Endocrine Control of Growth and Disorders of Growth

Question 1

what is the physiology of growth affected by?

Answer 1

Genetics
Nutrition
Hormones

Question 2

what hormones have an impact on growth?

Answer 2

Growth hormone (& GHRH vs GHIH)
IGF-1
Thyroid hormones
Insulin
Sex Steroids (particularly at puberty)
Cortisol (antagonistic)

Question 3

what are the two periods of rapid growth in humans?

Answer 3

infancy and puberty

Question 4

describe the period of growth in infancy?

Answer 4

Growth in the foetal period and the first 8-10 months of life is largely controlled by nutritional intake thyroid hormones and insulin. Growth Hormone becomes significant from around 10 months

Question 5

describe the period of growth in puberty?

Answer 5

due to androgens and oestrogens, produce spikes in GH secretion that ↑ IGF-I →↑ growth. The same sex steroids also terminate growth by causing the epiphyses of the long bones to fuse.

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 6

different periods of growth are dominated by different hormones, describe their different influences?

Answer 6

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.

Thyroid hormones, insulin and IGF-II dominate intra-uterine growth.

Question 7

why are thyroid hormones essential for growth?

Answer 7

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

Question 8

what is congenitial hypothyroidism?

Answer 8

a condition where babies are born of normal size but are unable to produce their own TH. If left untreated they have retarded growth and development. They retain infantile facial features.

Question 9

what is maternal iodine deficiency?

Answer 9

Maternal iodine deficiency during pregnancy (rare) may result in severely retarded intra-uterine growth.

Question 10

describe the appearance of a hypothyroid child?

Answer 10

Question 11

what is growth hormone?

Answer 11

a peptide hormone released from the anterior pituitary. Aka somatotropin. Released from somatotroph cells (“troph” relating to growth).

Question 12

what is release of growth hormone controlled by?

Answer 12

elease of two hypothalamic neurohormones with opposing action:

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

Growth Hormone Releasing Hormone (GHRH)
The balance of GHRH : GHIH is determined by the composition of factors that impinge on the hypothalamus.

Question 13

when does GH become the dominant influenxe on the rate at wich children grow?

Answer 13

10 months of age

Question 14

what does GH require before stimulating growth?

Answer 14

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 15

does GH secretion contrinue throughout adult life?

Answer 15

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

Question 16

what does GH promote?

Answer 16

an increase in both cell size (hypertrophy) and cell division (hyperplasia) in its many target tissues.

Question 17

what receptors does GH act on?

Answer 17

tyrosine kinase receptors

Question 18

what effect does GH binding to tyosine kinase receptors have?

Answer 18

The resulting phosphorylation of intracellular targets brings about a myriad of effects that can be generalised into two broad actions:

Growth of long bones (indirect action mediated via IGF-I)
Regulation of metabolism (direct action)

Question 19

is the effect of GH on skeletal growth indirect or direct?

Answer 19

The effect of GH on skeletal 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.

Question 20

what is IGF-1?

Answer 20

has “insulin-like” qualities in that it stimulates glucose uptake in muscle, and in bone.

Question 21

what is IGF-1

Answer 21

has “insulin-like” qualities in that it stimulates glucose uptake in muscle, and in bone.

Question 22

when is IGF-1 secreted primarily?

Answer 22

secreted primarily by the liver in response to GH release, and IGF-1 controls GH release through a negative feedback loop.

Question 23

what is the functional importance if IGF-11?

Answer 23

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

Question 24

what type of hormones aare GH and IGF-1?

Answer 24

peptide hormones

Question 25

how are GH and IGF transported?

Answer 25

ike steroid and thyroid 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 26

how does IGF exhibit negative feedback?

Answer 26

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

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

Question 27

when do epiphyseal plates close?

Answer 27

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

Question 28

what are the effects of bone growth?

Answer 28

Question 29

what are the diret effects of GH?

Answer 29

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.

Question 30

when is GH said to be diabetogenic?

Answer 30

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 31

unlike cortisol and just like insulin what does GH do?

Answer 31

Increases amino acid uptake and protein synthesis in almost all cells = anabolic effect (cortisol stimulates protein catabolism).

Question 32

summarise the direct effets of GH?

Answer 32

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

Question 33

when are large quantities of GH present in piuitaries?

Answer 33

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

Majority of GH released during first 2 hours of sleep (deep delta sleep). 20X ↑ 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 34

what stimuli increase GH?

Answer 34

Actual or potential ↓ 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 ↓ in substrate supply. In exercise and in the cold ↑ demand for energy. All stimulate ↑ 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 ↑ 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?

Answer 35

Glucose

FFA

Ageing

Cortisol (although inhibitory effect on growth may be more to do with ↑ protein catabolism than stimulating GHIH release)

Question 36

what are examples of hypersecretion of GH?

Answer 36

gigantism

acromegaly

Question 37

what is gigantism?

Answer 37

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

Question 38

what is acromegaly?

Answer 38

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 39

what is ussually the cause of hypersecretion?

Answer 39

Endocrine tumours usually the cause.

surgery to remove tumour of somatostatin anologues to trest?

Question 40

what can cause hyposecretion?

Answer 40

A deficiency of GHRH. Response to administered GHRH may be normal.(Hypothalamic in origin)

2. A deficiency of GH. Response to administered GH (but not GHRH) may be normal. (Pituitary in origin)
3. Genetic mutations, or under expression, of GH receptor. Depresses downstream release of IGF-1 and peripheral tissues cannot respond to growth signal. Loss of IGF-1 inhibition of GH responsible for ↑ [GH] (remember negative feedback loop!).

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.

Question 41

what are nutritional aspects of growth?

Answer 41

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.
Injury and disease stunt growth because →↑protein catabolism (glucocorticoid effects).
Gestational diabetes can lead to very big babies through xs anabolism by foetal insulin