Growth

• When does most growth occur, and what factors affect this?

  In utero/intrauterine

  Maternal factors =age, height, altitude, genotype, stress, pre-eclampsia, substance abuse, nutrition, hypertension, prior IUGR

  Foetal factors = congenital heart disease, congenital diaphragmatic hernia, Turners syndrome, Patau syndrome, Edwards syndrome, Down syndrome

  Placental and cord abnormalities = placental insufficiency, incorrect cord insertion, placental tumour, single umbilical artery, circumvallate placenta

  Infections = TORCH, malaria - can be vertically transmitted via placenta or bodily fluids
• Hormonal control of intrauterine growth?

  Main growth hormones of postnatal life have little effect on pre-natal growth - near normal size at birth if have deficiency of GH etc

  Important hormones = IGF1/2, placental growth hormone, fetal insulin, placental lactogen
• Role of IGFs in prenatal growth?

  IGF1 produced in liver (based on nutrients/glucose in second 1/2 of pregnancy), receptor expressed in all tissues, controls fetal insulin and development of many tissues

  IGF in placenta determines partitioning of nutrients from mother to placenta to fetus

  Maternal IGF1 also regulated by fetal growth hormone, which acts to suppress maternal pituitary GH release
• Hormonal abnormalities affecting fetal growth?

  Diabetic mothers - maternal hyperglycaemia means fetal hyperglycaemia, increased body weight, fat deposits, increased length and lean body mass

  Leprechaunism - insulin receptor failure causes severe dwarfism

  Pancreatic agenesis/neonatal diabetes - no insulin, average 50% reduction in body weight

  Beckwith-Wiedemann syndrome = Excessive IGF2 production and somatic overgrowth - see macroglossia, organomegaly, omphalocele
• Effects of malnutrition on growth

  Intrauterine growth restriction - nutritional restriction reduces endocrine and paracrine IGF1, resets fetal development, slower growth rate, smaller but otherwise normal baby with reduced nutritional demands - accommodates for nutritionally deprived environment

  Marasmus - protein-calorie malnutrition, weight <60% median, muscle wasting, no oedema, low blood glucose, impaired immunity

  Kwashiorkor - Generalised oedema, altered pigmentation, child withdrawn and won't eat, not necessarily underweight due to oedema, heptomegaly etc - when high cars, low protein
• Overview of role of GH?

  Doesn't target a specific gland, exerts effects on all tissues - causes growth in almost all body tissues capable of growing - increased cell size and mitosis, differentiation of certain cell types (bone growth cells and early muscle cells etc)

  191 amino acid protein

  GH injections rats caused marked increase in growth
• Metabolic effects of GH?

  Increased protein synthesis and deposition most cells of body - increased amino acid transport into cells, enhance translation, reduction catabolism of proteins (via fatty acids)

  Increased mobilisation of fatty acids from adipose tissue, so increased in blood and available for energy use - slower process than effect on proteins

  Reduced glucose use in body (conserves) - increased production liver, insulin secretion, reduced glucose uptake muscle and fat

  Ketogenic effect excess GH
• GH-induced insulin resistance?

  Don't know mechanism by which this is invoked, may be due to increased fatty acid concentration and lipolysis

  GH causes insulin release to stimulate uptake of glucose

  Effects can be described as diabetogenic
• Describe stimulation of cartilage and bone by GH

  Increased growth skeleton through multiple effects bone - increased protein deposition blasts (bone thicker), increased reproduction blasts, increased conversion chondrocytes to blasts

  GH stimulation means long bones grow at epiphyseal cartilages, deposition new cartilage, conversion to new bone, then fusion shaft and epiphysis late adolescence so not further lengthening of long bone can occur

  Blasts deposit bone, clasts remove

  Stimulates IGF from liver - IGF deficiency (normal GH) have dwarfism etc, so involved in growth
• Regulation GH secretion?

  Reduction with age after adolescence

  Secreted in pulsatile pattern, multiple factors stimulate - starvation, hypoglycaemia, exercise, excitement, trauma, ghrelin, some amino acids

  Increases in first 2 hours of sleep

  Hypoglycaemia more potent stimulate under acute conditions, protein depletion under chronic conditions

  Controlled by GHRH and somatostatin from neurons in arcuate + ventromedial nuclei, and periventricular neurons respectively - via cAMP, calcium, also increase GH transcription

  Negative feedback - inject GH and see reduction endogenous GH
• Panhypopituitarism?

  Reduced secretion all anterior pituitary hormones - can be congenital or from tumour compressing pituitary

  Causes hypothyroidism, reduced production glucocortcoids, reduced secretion gonadotrophic hormones

  Dwarfism if childhood, no puberty of sexual development

  Can treat early with GH from recombinant E. Coli
• Giantism?

  Excessive GH before adolescence - excess activation GH producing cells

  Causes rapid growth body tissue and bones

  Can cause hyperglycaemia, beta cell overload, diabetes mellitus

  Generally due to tumours, block further effects by removing tumour
• Acromegaly?

  Tumour after adolescence (once bones fused)

  Bones become thicker, soft tissue continue to grow - marked enlargement in bones of hands, feet, face