Normal Growth and Clinical Aspects Flashcards
growth is regulated by a number of factors
what are they?
- 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
- Thyroid hormones
- I nsulin
- Sex steroids (esp. at puberty) - more growth around puberty
- Availability of nutrients - nutrients provide substrates for growth
- Stress - Stress has a complicated effect on growth – increased release of GH but also cortisol which is catabolic so breaks down things
- Genetics
What type of hormone is GH?
Where is it release and by what cells?
What is it also known as?
GH is a peptide hormone
released from the anterior pituitary
Aka somatotropin
Released from somatotroph cells (“troph” relating to growth)
What is the release of GH controlled by?
GH release is controlled via the release of two hypothalamic neurohormones with opposing action
GH release is controlled via the release of two hypothalamic neurohormones with opposing action
what are they?
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
GH has a wide spectrum of biological activity that can be definied by two broad categories:
what are they?
- Growth and development (indirect action) - Stimulates another hormone that causes elongation of long bones
- Regulation of metabolism (direct action) - direct action on regulating metabolism and influences metabolism of cells
What recpetors do GH bind to?
Binds to tyrosine receptor like insulin, switches intracellular proteins on and off
When does GH affect growth and development of a child?
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
what does GH require in order to cause growth and development?
GH requires permissive action of thyroid hormones and insulin before it will stimulate growth
How does hypothyroidism, or poorly controlled diabetes affect the growth of a child?
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
Does GH secretion happen in adults, if so why?
GH secretion continues throughout adult life as it is continues to be essential in the maintenance and repair of tissue
What effect does GH have on cells allowing growth?
Growth-promoting effect of GH is mediated through stimulation of both cell size (hypertrophy) and cell division (hyperplasia) in its many target tissues
The effect of GH on growth is almost entirely ________
indirect
The effect of GH on growth is almost entirely indirect, so how is growth achieved?
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
IGF-1 has structure very similar to _________
pro-insulin
What receptors doe IGF-1 bind to and what effects does it cause?
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
WHat secretes IGF-1, when is it released and what is its effect on 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.
What is IGF-II
IGF-II also exists but it’s functional importance appears to limited to the foetus and neonate
How is GH and IGF-1 transported in the blood?
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
What is the benefit of GH and IGF-1 being boudn to carrier proteins in the blood
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
How does IGF cause engative feedback on GH?
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
why does GH increase BG
as it blocks insulin
What are the effects of GH/IGF-I on bone growth?
- 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)
- 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
When does longitudinal bone growth end?
Epiphyseal plates close during adolescence under the influence of sex steroid hormones then no further longitudinal growth is possible
how does GH cause regulation of metabolism (direct effects of GH)?
- 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 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, how does GH affect metabolism?
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)
what is th eonly thing to increase glucose uptake?
insulin
__, like insulin and glucagon, has significant impact on ________ ____________
GH, like insulin and glucagon, has significant impact on glucose metabolism
In short, what are the direct effects of GH?
- 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
Where is GH secreted from? and at what age?
Large quantities of GH are present in pituitaries of both adults and children, with highest rates of secretion occurring in teenage years
when throughout the day is GH released?
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
what is this image showing?
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
contorl of GH secretion is heavily influenced by what?
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
What stimuli increase GHRH secretion (increased GH)?
- 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.
- Increased amounts of amino acids in the plasma, eg protein meal. GH promotes amino acid transport and protein synthesis by muscle and liver.
- Physical stress and illness although growth may actually be stunted due to catabolic action of cortisol
- Delta sleep. increase in GH in delta sleep may be related to growth spurts in children and adolescents and tissue repair in adults.
- Oestrogen and testosterone stimulate GH release from the pituitary directly as well as decreasing IGF mediated negative feedback. Responsible for growth spurt in puberty.
What stimuli increase GHIH (Somatostatin secretion) (decrease GH)?
- Glucose
- FFA
- REM sleep (Subjects deprived of REM sleep have increased GH secretion)
- Cortisol (although inhibitory effect on growth may be more to do with increased protein catabolism than stimulating GHIH release)
The physiology of growth is a very complex phenomenon and is affected by what 3 factors?
- hormones
- nutrition
- genetics
what hormones are important for growth?
GH, IGF-I, thyroid hormones, sex steroids, glucocorticoids and insulin
How does the influence of different hormones change throughout life?
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
WHat develops growth of the brain and what heepsn if it isnt present?
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
Thyroid hormones are essential for normal growth, particularly important for development of the ________ ____________ in utero and early childhood
nervous system
How does thyroid hormone effect GH/IGF-I?
Effects are permissive to GH/IGF-I
What is congenital hypothyroidism and what effects does it have?
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
describe child growth in this picture
Hypothyroid children retain infantile proportions, whereas children deficient in GH are proportionally normal, just small
WHat sort of diet provides the correct nutrition for growth?
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
How does injury or disease affect growth? and what happens after the injury or disease?
Injury and disease stunt growth because it causes increased protein catabolism (glucocorticoid effects)
period of catch up where the child returns to normal height
hwo do genetic factors affect growth?
Helps determine maximum growth
Interaction between genetic factors and nutrition
In humans there are 2 periods of rapid growth, what are they?
infancy
puberty
What rapid growth occurs in infancy?
amazing growth spurts 2.5cm in a few days and then nothing i.e. episodic, mechanism not known
what rapid growth occurs in puberty?
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
what is the usual cause of GH hypersecretion?
tumours
what things can hypersecretion of GH cause?
Gigantism
Acromegaly
how is gigantism caused?
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
how is agromegaly caused?
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
how do you treat hypersecretion of GH?
Surgery to remove tumour or somatostatin analogues to treat
what would the body be like of someone with acromegaly?
normal neight but enlarged hands and feet and facial features
Basic science to think about in understanding reduced growth
Dwarfism may be due to what?
- A deficiency of GHRH. In this case GH response to administered GHRH may be normal. (Hypothalamic in origin)
- GH secreting cells may be abnormal. So less GH will be produced in response to GHRH. (Pituitary in origin)
- 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!)
- Genetic mutations. Pygmies have a genetic mutation that impairs the ability of cells to produce IGF-I in response to GH
- 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
- 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)
