Sapolsky, Chapter 6

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Sapolsky, Chapter 6

• Dwarfism and the Importance of Mothers

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How do we grow???

• A mountain of spaghetti, salad, garlic bread, 2
  slices of cake ? bone???
• Your femur is made up of tiny pieces of your
  mothers chicken pot pie that you ate throughout
  your youth?

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Bone is living tissue.
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The epiphyseal plate is cartilage. To grow, the
distal end adds more cartilage, and the proximal
end becomes bone.
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Bone growth
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Growth doesnt come cheap

• Calcium ? bones amino acids ? proteins,
  including muscle fatty acids ? cell walls
  glucose pays for the building costs.
• Growth hormone Breaks down fat cells to release
  fatty acids to be used for growing cells.
• Also enhances protein synthesis. GH is important
  for wound healing as well as growth.

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GH causes liver other tissues to secrete
somatomedins (insulin-like growth factor, IGF-1),
which ? growth.
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Somatomedins

• Produced in the liver and other peripheral
  tissues in response to GH.
• Increase cell division and maturation of numerous
  kinds of cells.
• Work synergistically with GH.

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Thyroid hormone

• Promotes growth hormone release.
• Increases responsiveness of bones to
  somatomedins.
• Regulates metabolism in all cells of body.
• Insulin
• Increases transport of amino acids and glucose
  into cells.

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TRH ? TSH ? T3 T4(tri-iodothyronine
thyroxine)
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Thyroid combines tyrosine (amino acid) with
iodine ? T3 T4. It makes 4 X more T4, but T3 is
4X more potent.
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Steroid hormones

• Estrogen Promotes growth of long bones, by
  acting on bone and by increasing growth hormone
  (GH) secretion
• Testosterone Acts similarly to estrogen and also
  enhances muscle growth.
• Also speeds cessation of bone growth by maturing
  ends of bones.
• Congenital adrenal hyperplasia (CAH) in boys
  early fast growth, but stop growing too early.

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CAH ? rapid growth, early puberty, early
cessation of growth
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Control of GH

• GHRH is secreted in bursts from neurons in
  mediobasal hypothalamus, especially the arcuate
  nucleus.
• It is released in the median eminence into the
  portal system that goes to the anterior
  pituitary, which in turn releases GH into the
  systemic circulation.
• GHRH also increases synthesis of GH.

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Control of GH

• GH is released almost exclusively during the deep
  slow-wave sleep early in the night.
• Elderly people have little deep slow wave sleep
  and little GH, which results in poor wound
  healing.
• Other neurons around the arcuate send axons to
  the lateral hypothalamus to increase feeding.

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Control of GH

• Somatostatin (GHIH) neurons are in anterior
  hypothalamus and send axons to both the median
  eminence and GHRH neurons in the arcuate nuc.
• They inhibit both synthesis and release of
  GHRH (in arcuate neurons) or GH (via the portal
  system to the anterior pituitary).
• Somatostatin also decreases intestinal absorption
  and decreases insulin secretion.

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Anterior pituitary
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Control of GH

• Anterior pituitary GH-secreting cells
  (somatotrophs) are the most numerous type of cell
  (30-40 in males and 20-30 in females).
• GH is highest immediately before and after birth.
• Its also important for adolescent growth spurt.

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Prenatal stress

• Childhood a time for learning what to expect.
• What goes up, comes down.
• Mommy will return.
• Pregnancy learning about how plentiful food
  is metabolic imprinting.
• If undernourished thrifty metabolism.
• Dutch Hunger Winter at end of WW II

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Prenatal stress

• Famine in 1st trimester ? heart disease, obesity,
  unhealthy cholesterol ratio.
• Famine in 2nd or 3rd trimester ? increased
  diabetes risk.
• Problems occurred only if food was plentiful
  after birth.
• Siege of Leningrad not much food afterward ?
  less obesity Type II diabetes afterward

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Prenatal stress

• True in less dramatic times, too.
• Lower-weight babies (adjusted for length) ? risk
  for Metabolic Syndrome
• High glucose, high insulin, insulin resistance
• High BP
• LDL gtgt HDL, too much fat in blood
• Apple shape
• Lowest vs. highest wt
• 18 X greater risk for Metabolic Syndrome
• 50 higher risk of death from heart disease

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Non-nutritional stress

• Similar effect
• Increased GCs teach fetus that world is
  stressful.
• Prenatally stressed rats smaller hippocampus ?
  high GCs
• (due to less negative feedback)
• Worse memory
• Similar effects in monkeys and humans
• Increased Type II diabetes, high BP

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Non-nutritional stress

• Demasculinize male rats
• GCs opioids interfere with testosterones
  effects.

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Mounting by male rats is decreased by pre- or
neonatal stress.
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Non-nutritional stress

• Increased anxiety
• Amygdala has more receptors for CRH
• and fewer receptors for endogenous
  benzodiazepines (Valium, Librium), which
  increase GABAs inhibitory (calming) effects.

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Location of the amygdala
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Non-nutritional stress

• Effect is passed on to offspring!
• Mom retains more of the nutrients ? less for the
  fetus ? fetus learns that there is too little
  food ? thrifty metabolism.
• If mom has Type II diabetes, her fat cells
  release hormones that urge other fat muscle
  cells to be insulin-resistant.
• Those hormones get to fetus ? underweight.

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Growth inhibition during stress

• Stress dwarfism, psychosocial dwarfism, or
  psychogenic dwarfism extremely rare.
• Products of vast, grotesque family
  psychopathology. Overcome by parentectomy.
• King Frederick II of Sicily Language
  experiment none of the kids survived.
• Lauren Belfer (City of Light) Almost no infants
  survived in orphanages at turn of century.

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Growth inhibition during stress

• 1900s -1930s Child rearing intensely Spartan
  vicious practice of picking up a child when it
  cried
• Children in 2 orphanages after WW II. Fraulein
  Grun vs. Fraulein Schwarz

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Stress dwarfism

• Condition GH Growth Calories
• Entry to hosp 5.9 0.5 cm 1663
• 100 days later 13.0 1.7 1514
• Nurse vacation 6.9 0.6 1504
• Nurse returns 15.0 1.5 1521

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Peter Pan
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The mechanisms underlying stress dwarfism

• Hormones Hypothalamus GHRH (growth hormone
  releasing hormone) vs. somatostatin (or GHIH,
  growth hormone inhibiting hormone) sent to
  anterior pituitary
• Growth problems in kids over 3 mostly due to
  decreased GH and related problems
• Probably main problem too much GHIH
• or pituitary is too sensitive to GHIH
• or insensitive to GHRH

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The mechanisms underlying stress dwarfism

• Somatomedins GH bind to receptors on cells ?
  grow and divide.
• Psychogenic dwarfism cells become insensitive to
  GH and somatomedins.

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The mechanisms underlying stress dwarfism

• Sympathetic N.S. overactivity ? blocks growth
  hormone secretion.
• Glucocorticoids Block GH secretion decrease
  sensitivity to GH decrease synthesis of new
  proteins and DNA.
• Hormone levels 2 to 3 X normal disrupt growth
• Major stressors increase hormone levels up to 10
  X normal.

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The mechanisms underlying stress dwarfism

• Gastrointestinal problems
• Increased Symp. N.S. activity decreases
  digestion.
• Affects primarily infants

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The need for active touch

• Rats Anesthetized mother doesnt increase GH
  mimicking active stroking does.
• Humans Tiffany Field 15 min periods 3/day,
  stroking, moving limbs of premature babies kids
  grew 50 faster, were more active and alert,
  matured faster, released from hospital 1 wk.
  earlier. Still healthier months later.
• Could save 1billion/year and produce healthier
  kids for years after.
• Sometimes a stressor is the absence of a needed
  stimulus.

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Growth and growth hormone in adults

• Why do adults secrete GH???
• Heal wounds.
• Remodel bone (along with somatomedins,
  parathyroid hormone, and vitamin D.
• Bone is Federal Reserve of bodys calcium.
• Glucocorticoids counteracts effects of GH.
• In large quantities (as in Cushings syndrome or
  treatment of leukemia, etc.) they can produce
  osteoporosis.
• Chronic stress may damage bone.

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Stress and growth hormone secretion in humans

• Immediately after stress onset, GH levels rise.
• This helps to remove nutrients from storage sites
  for new construction.
• But if somatomedin is blocked by glucocorticoids,
  the nutrients are available for the current
  emergency.
• However, somatomedin is not completely blocked,
  so GH needs to be shut down after a while, so it
  does not start a new, expensive new growth
  project.

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Stressful rites of passage

• Tom Landauer John Whiting
• Compared those from same gene pool that did or
  did not have stressful rituals.
• If stressor occurred in first 2 years, growth was
  stimulated from 2-6 yrs, no effect 6-15 yrs,
  growth was inhibited.
• Couldnt completely rule out effects of diet or
  killing off the weakest babies.

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The L word

• Harlow took on behaviorism Its not
  reinforcement thats important.
• Did his experiments go too far?

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Harlows monkey with cloth mother
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Summary

• Growth hormone is released from Ant. Pit.
• Release is controlled by GHRH and somatostatin
  (GHIH)
• Somatomedins produced by liver and other tissues
  stimulate bones to grow and other cells to divide
  and mature.
• Thyroid hormones ? GH release, bone
  responsiveness to somatomedin, metabolism
  everywhere.

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Summary

• Estrogen testosterone ? bone growth, stimulate
  GH release also ? maturation of epiphyseal
  plates (stop growth)
• Prenatal hunger or other stress ? thrifty
  metabolism ? risk of Type II diabetes, high BP,
  heart disease.
• Effects of stress can be passed on to offspring.

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Summary

• Stress dwarfism caused by decreased GH and
  somatomedins decreased digestion.
• Rat, monkey human newborns need active
  touching, cuddling.
• Adults need GH to heal wounds remodel and
  strengthen bone.