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MSc Endocrinology > Growth And Growth Disorders > Flashcards

Growth And Growth Disorders Flashcards

1
Q

What are the phases of Growth?

A
  • Prenatal Growth
  • Postnatal Growth
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2
Q

What are the periods of Prenatal Growth?

A

Embryonic growth

  • Occurring in the 1st 8 weeks after conception and the chief time for organogenesis

Foetal growth

  • Occurs from 8 weeks to birth
  • At the end of 1st trimester, 14 grams, at the end of the 2nd 600 grams and at the end of 3rd trimester, 2600-3700 grams
  • The 3rd trimester is period of most rapid growth
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3
Q

What are the periods of Postnatal Growth?

A

Infantile Growth (Last from birth to 2 years)

  • Immediately after birth an infant loses 5-10% of birth weight
  • Weight starts to be gained by around 2 weeks
  • Rapid but decelerating stage of growth
  • Nutrition dependent stage. Half the adult height is reached by around 2 years of age so nutrition is very important for growth

Midchildhood Growth

  • 2 years to pubertal growth spurt
  • Relatively constant growth with increase in height around 5 cm per year
  • Growth hormone dependent

Pubertal growth

  • Rapid acceleration in growth to a peak of 10 cm per year
  • Puberty starts around age 10-11 in girls, 11-12 in boys
  • Around 4 years duration
  • Growth ends when the epiphyses fuse. Pubertal growth is gonadal steroid and growth hormone dependent
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4
Q

What is the benefit of Growth Charts?

A
  • Height and weight are monitored using growth charts
  • Different charts are used depending on age and sex, and specialised ones are available to monitor children born prematurely
  • Centile lines are on the charts, with the 3rd and 97th centiles encompassing ± 2SD from the mean
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5
Q

What determines target heights?

A
  • Genetic factors are important determinants of growth and height potential. It is important to look at parental height when assessing the growth of a child
  • Predicted adult height is the mean parental height with the addition of 6.5 cm for boys and the subtraction of 6.5 cm for girls.
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6
Q

What is Growth Hormone?

A
  • Single chain polypeptide homone with 191 amino acids Synthesised, secreted and stored by somatotroph cells
  • Circulating GH molecules are heterogenous 22kDa form is the major physiological GH, accounting for 75% of pituitary GH secretion
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7
Q

How are the different molecules of growth hormone differing?

A
  • Amino acids 32-46 are deleted by alternative splicing to yield the 20kDa form, which is ~10% of pituitary GH.
  • This has slower clearance than the 22 KDa form.
  • The 20 kDa form has diabetogenic effects, which are lacking in the 22 kDa form.
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8
Q

Describe the Hypothalamic-Pituitary-Growth hormone axis

A

Stimualtion of GH

  • GH secretion is stimulated by GHRH from hypothalamus
  • Ghrelin is produced by the stomach causes GH release by direct action on the pituitary & stimulating GHRH release

Inhibition of GH

  • Inhibited by somatostatin, both secreted by the hypothalamus
  • IGF-1 acts on the pituitary gland to inhibit GH secretion as part of a negative feedback loop, and IGF-1 and GH stimulate production of somatostatin by the hypothalamus in a negative feedback loop. GH induces IGF-1 production by the liver & extra-hepatic tissues
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9
Q

What are factors affecting GH secretion?

A

Increased secretion

  • Exercise
  • Physical stress
  • Trauma
  • Hypovolaemic shock
  • Infusion of single amino acids e.g. arginine
  • Gonadal steroid responsible for rise in GH secretion in puberty

Decreased secretion

  • Emotional deprivation
  • Hyperglycaemia
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10
Q

How is Growth Hormone secreted?

A
  • Growth hormone is secreted in a pulsatile manner
  • Major GH pulses occur during the 1st episode of slow wave sleep. These pulses account for 70% of daily GH secretion
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11
Q

What is the mechanism of binding of Growth hormone?

A
  • GH complexes with 2 GH receptor components
  • This causes receptor dimerisation which is critical for signalling which occurs via the JAK/STAT phosphorylation cascade
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12
Q

What are the functions of Growth Hormone?

A

Epiphyseal growth

  • Stimulation of osteoclast differentiation and activity
  • Stimulation of osteoblast activity
  • Increase of bone mass by endochondral bone formation

Adipose tissue

  • Acute insulin-like effects
  • Increased lipolysis
  • Inhibition of lipoprotein lipase
  • Stimulation of hormone sensitive lipase
  • Decreased glucose transport
  • Decreased lipogenesis

Muscle

  • Increased amino acid transport
  • Increased nitrogen retention
  • Increased energy expenditure
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13
Q

What is the structure of IGF-1?

A
  • Many of the anabolic and mitogenic actions of growth hormone are mediated through IGF-1
  • IGF-1 is a 70 amino acid basic peptide consisting of A and B chains joined by disulphide bonds. The connecting C peptide region is 12 amino acids long and has no homology with the C peptide region of pro-insulin
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14
Q

What is the mechanism of action of IGF-1?

A
  • Growth hormone is the primary regulator of IGF-1 gene transcription
  • IGF-1 can bind to the insulin receptor and to IGF receptors.
  • Mitogenic & metabolic effects of IGF-1 occur through binding of IGF-1 to the type I IGF receptor.
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15
Q

What causes rise in IGF-1 during puberty?

A

Rise in IGF-1 in puberty is due to the pubertal rise in GH secretion and also to a direct effect of the gonadal steroids

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16
Q

How is IGF-1 circulated in blood?

A
  • IGF-1 circulates in plasma complexed to IGF binding proteins that extend the serum half life of IGF-1, transport it to target cells & modulate its interaction with surface membrane receptors
  • In adult serum, 75-80% of IGF-1 is carried in a ternary complex consisting of one molecule of IGF-1, one of IGFBP3 plus one of an 88 kDa protein called the Acid Labile Subunit
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17
Q

How are growth abnormailities assessed in the first instance?

A
  • Monitor growth velocity. Height should be measured on two occasions 6 months apart to minimise measurement error
  • The height should be plotted on a growth chart.
  • A child growing along a centile line has normal growth velocity

Genetic short stature – appropriate height for height of parents

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18
Q

What are primary growth disorders?

A
  • Turner’s syndrome 45 XO
  • Down’s syndrome Trisomy 21
  • 18q deletions
  • Osteochondrodysplasias (Genetic transmission, Abnormalities in size & shape of bones of limbs, spine &/or skull, Radiological abnormalities of bones)
  • Intrauterine growth retardation (IUGR). These are small for gestational age infants. The earlier in gestation that foetal growth is impaired, the less likely it is that complete recapture of lost growth will occur
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19
Q

What are causes of IUGR?

A

Maternal & placental factors

  • Maternal nutrition
  • Maternal drug/alcohol use
  • Placental damage

Intrinsic foetal factors

  • Russell-Silver syndrome: Slow growth, head growth normal
  • Noonan’s syndrome: Congenital heart defects and short stature
  • Cockayne’s syndrome: Short stature, premature ageing appearance
  • Progeria: Slow growth, rapid ageing
  • Prader-Willi syndrome: Constant hunger, restricted growth, learning difficulties
20
Q

What are secondary growth disorders?

A
  • Emotional deprivation
  • Malnutrition (Marasmus is overall calorie deficiency, Kwashikor is inadequate protein intake)
  • IGF-1 concentrations are reduced. GH normal or raised in Kwashikor, normal or low in marasmus
  • Chronic disease – often related to poor food intake, malabsorption &/or increased metabolic rate. It is important to identify these causes to differentiate from Growth Hormone disorders.
  • Endocrine disorders
21
Q

What are chronic diseases that causes secondary growth disorders?

A
  • Poorly controlled diabetes mellitus
  • Pulmonary disease
  • Chronic liver disease
  • Renal disease
  • Chronic inflammtion & infection
  • Inborn errors of metabolism (glycogen storage disorders, mucopolysaccharidoses, mucolipidoses)
  • Cardiovascular disease
  • Malabsorption and GI disease
  • Chronic anaemias
22
Q

What are endocrine disorders leading to secondary growth disorders?

A
  • Cushing’s syndrome - glucocorticoid excess impairs skeletal growth, inhibits osteoblastic activity & enhances bone resorption
  • IGF-1 deficiency
  • Hypothyroidism
  • GH deficiency
  • Rickets
  • Constitutional delay puberty
  • Pseudohypoparathyroidism type 1a
23
Q

What is Constituitional Delay in puberty?

A
  • Late pubertal growth spurt so short compared to peers
  • Usually boys, often a family history
  • Can be diagnosed by comparing chronological age to bone age determined from X-ray of hand and wrist
  • Chronological age greater than bone age in these patients
  • Onset of puberty can be accelerated by giving testosterone but this will result in reduced height potential
24
Q

What are causes of growth hormone deficiency?

A
  • Congenital abnormalities of Hypothalamus
  • Tumours involving hypothalamus or pituitary gland
  • Radiation treatment to brain
  • Inflammation of brain/hypothalamus
  • Trauma
  • Genetic abnormalities of GH production
  • GHRH/GHRH receptor defects
25
Q

What are symptoms of Growth hormone deficiency?

A
  • Short stature
  • Decreased height velocity
  • Increased skin folds
  • Delayed bone age
  • Mid face crowding
  • Hypoglycaemia & fits
  • Infantile genitalia
  • Delayed dentition
  • Prolonged jaundice
26
Q

What are causes of IGF-1 Deficiency?

A

Often caused by GH deficiency

May be due to GH insensitivity

  • GH receptor abnormalities
  • Post receptor abnormalities of GH signal transduction
  • Primary defects of IGF-1 biosynthesis

Secondary causes include antibodies to GH or GH receptor.

27
Q

What are physiological tests for Growth Hormone?

A

Exercise Test

  • GH secretion increases during exercise
  • Patient is exercised vigorously for at least 15 minutes with a heart rate of >150 bpm
  • Samples for GH taken before exercise & 10 minutes post exercise
  • Normal response is GH >6.5 µg/L
  • Subnormal response seen in 20% of normal children so further testing required if patient fails test

Sleep studies

  • GH is released during slow wave sleep
  • GH sampling at l5 x 2 minute intervals during sleep
  • Well accepted by children but heavy on manpower
28
Q

What are pharmacological tests of Growth Hormone?

A
  • Insulin tolerance test
  • Glucagon Stimulation test
  • Clonidine Stimulation test: Give 0.15mg/m2 of clonidine orally and take samples of growth hormone at 30, 60, 90, 120, 150 180 minutes
  • Arginine Stimulation test: Give 0.5g/kg of Arginine to a maximum of 30g in 100ml over 30 minutes and take samples of growth hormone at 30, 60, 90, 120, 150 minutes
29
Q

What is the expected results of Clonidine and Arginine Stimulation test and what has to be done in pre-pubertal children?

A

Normal increase in GH to peak GH >6.5 µg/L

Give sex steroid priming in children over 10 years of age

  • Male 100 mg testosterone i.m. 4 days before test
  • Female 200 µg ethinyl oestradiol orally for the 3 days prior to the test
30
Q

How is GH deficiency treated in children?

A
  • Growth hormone replacement given to children shown to be deficient. This is given subcutaneously in daily doses
  • Recombinant IGF-1 can be given to patients with GH insensitivity
  • If isolated GH deficiency diagnosed as a child, GH treatment is stopped for 2-3 months once growth is <2 cm/year, and the GH axis is again tested.
  • If deficiency still present, GH is continued until age 25, then patient assessed as adult & adult criteria apply
  • If GH deficiency diagnosed age 18-25, GH replacement is given up to age 25 to optimise peak bone mass, then patient is assessed on adult criteria
31
Q

What are the effects of GH deficiency in adults?

A
  • Increased cardiovascular risk
  • Depression & Anxiety
  • Unfavourable lipid profile (raised LDL specifically)
  • Sexual dysfunction
  • Fatigue
  • Osteopenia/Osteoporosis
  • Increased vescral fat
  • Decreased exercise tolerance & muscle mass
32
Q

How is GH deficiency treated in adults?

A
  • Growth hormone replacement is not automatically given to adults with growth hormone deficiency
  • NICE recommend replacement in patients with an increase of 9 mU/L (3 µg/L) or less in ITT or similar test PLUS impaired quality of life judged by scoring 11 or above in the Quality of life assessment of growth hormone deficiency in adults questionnaire (QoL-AGHDA)
  • The QoL score must improve by at least 7 points after 9 months of treatment for patients to continue receiving replacement therapy.
33
Q

What is Growth hormone excess known as?

A
  • Gigantism in children: Should be considered in children >3SD above normal mean height for age or >2SD above adjusted mean parental height
  • Acromegaly in adults
34
Q

What are chromosomal abnormalities that can lead to tall stature?

A

Klinefelter’s Syndrome

  • XXY
  • Male with tall stature

Marfan’s Syndrome

  • Defect in FBN1 gene which encodes fibrillin-1, a connective tissue protein
35
Q

What causes Acromegaly?

A

Growth hormone excess that occurs after epiphyses fuse does not cause an increase in height. There is a coarsening of features:

  • Hands, feet, head may increase in size
  • Patient may develop diabetes
  • There may be headaches & paraesthesias
36
Q

What are consequences of Acromegaly?

A
  • 50% of patients die before 60 years of age
  • CVD is biggest causes of death (Cardiomyopathy & increased size of left ventricle, Hypertension, arrhythmias, ischaemic heart disease)
  • Headache
  • Visual field loss
  • Respiratory problems (Kyphosis, Obstructive sleep apnoea)
  • Stroke
  • Type II diabetes, IGT
  • Hyperlipidaemia
37
Q

How is Growth hormone excess diagnosed?

A
  • Baseline GH cannot exclude GH excess as elevated GH may occur with stress & low values are seen in up to 8% of acromegalic patients
  • OGTT is carried out in non-diabetic patients as hyperglycaemia suppresses GH in normal patients
  • OGTT may be unnecessary in diabetic patients if GH measured when patient hyperglycaemic
38
Q

How is OGTT carried out in diagnosis of GH excess?

A

Patient should fast for 10-16 hours prior to test

  • Give patient 75g anhydrous glucose in 250-300 mL of water to be drunk over 5 minutes at the beginning
  • Take samples of growth hormones and glucose at 0, 30, 60, 90 and 120 minutes
39
Q

How is the OGTT test for GH excess interpreted?

A
  • Normal subjects suppress GH to < 1 µg/L during the test
  • There is no suppression in GH excess & there may be a paradoxical rise in GH
40
Q

What are the problems with diagnosis of GH excess?

A
  • Marked variability in GH assays
  • Many different assays available & the variability in GH measured can exceed 200%, making it difficult to apply international consensus guidelines to local results
  • Some acromegalic patients suppress GH on OGTT making diagnosis very difficult. This may in part be explained by the poor performance of GH immunoassays.
41
Q

How does IGF-1 in GH excess?

A
  • IGF-1 levels have been shown to be determined by baseline (spontaneous nadir) GH levels
  • In acromegalic patients who suppress GH on OGTT, raised IGF-1 levels may be the only way of making a diagnosis
  • IGF-1 concentrations are used to monitor treatment of acromegaly, & are considered more useful than GH for this.
  • However, there is variability in IGF-1 assays as well as GH assays, which may be a problem if patients are being monitored in more than one centre
42
Q

How is GH excess treated?

A
  • Surgery
  • Radiotherapy
  • Medical Therapy
43
Q

How is Surgery for GH excess carried out?

A
  • 75-80% of tumours are macroadeonomas at diagnosis which are more amenable to surgery than microadenomas
  • Surgery is generally the first-line treatment
  • The transphenoidal route is most often used to remove tumours that are considered operable
44
Q

How is Radiotherapy for GH excess carried out?

A
  • Generally external radiotherapy centred on the tumour
  • This causes variable degrees of anterior pituitary dysfunction in 80-100% of patients after 10-15 years
  • More highly focussed irradiation e.g. gamma-knife radiotherapy may be used in some centres to avoid this
45
Q

What is medical treatment of GH excess?

A

Somatostatin analogues

  • Suppress GH secretion by binding to somatostatin receptors on somatotrope adenoma cells
  • Octreotide is injected by the patient 2-3 x per day. A slow release version is now available for i.m. injection once a month
  • Lanreotide is a slow release preparation for deep subcutaneous injection every 28 days
  • These drugs normalise IGF-1 in 50-80% of patients & reduce tumour volume in 20-70% of patients
  • The treatment must be continued indefinitely
  • Side effects include gallstones

GH receptor antagonist

  • Pegvisomant is the only GH receptor antagonist currently available. Blocks the effects of GH on target organs by binding to GH receptors & preventing their dimerisation thus blocking signal transduction
  • It is given daily s.c. at a dose of 10, 15 or 20 mg, with the dose being increased until IGF-1 concentrations have normalised. Normalisation occurs in 90% of patients
  • Treatment is reserved for patients in whom somatostatin analogues have failed. A small number of cases of raised transaminases have been reported

MSc Endocrinology (16 decks)

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