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GH axis Flashcards

1
Q

What regulates GH secretion?

A
  • ghrelin - somatostatin When hungry GH released as GH makes glucose stay in blood
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2
Q

How is GH released?

A
  • stored and released from preformed granules in AP
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3
Q

What is the structure of GH?

A
  • single chain protein - 2 disulphides binds 2 forms: - 22kD (major) - 20kD (minor) Half life = 15 mins (activity) Similar to prolactin
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4
Q

What regulates the secretion of GH?

A
  • GH acts on Gs receptors on somatotrophs to activate adenyl cyclase and PKA - somatostatin acts on Gi receptors on somatotrophs to inhibit adenyl cyclase - inhibits release of GH rather than accumulation
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5
Q

What is the internal signalling cascade for GH?

A
  • GHRH binds to Gs receptor - activates adenyl cyclase - which makes cAMP - which makes PKA - PKA phosphorylates CREB - CREB causes FOS to bind upstream of gene - Causes PT1 which is a transcription factor to bind to gene and cause transcription of GH - without PT1 there may be no GH production e.g if PT1 is mutated
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6
Q

What stimulates GH release?

A
    • androgens - oestrogens Sensitise somatotrophs to GHRH - accounts for pubertal rise in GH and the growth spurt 2. amino acid such as arginine will stimulate GH release - when starving we break down proteins and GH detects to keep glucose in blood 3. Thyroid hormones NB. Glucose, cortisol and free fatty acids surprise GH release
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7
Q

How does the growth hormone receptors work?

A
  • Hormone binding on two binding sites realigns the subunits by rotation - the catalytic domains of the associated tyrosine protein kinase JAK2 are then juxtaposed (there is a signal to keep the two receptor molecules together) - activated JAK2 phosphorylates the GHR on tyrosine residues - this recruits members of the signal transfer and activator of transcription (STAT) - STAT dimerisation and translocation to the nucleus to modulate target gene transcription such as IGF-1 and SOCS (suppressor of cytokines signalling) - SOCS is turned on when receptor has been for a set period of time and terminate the GH signalling cascade
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8
Q

What is Laron syndrome?

A
  • insensitivity to GH (normal circulating GH but no biological activity) - mutations in GHR
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9
Q

How does GH cause insulin resistance?

A
  • GH increases free fatty acids flux from adipose tissue which can impair insulin action - Excessive SOCS1 and SOCS3 associated with insulin resistance and down regulation of insulin signalling
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10
Q

What is the human GH gene family?

A
  • located on chromosome 17 1. GH-N expresses preferentially in somatotropes of anterior pituitary 2. GH-V and CS genes expressed in synctiotrophoblasts of placenta 3. HS I and II = pituitary specific 4. HS IV = placenta specific 5. HS III and V = pituitary and placenta
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11
Q

What are the two receptors that respond to GH?

A
  1. Lactogenic receptors 2. Somatogenic
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12
Q

What are the physiological actions of GH?

A
  1. Decrease glucose metabolism - opposing insulin 2. Increases lipolysis 3. Increases protein synthesis (anabolic) 4. Increases milk yield in cows 5. Increases IGF production from liver 6. Increases chondrocyte and cartilage formation 7. Post natal growth promotion 8. Clonal expansion of chondrocytes - causing long bones to increase in length 9. Growth of bones, soft tissue and viscera
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13
Q

What does IGF1 act on?

A
  • via insulin like receptors - aka somatomedin C - like proinsulin + red tail
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14
Q

How does GH affect fibroblasts?

A
  1. transforms fibroblasts within connective tissue to differentiate into chrondocytes - IGF1 increase no. of chondrocytes which increases length in bones 2. also produces differentiation of osteoblasts 3. increase fat cells that help nurture osteoblasts
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15
Q

How does GH affect the growth plate?

A
  1. GH acts on fibroblasts at the top to convert them into chondrocytes
  2. IGF1 released by GH makes the chondrocytes clonally expand
  3. Below this layer there is calcifying cartilage
  4. Below the calcifying cartilage there is another fibroblast layer on which GH, IGF1 and FGF act to cause the fibroblasts to differentiate into ostebloasts and clonally expand them (IGF1
  5. From the osteoblasts you then get osteoid and isolated osteocytes

–> Bone forms in the lower margin so you get extenstion in length

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16
Q

How do you do a bioassay for GH in vivo?

A
  1. Remove pituary from pre-pubertal rat
  2. Inject GH
  3. Remove tibia/cut bone sections
  4. Measure growth plate thickness to see how effective GH is
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17
Q

Why is growth predominantly due to nutrients when young?

A

Because significant GH receptors appear at 7 months of age

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18
Q

What endocrine regulation of growth is there?

A

Thyroid

Adrenal

Parathyroid - regulate calcium levels

Gonadal - make AP more sensitive to GH releasing hormones

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19
Q

What closes the growth plates?

A

Increased androgens in boys

Increased oestrogens in girls

At the end of puberty long bones duse and can no longer gain anymore height

NB. In prepuberty era these increase growth

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20
Q

What is the role of aromatase?

A
  1. Found in the growth plates of BOTH girls and boys
  2. Aromatase converts androgens to oestrogen
  3. Growth plate fusion is dependent on estrogen in both girls and boys
  4. Aromatase inhibitors can be given to prevent growth plate fusion in boys so they can have a greater height potential
  5. NB: not given to girls as would cause masculisation of features
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21
Q

What does immunoassay measure?

A
  • Uses ELISA
  • Large scale routine use
  • Very precise and sensitive
  • Does not measure biological potency directly
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22
Q

What are bioassays?

A
  1. Used to measure potency of new batches of RECOMBINANT GH
  2. Rarely used to check bioactivity of patient GH
  3. Insensitive and imprecise

Method:

  1. hGH receptors/immortlaised target cells on microtitre plate
  2. Measure response of each batch (one plate per batch) using colorimetric/luminescent responses via reporter genes. The higher the response the more colour there
  3. Each batch has a dose response curve and is compared against the international GH standard response
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23
Q

How do you measure height under 2 year olds?

How do you measure height for over 2 year olds?

A
  1. Measure supine height
  2. a. Standing height
    b. Use a stadiometer
    c. Careful positioning
    d. Reproducible (1 CV%)
    e. Repeat regularly
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24
Q

Why do we draw rate graphs rather than actual height?

A
  1. Height graphs give very wobbly line as height constantly changing and we shrink a bit when we get older
  2. In rate graph:
    a. smooths out single measurements
    b. Plateua followed by growth spurt
    c. Falls to zero at end of puberty

NB. Girls start and stop puberty earlier and attain final height earlier than boys

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25
Q

How do you check for bone age/maturation?

A
  1. Use wrist radiographs
  2. Compared epiphyseal growth plate vs age related reference ranges
  3. Cumulative scores for several bones (2% CV)
  4. Difficult with skeletal dysplasias (dwarfism, short stature etc)
26
Q

What are the tanner stages for boys external genitalia?

A

Stage 1: Prepubertal stages

Stage 2: Scrotum skin reddens, changes texture and enlarges along with testes

Stage 3: Penis increases in length, further growth in testes

Stage 4: Penis increases in breadth, scrotum enlarges more, testes enlarges, scrotum skin darker, development of glans

Stage 5: Adult genitalia

27
Q

What are the tanner stages for girls?

A

Stage 1: Prepubertal

Stage 2: Breast bud stage with elevation of breast and papilla, enlargment of areola

Stage 3: Further enlargement of breast and areola, no seperation of their contour

Stage 4: Areola and papilla form a secondary mound above level of breast

Stage 5: Mature stage, projection papilla only, related recession of areola

28
Q

What are the tanner stages for pubic hair?

A

Stage 1: Prepubertal (can see velus hair similar to abdominal wall)

Stage 2: Sparse growth of long, slightly pigmented, straight or curled, at base of penis or along labia

Stage 3: Darker, coarser and more curled hair, spreading sparsely over junction of pubes

Stage 4: Hair adult in type, but covering smaller area than in adult, no spread to medial surface of thighs

Stage 5: Adult in type and quantity

29
Q

What must be considered when comparing height to a population?

A
  1. Appropriate reference population must be used E.g. comparing brown person to white population
  2. Generations change, linked to improved nutrition and economic conditions

E.g. people are becoming are taller

30
Q

What is the standard deviation score and how do you calculate it?

A
  1. Normalised system derived from the position of an individual on the population chart showing height vs age

SD scored = (observed - mean height)

Normal SD scores: -2 to +2

31
Q

At what percentiles should people seek help?

A
  1. Above 87th
  2. Below 3rd
32
Q

How do you measure serum GH?

  1. Immunoassay
  2. Need 0.5ml blood

BUT GH released in pulsatile manner and the most GH is secreted in stage 3/4 of sleep

A
33
Q

What are alternative stimulators in the provocative test?

A
  1. Ghrelin - 1-2hrs
  2. GHRH - response in 15-20mins
  3. Bovril (contains arginine)
  4. Exercise - GH very sensitive to exercise
34
Q

Why do you see a late rise in GH in a GH surpression test?

A
  1. High glucose stimulates insulin which means GH would be induced i.e. a mini-ITT naturally induced at the end of the surpression test

Someone with excess GH will NOT respond to a supression test

35
Q

When does GH secretion naturally decline?

A
  • During and after the 3rd decade
36
Q

What else can be measured to assess growth problems except GH?

A
  1. IGF-1: not widely used and confined to specialist centres
  2. IGF1 binding protein - confined to specialist centres for difficult cases. Research rather than routine.
37
Q

What height augmentation technqiues are there?

A
  1. rhGH
  2. IGF1
  3. Aromatase inhibitors - for children
  4. GnRH agonists (stop oestrogen production) - for children
  5. Anabolic steroids (historical)
38
Q

What are the classic signs and symptomps for idiopathic GH deficiency? What is the treatment?

A
  1. Proportionate growth/normal appearance
  2. Truncal obesity/immature face
  3. Low rate of growth: low SD
  4. No or poor GH response to an ITT provocation test
  5. Nil or feeble peals in 24 hour profile
  6. Low IGF-1

Treatment:

Daily intramuscular rhGH (if enough prepubertal time) - usually at night

V. expensive treatment so different countries have diff cut offs for when a provocative test has failed

39
Q

What are signs and symptoms for Laron syndrome patients? What is the treatment?

A
  1. Rare
  2. Autosomal recessive
  3. Very low SDS/growth velocity
  4. Proportionate growth/immature face (enlargment of forehead, depressed nasal bridge)
  5. Normal GH levels
  6. Low IGF1 - as downstream signalling not happening

Explanation: Mutation in GH receptor or GH hormone itself

Spectrum disorder - depends on mutation/deletion site

Test: Test binding of GH to GHBP (= extracellula domain of receptor but in circulation :. gene transcribed twice)

Most severe: no binding

Less severe: reduced binding affinity

Treatment: rhGH not effective (as resistant)

Trials with IGF1 - but may cause hypoglycemia and aged appearance

40
Q

What can a partial deletion in gene for IGF-1 cause?

A
  1. Usually lethal to embryo when full deletion
  2. Severe intrauterine growth retardation
  3. Post-natal growth failure
  4. Sensorineural deafness/mental retardation/GH resistance

Treatment: mainly managing symptoms as cannot do anything about GH

41
Q

What are the signs and symptoms of achondroplasia?

A
  1. Disproportionate growth failure
  2. Short limbs and fingers/toies with trident hands
  3. Normal GH
  4. No response to GH treatment
  5. Large head with prominent forehead frontal bossing
  6. Small midface with flattened nasal bridge
  7. Spinal kyphosis or lordosis
  8. Varus (bowleg) or valgus (knock knee)

Cause: Mutation in FGFR3 gene, dominant allele, 80-90% spontaneous, homozygous affected dies shortly before or after birth

NB. There is nothing wrong with GH

Complications: ear infections (eustachian tube blockages), sleep apnea (central or obstructive), hydrocephalus and spinal compression

Extra info on mutation: Two FGFR3 mutations identified, both occur at nucleotide 1138 of cDNA sequence and result in glycing or arginine substitution at codon 380

Mutations: A to G transition (97% patients)

G to C transversion

Treatment: Alleviate symptoms

Phase 1 started 2012 C-Natiuretic peptid

Phase 2 2016

42
Q

What are the signs and symptoms of hypothyroidism?

A
  1. Shorter limbs
  2. Not achieving full growth potential
  3. GH low
  4. T3/T4 low

–> Low TH means less GH expression and secretion as directly stimulated by thyroid hormone

–> Eary detection and treatment will allow some catchup growth depending on age

43
Q

What are the signs and symtoms of juveline Cushing’s syndrome?

A
  1. Proportionate limbs
  2. Not achieving full growth potential
  3. Truncal obesity
  4. Symptoms of excess cortisol (cortisol surpressed GH secretion and action, also has whole range of negative effects on bone and muscles)
  5. GH low

Treatment: find cause of excess cortisol (adrenal or pituatary tumour) and normalise cortisol levels and catch up growth will occur

44
Q

What are the signs and symptoms pseudoparathyroidism?

A
  1. Proportionate limbs
  2. Not achieving full growth potential
  3. Round face
  4. Short 4th metacarpal
  5. High PTH but resistance to PTH (so GH will not help these people)
  6. Normal GH (but looks like they have low GH)

Treatment: Managing calcium and phosphate of body through other sources can help

45
Q

Signs and symptoms of turner’s syndrome?

A
  1. Short stature
  2. Webbed neck
  3. GH not affected but genetic abnormality do reduce GH output so do respond to GH treatment
46
Q

What is precocious puberty?

A
  1. Going into puberty earlier than expected
  2. Early sexual maturity
  3. Initially rapid growth
  4. But growth stops early
  5. Premature epiphyseal fusion

–> Associated with derangement in gonads, excess production of androgens and oestrogen causing premature epiphyseal fusion, delaying puberty will allow them to grow for longer

47
Q

What is delayed puberty?

A
  1. Puberty after 15 years - common
  2. More males than females
  3. Growth slows around 10 years of age
  4. Height falls below 3rd centile
  5. Bone age delayed by 2 years
  6. LH/FSH low
  7. GH normal
  8. Catch-up growth occurs
  9. Once grow through puberty reach full growth potential
48
Q

How do you treat delayed puberty?

A
  1. OXANDROLONE - anabolic steroid
  • weak androgen
  • cannot be aromatised to oeastrogen
  • stimulates growth of boys with pubertal delay
  • increases natural GH
  • lower doses used for girls
49
Q

Why does anorexia nervosa prevent growth?

A
  1. Hypothalamic turn off
  • Low GnRH release
  • Fasting GH and cortisol raised
  • Hormones are there but need GnRH signal
  • Need to reach a certain weight before body believes it is ready to start growing
50
Q

What is intrauterine growth retardation?

A
  1. Low birth weight
  • Placental insuffiency - poor blood flow and nutrition
  • Poor catch up growht
  • Treatment: rhGH –> will not grow normally otherwise
51
Q

How can cranial irradation cause low weight?

A

E.g. for leukemias or brain tumours

  • Pituitary particularly sensitive to radiation
  • Low GH
52
Q

How do chronic ilnesses prevent growth?

A
  1. Congenital heart disease
  2. Chronic obstructive or infective pulmonary disease
  3. Chronic renal failure
    * All affect the thriving of a child - need to look at underlying condition and not GH
53
Q

How does psychological deprivation prevent growth?

A
  1. Emotional and social upheaval
  • Hypothalamic turn off
  • Lack of GnRH and GHRH due to this
54
Q

How does excessive GH secretion cause delayed puberty?

A
  1. Compromised pituitary function due to somatotophic compression of other pituitary cells such as GnRH in restricted area of sella turcica giving reductions in other pituitary functions
  • Gigantism normally due to benign tumour of somatotropds
  • Autonomous, unregulated, non-pulsatile GH secretion
  • Most common pituary tumours in order (poor prognosis if untreated):
  1. PRL
  2. ACTH
  3. GH
  • LH, FSH, TSH very rare
55
Q

How would you remove a pituitary tumour?

A

Transphenoidal route

  • Sometimes surgery is successful if the normal but compressed pituitary tissue has been preserved
  • If not = difficulties in growth, development and sexual maturation may persist - careful replacement therapy needed for life
56
Q

What are the signs and symptoms of acromegaly?

A
  1. Pituitary tumours in 25% - usually stain for prolactin
  2. Raised GH causes raised IGF1
  • Proliferation of bone, cartilage and soft tissues and increase in size of other organs
  • Enlarged hands and feet, jaw protrusion and dental malocclusion
  • Raised GH opposes insulin
  • Increased risk of diabetes mellitus with associated symptomps
  • Also neural patholgy: increased size of bone –> carpal tunnel syndrome
57
Q

What are the treatments for acromegaly?

A
  1. Somatostatin analogue (octeotride)
  2. Dopamine analogue (bromocriptine)
  3. Mutated GH which prevents the receptor from dimerising/activating (modification of site 2 not 1 as site 1 would cause more binding)
58
Q

Treatment for acromegaly?

A
  1. Surgery: transphenoidal route duided by MRI scan or transfrontal if tumour is large
  2. Radiotherapy: conventional supervoltage: slow effect in tumour reduction –> often results in eventual hypothyroidism
59
Q

What can cause a pituitary tumour?

A
  • Promoted by hormones and growth factors implicated in pituitary development (rarely associated with oncogenes and TSGs)
60
Q

When would you use growth hormone?

A

In children:

  • Growth hormone deficiencyi n children
  • Growth hormone use following cranial irradiation
  • Small for gestational age(SGA)
  • Growth delay in children with chronic renal failure
  • Turner Syndrome
  • Prader-Willi Syndrome

In adults:

GH deficiency continued into adulthood - GH keeps muscle bulk and increases quality of life

61
Q

What causes growth in foetus?

A

IGF-2

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