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Growth

  • Complex process
  • Involves hyperplasia and hypertrophy
  • Requires protein accretion (laying down protein)
  • Individual increases in length and size.
    • Not just putting on weight - that is getting fat or putting on water
  • Accompanied by an orderly sequence of maturational changes
    • Puberty (see later lecture)

Human growth pattern

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  • Lots of growth happening in infancy
  • Then a growth spurt in puberty
  • At the end of puberty, we stop growing in height because the epiphyseal plates in long bones close over (even if you give growth hormones)

Growth varies with tissue type

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  • Shows percentage of growth where we have a linear measurement from 0 (birth) to 100 (20 years) percent
  • Brain and head grow quickly
  • Body and visceral organs fit with the growth pattern shown in the last slide (highest growth in youngsters and puberty
  • Reproductive organs grow mainly in puberty
  • Lymphoid tissue is much larger at age 12 than at age 20

Head circumference

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  • You're born with a relatively big head and relatively small feet
  • Deviations of head circumference can indicate abnormalities

Body proportions

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  • 2 month foetus
    • half its height is its head
    • about 1/4 of height is below the umbilicus
  • Newborn: 45% of length is below the umbilicus
  • Adult: 60% of length is below the umbilicus

Long bone growth

Young long bone (before epiphyseal plate fusion) and mature long bone (after epiphyseal plate fusion)
  • In order to grow in height, the long bones need to grow (in your legs)
  • Bone able to grow has an epiphyseal plate
    • Chondrocytes in epiphyseal plate multiply, lay down extracellular matrix, and this becomes ossified, and the bone grows
  • On the right, we have a bone that can no longer grow - lost the epiphyseal plates (fusion is due to oestrogen)
    • These bones can still change shape and remodel, but they're growing in a radial direction, not in length any more

Bone age

Bone age
  • In children, when worried about development, assess bone age
  • This is assessed by doing an x-ray of the hand
  • Patient B has a more developed bone structure than A (more extra little bits and much less gaps, more evidence of carpal bones)
  • B is a normal 3 year old. A is from a 3 year old with hypothyroidism - bone age is much below normal (look at the epiphyseal centres and the sharpness of the bones). Thyroid hormone is particularly important in helping bones grow

Factors affecting growth

Catch-up growth
  • Genetics
    • Mid parental height, add 6.5 cm, or take off 6.5 cm for females
    • Different nationalities have different heights - the tallest are the Dutch (avg Dutch male is 184)
  • Nutrition
    • Developing nations - the average 4 year old in Sweden is about the same height as the average 6 year old in Bangladesh
    • Can tell the rich kids from the poor kids in developing nations just by height
  • Psychological factors
    • Even if the child has perfectly good nutrition, but being in a stressful/abusive environment can cause hormonal changes that stunt growth - putting the child in a safe environment can restart growth
  • Injury and disease
    • E.g. chronic renal disease
    • "Catch up growth" - after illness, your growth will expedite to "catch up". When sick, your protein is broken down to provide nutrients to help the illness get better
    • Not clear what the mechanisms for catch up growth are
  • Hormones

Relative importance at different ages

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  • Thyroid hormones - very important for growth early on, but then importance drops off
  • Growth hormone is important in all of childhood
  • Androgens and oestrogens are important in puberty

Growth hormone

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  • Promotes growth of almost all tissues of the body that are capable of growing
  • Promotes
    • Increased cell size and mitosis
    • Differentiation of certain types of cells (eg osteoblasts and early muscle cells)

Production and release

  • Produced in somatotrophs in the anterior pituitary.
  • Stored in secretory granules until release.
  • Dominant form is 191 amino acids.
  • Release occurs in bursts throughout the day; especially during sleep - if you don't sleep enough, you won't grow
  • Also increased with exercise, stress, high protein meals, fasting.

Growth hormone levels throughout the day

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Control of release

Control of release involving the hypothalamus, anterior pituitary gland and liver/other organs (that supply IGF-1)
  • Although there is a stimulatory and an inhibitory factor coming from the hypothalamus, the main one is stimulatory (if you section it, then this inhibits growth)
  • Main regulator - GHRH; stimulates release.
  • SS = somatostatin; inhibits release.
  • Ghrelin - comes from the stomach but is also produced in the hypothalamus. It also seems to stimulate growth
  • Growth hormone has some direct effects on tissues and some via IGF-1 (insulin like growth factor) -- feeds back to pituitary and hypothalamus to affect growth hormone levels

Plasma levels

  • Circulates free or bound to binding protein (40%).
  • A large fragment of the extracellular domain of the GH receptor.
  • Levels elevated in newborns.
  • Then average resting levels fall, but spikes are larger especially during puberty (so mean level over 24 h is increased).
  • Mean level is 2-4 ng/ml in normal adults; 5-8 ng/ml in children.

Acute effects of GH

  • Metabolic
    • Decreased glucose uptake by muscle
    • Increased lipolysis in fat
    • Increased gluconeogenesis in liver
    • Insulin resistance (muscle, fat, liver) “Anti-insulin” or “diabetogenic”
    • BUT, GH alone doesn’t make cartilage grow in vitro.
      • The growth promoting effects are mediated via insulin-like growth factors (IGF1 and IGF2)
    • People with excess GH end up with diabetic-related diseases

Insulin-like growth factors (IGFs)

  • Mediate long term effects of GH
  • IGF-I, IGF-II
    • Can cause hypoglycaemia
    • If you put them on fat cells, does similar things to insulin
    • Has similar receptor to insulin receptor
  • Produced in target tissues especially liver
  • Levels relatively stable over 24 h
    • Binding proteins

These are factors that are produced inside the body of animals in response to GH, to cause growth. (Without IGF, growth isn't observed). Levels are relatively stable throughout the day, giving you a better idea of the levels.

Plasma levels of IGF-1

  • Peak in late childhood/puberty, then drop down
  • At puberty, there is lots of IGF1 to help that growth, but in infancy, there is lots of growth without lots of IGF-1. Therefore it isn't as important for growth (it might be that it's IGF-2, or other hormones, but clearly it doesn't seem like IGF-1 is causing it)

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Sex steroids

  • Especially important for growth spurt at puberty.
  • Effects on growth are due to
    • Protein anabolic effects of androgens
    • Increases GH response to stimuli like insulin and arginine
    • Increases plasma IGF-I levels (if GH present)
  • Estrogens ultimately terminate growth by causing fusion of the epiphyses in long bones.
    • Sexual precocity (early puberty) versus castration.
      • People who tend to go into puberty earlier tend to stop growing earlier, but eunuchs end up very tall

Thyroid hormone

Hypothyroidism vs dwarfism in terms of body proportions
  • Permissive role on GH effects
    • Growth in hypophysectomized animals faster with GH + T4 than GH alone.
    • Thyroid hormone and GH are stronger than GH on its own
  • Necessary for normal GH secretion
  • Widespread effects on ossification of cartilage, growth of teeth, contours of face and proportions of the body.
    • Cretins are short with infantile proportions, and mental retardation
  • Important for growth and development of brain

Infantile proportions in hypothyroidism

  • Similar proportions in hypothyroid 8 years old an normal 2 years old
  • Dwarf is small but has upper body/lower body ratios like a normal child (unlike hypothyroid person who has infantile proportions)

Insulin

  • Required for synthesis of proteins
  • If you have either GH or insulin, growth increase is subtle. But together, they have a strong growth period

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Adrenocortical hormone

  • Permissive action on growth
  • Adrenalectomized animals don’t grow well.
  • BUT, glucocorticoids inhibit growth especially in high doses.
    • eg high dose (systemic, not puffer) steroids for asthma

Other growth factors

  • Nerve growth factor (NGF)
  • Fibroblast growth factor
  • Angiogenesis factor
  • Vascular endothelial growth factor (VEGF)
  • Epidermal growth factor (EGF)
  • Hepatocyte growth factor (HGF)


  • Precise role incompletely defined
  • Tend to be tissue specific
  • Mainly act paracrine or autocrine fashion.

Causes of short stature

List is not all-encompassing

  1. Bone/cartilage diseases
    • Achondroplasia
      • Autosomal dominant
      • Mutation in fibroblast growth factor receptor 3
      • Common cause of dwarfism
      • Normal trunk and short limbs. Perfectly normal mental functions
  2. Endocrine disorders
    • Problems in the GH-IGF axis
      • GHRH deficiency
      • GH deficiency
      • GH insensitivity
    • Hypothyroidism - cretinism
    • Precocious puberty
  3. Chromosomal disorders
    • Down syndrome
    • Turner's syndrome
  4. Chronic diseases and malnutrition
  5. No known cause - "constitutional delayed growth"

Down syndrome

Down syndrome is characterised by an epicanthal fold and simian crease
  • 3 copies of chromosome 21
  • Oriental eye has an epicanthal fold, similar to that of patients with Down syndrome
  • They also have a single palmar crease - "Simian crease"
  • Just because you have one of these things doesn't mean you have Down syndrome - it's a collection of things

Turner's syndrome

Turner's syndrome
  • Shorter, webbed neck
  • Have only one X chromosome
  • Occurs in 1/3000 female births

Causes of tall stature (at final adult height)

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  1. Marfan’s syndrome (CT disorder, autosomal dominant, cardiovascular changes: dilation of aortic root, more likely to have dissecting aorta, eye signs (dislocation of the eye), and skeletal signs (very tall, hypermotile joints, arachnodactyly - fingers are very spindly)
  2. Endocrine disorders
    • Excess GH eg tumours of anterior pituitary
      • Gigantism vs acromegaly
    • Androgen/estrogen deficiency or resistance (eg testicular feminization)
  3. Disorders with excess sex chromosomes eg Klinefelter syndrome (XXY)

Abraham Lincoln may have had Marfan's syndrome

Gigantism

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  • E.g. tumour of the anterior pituitary gland (e.g. 12 year old who is 6'5")
  • Gigantism occurs if you have too much GH during childhood

Acromegaly

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  • Fingers and hands are particularly big - excess GH late in life after long bonds stop growing
    • Coarsening of facial features, jaw, facial bones, hands, feet
      • These continue to grow because they can still respond to GH
  • Androgen/oestrogen deficiency or resistance (stops you from closing epiphyseal plates; e.g. testicular feminisation)

Klinefelter's syndrome

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  • 47XXY (two X chromosomes)
  • Having the Y chromosome, means he has normal male external genitalia
  • Particularly tall (oestrogen)
  • Has female body shape (carrying angle - the angle between upper and lower arm - more curved upper arm)
  • Occurs in 1/400 - 1/600 male births

XYY

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  • 47, XYY
  • Supermale, extra height and strength