55

what would the body be like of someone with acromegaly?

Answer 55

normal neight but enlarged hands and feet and facial features

Question 56

Basic science to think about in understanding reduced growth Dwarfism may be due to what?

Answer 56

1. A deficiency of GHRH. In this case GH response to administered GHRH may be normal. (Hypothalamic in origin) 2. GH secreting cells may be abnormal. So less GH will be produced in response to GHRH. (Pituitary in origin) 3. End organ is unresponsive to GH (Laron Dwarfism). Individuals may have increased­ [GH] in plasma. Defective GH receptor prevents IGF-1 release and peripheral tissues cannot respond to growth signal. Loss of IGF-1 inhibition of GH responsible for ­increased [GH] (remember negative feedback loop!) 4. Genetic mutations. Pygmies have a genetic mutation that impairs the ability of cells to produce IGF-I in response to GH 5. Precocious puberty. XS GnRH release stimulates puberty via promoting sex hormone release. These children have stunted growth because long bones fuse early under influence of sex hormones 6. Hypothyroid dwarfism – children retain infantile features with stunted growth due to loss of permissive effect of TH on GH. Impact may be moderated by early detection and supplementation with TH. Compare with congenital hypothyroidism (hypothyroid in utero)