1. Endocrine SystemEndocrine System
Lecture 38: Central Endocrine Glands:Lecture 38: Central Endocrine Glands:
Hypothalamus and Pituitary (H-P axis)Hypothalamus and Pituitary (H-P axis)
Endocrine control of growthEndocrine control of growth
Lecture 39: Peripheral Endocrine Glands under H-P control:Lecture 39: Peripheral Endocrine Glands under H-P control:
Thyroid and AdrenalThyroid and Adrenal
Lecture 40: Central Endocrine Glands:Lecture 40: Central Endocrine Glands:
Circadian RhythmsCircadian Rhythms
Lecture 41: Peripheral Endocrine Glands:Lecture 41: Peripheral Endocrine Glands:
Fuel Metabolism/Calcium MetabolismFuel Metabolism/Calcium Metabolism
2. Lecture 38: Central Endocrine Glands: H-P axis/Lecture 38: Central Endocrine Glands: H-P axis/
Endocrine control of growthEndocrine control of growth
Reading: remainder of chapter 18
3. • integration of neural and endocrine systemsintegration of neural and endocrine systems
• hypothalamus:hypothalamus:
a) large number of inputsa) large number of inputs
b) integrates signals from internal andb) integrates signals from internal and
external environment to coordinate anexternal environment to coordinate an
endocrine responseendocrine response
c) directly controls the pituitaryc) directly controls the pituitary
• pituitary (hypophysis)pituitary (hypophysis)
a) anterior and posterior compartmentsa) anterior and posterior compartments
b) secretes 8 well characterized hormonesb) secretes 8 well characterized hormones
controlling an array of functionscontrolling an array of functions
Hypothalamus and Pituitary (H-P axis)Hypothalamus and Pituitary (H-P axis)
5. The hypothalamus andThe hypothalamus and
posterior pituitary formposterior pituitary form
a secretory system for:a secretory system for:
VasopressinVasopressin
- enhances water retentionenhances water retention
by kidneysby kidneys
- causes contraction ofcauses contraction of
arteriolar smooth musclearteriolar smooth muscle
OxytocinOxytocin
- stimulates contraction ofstimulates contraction of
uterine smooth muscle duringuterine smooth muscle during
childbirthchildbirth
- may influence maternal-infantmay influence maternal-infant
bondingbonding
7. Vascular link between hypothalamus andVascular link between hypothalamus and
anterior pituitaryanterior pituitary
8. Hypothalamic control of anterior pituitaryHypothalamic control of anterior pituitary
- secretion of each anterior pituitary hormone issecretion of each anterior pituitary hormone is
controlled by a hypothalamiccontrolled by a hypothalamic hypophysiotropic hormonehypophysiotropic hormone
- two types:two types:
releasing hormonereleasing hormone e.g. GHRHe.g. GHRH
inhibiting hormoneinhibiting hormone e.g. PIHe.g. PIH
- there is not a perfect one-to-one correspondencethere is not a perfect one-to-one correspondence
9. Control hierarchy among theControl hierarchy among the
hypothalamus, anterior pituitaryhypothalamus, anterior pituitary
and target tissueand target tissue
generalgeneral
pathwaypathway
specificspecific
exampleexample
11. Summary - comparison of hypothalmic controlSummary - comparison of hypothalmic control
of anterior vs posterior pituitaryof anterior vs posterior pituitary
HypophysiotropicHypophysiotropic
hormoneshormones
““hypophysis”hypophysis”
12. Endocrine control of growthEndocrine control of growth
Factors affecting growthFactors affecting growth
• genetic determinationgenetic determination
• adequate dietadequate diet
• disease- and stress-free environmentdisease- and stress-free environment
• growth hormones and other hormonesgrowth hormones and other hormones
Normal growth curveNormal growth curve
13. Growth Hormone (GH)Growth Hormone (GH)
• metabolic effects: mobilize fat stores as a majormetabolic effects: mobilize fat stores as a major
energy source while conserving glucoseenergy source while conserving glucose
• cell growth: hyperplasia and hypertrophycell growth: hyperplasia and hypertrophy
• bone growth (next slide)bone growth (next slide)
16. Other Hormones Affecting GrowthOther Hormones Affecting Growth
Thyroid hormone - permissive for GHThyroid hormone - permissive for GH
Insulin - bidirectional effect on growthInsulin - bidirectional effect on growth
Androgens and Estrogens - cause closureAndrogens and Estrogens - cause closure
of the epiphyseal platesof the epiphyseal plates
18. Lecture 39: Peripheral Endocrine Glands -Lecture 39: Peripheral Endocrine Glands -
Thyroid and AdrenalThyroid and Adrenal
Reading: chapter 19, thyroid and adrenal glands
19. Thyroid GlandThyroid Gland
Follicular cellsFollicular cells
- secrete T4 (thyroxin) and T3.- secrete T4 (thyroxin) and T3.
ColloidColloid
- contains thyroglobulin- contains thyroglobulin
(produced by follicular cells).(produced by follicular cells).
20. Thyroid hormone - synthesis, storage, secretion and transportThyroid hormone - synthesis, storage, secretion and transport
(1) Thyroglobulin is produced in the ER/Golgi of follicular cells and is then
secreted into the colloid. Thyroglobulin contains many tyrosines.
(2) Iodine is actively transported from the blood into the colloid.
Almost all iodine in the body is collected by the thyroid.
(3) In colloid, individual tyrosines become either mono- or di-
iodinated (MIT or DIT).
(5) Upon stimulation, follicular cells phagocytize a piece of the colloid.(4) While still on the thyroglobulin, tyrosines couple together.
Coupling of two DIT’s produces T4. Coupling of one DIT and
one MIT produces T3. MIT’s do not couple together.
(7) Iodine is retrieved from DIT and MIT via a highly specific cytoplasmic enzyme.(6) Endocytotic vesicle fuses with lysosome. Lysosomal enzymes cleave the
colloid, releasing T4, T3, DIT and MIT. T4 and T3 are highly lipophilic and
diffuse through the outer membrane into the blood.
21. 1) Primary determinant of basal metabolic rate –1) Primary determinant of basal metabolic rate – increases oxygenincreases oxygen
consumptionconsumption::
- Onset is slow (hours) and duration is long (days).- Onset is slow (hours) and duration is long (days).
- Calorigenic i.e. can regulate body temperature.- Calorigenic i.e. can regulate body temperature.
2) Permissive for GH, epinephrine, norepinephrine.2) Permissive for GH, epinephrine, norepinephrine.
- Increases target cell responsiveness to catecholamines by increasing receptors.- Increases target cell responsiveness to catecholamines by increasing receptors.
Can lead to increased heart rate and force of contraction.Can lead to increased heart rate and force of contraction.
- Stimulates GH secretion and increases effectiveness of somatomedins.- Stimulates GH secretion and increases effectiveness of somatomedins.
Effects of thyroid hormoneEffects of thyroid hormone
23. HypothyroidismHypothyroidism
- Caused by failure of thyroid gland, failure of H-P axis, or lack of dietary- Caused by failure of thyroid gland, failure of H-P axis, or lack of dietary
iodineiodine
- Leads to myxedema in adults, cretinism in children.- Leads to myxedema in adults, cretinism in children.
- Treatment is replacement therapy with exogenous thyroid hormone or- Treatment is replacement therapy with exogenous thyroid hormone or
iodine.iodine.
HyperthyroidismHyperthyroidism
- Caused by autoimmunity (Graves), excess in H-P axis, or thyroid tumor.- Caused by autoimmunity (Graves), excess in H-P axis, or thyroid tumor.
- Graves disease often accompanied by exopthalmos (bulging eyes).- Graves disease often accompanied by exopthalmos (bulging eyes).
- Treatment is partial removal of oversecreting thyroid, radioactive iodine, or- Treatment is partial removal of oversecreting thyroid, radioactive iodine, or
antithyroid drugs.antithyroid drugs.
Abnormalities of thyroid functionAbnormalities of thyroid function
27. Table 19-1Table 19-1
HypothyroidismHypothyroidism
- Caused by primary failure of thyroid gland- Caused by primary failure of thyroid gland
- Secondary to hypothalamic or anterior- Secondary to hypothalamic or anterior
pituitary failurepituitary failure
- Lack of dietary iodine- Lack of dietary iodine
HyperthyroidismHyperthyroidism
- Abnormal presence of thyroid-stimulating- Abnormal presence of thyroid-stimulating
immunoglobulin (Graves)immunoglobulin (Graves)
- Secondary to excess hypothalamic or- Secondary to excess hypothalamic or
anterior pituitary secretionanterior pituitary secretion
- Hypersecreting thyroid tumor- Hypersecreting thyroid tumor
Do you predict a goiter?Do you predict a goiter?
Goiter can occur with either hypo- or hyper-thyroidism, depending on the etiology.Goiter can occur with either hypo- or hyper-thyroidism, depending on the etiology.
29. Adrenal cortex hormonesAdrenal cortex hormones
MineralocorticoidsMineralocorticoids
Aldosterone – promotes Na retention and K elimination in the kidneys.Aldosterone – promotes Na retention and K elimination in the kidneys.
Essential for life.Essential for life.
Hypersecretion leads to hypernatremia and hypokalemia.Hypersecretion leads to hypernatremia and hypokalemia.
Glucocorticoids (Glucocorticoids (cortisol;cortisol; next slides)next slides)
Sex hormone (DHEA)Sex hormone (DHEA)
30. CortisolCortisol
Metabolic effects of cortisolMetabolic effects of cortisol
- increase blood glucose by decreasing glucose uptake everywhere- increase blood glucose by decreasing glucose uptake everywhere
except the brain and by increasing hepatic gluconeogenesisexcept the brain and by increasing hepatic gluconeogenesis
- increase free fatty acids- increase free fatty acids
- increase blood amino acids- increase blood amino acids
Permissive for catecholamines to induce vasoconstrictionPermissive for catecholamines to induce vasoconstriction
Stress adaptationStress adaptation
Anti-inflammatory and immunosuppressiveAnti-inflammatory and immunosuppressive
Regulated by hypothalamic-pituitary-adrenal cortex axisRegulated by hypothalamic-pituitary-adrenal cortex axis
(CRH, ACTH)(CRH, ACTH)
32. DHEADHEA
Weak masculinizing hormoneWeak masculinizing hormone
In males, more abundant but weaker than testosteroneIn males, more abundant but weaker than testosterone
In females, significant role in pubertal growth spurt, sex driveIn females, significant role in pubertal growth spurt, sex drive
Hypersecretion in childhood (adrenogenital syndrome):Hypersecretion in childhood (adrenogenital syndrome):
males - precocious pseudopuberty (no sperm production)males - precocious pseudopuberty (no sperm production)
females - pseudohermaphroditismfemales - pseudohermaphroditism
36. Catecholamine secretion by adrenal medulla isCatecholamine secretion by adrenal medulla is
controlled by the sympathetic nervous systemcontrolled by the sympathetic nervous system
37. Effects of catecholaminesEffects of catecholamines
- reinforce sympathetic response i.e.reinforce sympathetic response i.e. “fight or flight”“fight or flight”
- increased cardiac outputincreased cardiac output
- generalized vasoconstrictiongeneralized vasoconstriction
- vasodilation of vessels supplying heart, muscles and lungsvasodilation of vessels supplying heart, muscles and lungs
- increased glucose and fatty acids in bloodincreased glucose and fatty acids in blood
- increased alertnessincreased alertness
38. Catecholamine secretion by adrenal medullaCatecholamine secretion by adrenal medulla
is part of the generalized stress responseis part of the generalized stress response
39. Lecture 40: Central Endocrine Glands:Lecture 40: Central Endocrine Glands:
Circadian RhythmsCircadian Rhythms
Reading: none
42. 0 hr
48 hr
96 hr
144 hr
24 hr
192 hr
240 hr
288 hr
336 hr
26 hr
Photoentrainment and “free run”
Removal of light/dark cues does not eliminate the circadian rhythm,
but reveals the natural period of the endogenous generator
43. Focal ablation of SCNFocal ablation of SCN
eliminates circadian rhythmseliminates circadian rhythms
Mammalian SCN integrates multiple inputs,Mammalian SCN integrates multiple inputs,
but light is the dominant stimulus for entrainmentbut light is the dominant stimulus for entrainment
The suprachiasmatic nucleus (SCN)The suprachiasmatic nucleus (SCN)
is the endogenous generatoris the endogenous generator
44. The photoreceptor responsible for entrainment are located where?
• In some birds, who have thin skulls that are partially translucent, these photoreceptors are
found in the brain itself.
• For mammals, the answer was unknown until 2003.
• One prior hypothesis proposed a blood borne photoreceptor. Experiments to test this
hypothesis attempted to ‘reset’ human circadian rhythm by shining light on the back of the
knees, where the light would most readily pass through skin and expose the bloodstream.
The results were inconclusive.
• In 1981, Nelson & Zucker demonstrated that bilateral enucleation (of the eyes) eliminated
photoentrainment to very bright natural light stimuli.
• In 1995 Moore and colleagues demonstrated a direct retinal projection to the
suprachiasmatic nucleus. They called this projection the retinohypothalamic tract.
• These two results seemed to point to the obvious hypothesis, that classical photoreceptors
in the eye provided the information responsible for photoentrainment.
• BUT …
45. Wild type
rdta/cl
PhaseShift(min)
Irradiance (µW/cm2
)
Green
Cone
UV
Cone
Rods
Wild type rdta/cl rdta, loss of rods early in development
cl, genetically targeted ablation of cones
Photoentrainment persists in mice lacking rods & cones
Phase shift is nearly normal in rdta/cl knockout mouse.
Phase shift = sensitive assay for photoentrainment
46. Unlabeled GC
Detached Rhodamine labeled GC
Retinal ganglion Cells Projecting to the SCN
are Intrinsically Photosensitive (and express melanopsin)
Normal
CoCl2 &
blockers of
Glu, Glycine,
& GABA
receptors
Rhodamine labeled GC
500 nm light pulse
47. WT Opn4-/-
;rd/rd
Melanopsin/rod/cone Knockout Mice Fail to Entrain to Light-
Dark Cycles
Melanopsin
Opn4-/-
targeted ablation of Melanopsin gene
rd/rd primary degeneration of Rods w/ secondary loss of Cones
Melanopsin/rod/cone knockout mouse goes into free run
i.e. no photoentrainment
48. Pineal GlandPineal Gland
• tiny structure located in center of braintiny structure located in center of brain
• secretes melatonin, 10-fold higher in darknesssecretes melatonin, 10-fold higher in darkness
• works in conjunction with suprachiasmatic nucleus (SCN)works in conjunction with suprachiasmatic nucleus (SCN)
to entrain circadian rhythms with external cuesto entrain circadian rhythms with external cues
• additional effects of melatonin in humans:additional effects of melatonin in humans:
a) at high levels, shuts down ovulationa) at high levels, shuts down ovulation
b) highly effective anti-oxidantb) highly effective anti-oxidant
c) induces natural sleepc) induces natural sleep
d) enhances immunityd) enhances immunity
49. Lecture 41: Peripheral Endocrine Glands:Lecture 41: Peripheral Endocrine Glands:
Fuel Metabolism/Calcium MetabolismFuel Metabolism/Calcium Metabolism
Reading: chapter 19, endocrine control of fuel metabolism,
endocrine control of calcium metabolism
50. MetabolismMetabolism – all of the chemical reactions that occur within cells– all of the chemical reactions that occur within cells
Fuel metabolismFuel metabolism – reactions involving energy-rich organic molecules:– reactions involving energy-rich organic molecules:
carbohydrate, fat or protein.carbohydrate, fat or protein.
AnabolismAnabolism
- manufacture of macromolecules from smaller subunits i.e. aa -> protein- manufacture of macromolecules from smaller subunits i.e. aa -> protein
- storage of nutrients for later use in energy production- storage of nutrients for later use in energy production
CatabolismCatabolism
- hydrolysis of macromolecules into small subunits i.e. glycogen ->glucose- hydrolysis of macromolecules into small subunits i.e. glycogen ->glucose
- oxidation of smaller subunits to yield energy for ATP production- oxidation of smaller subunits to yield energy for ATP production
Reaction in fuel metabolismReaction in fuel metabolism
- glycogenesis- glycogenesis
- glycogenolysis- glycogenolysis
- gluconeogenesis- gluconeogenesis
- protein synthesis- protein synthesis
- protein degradation- protein degradation
- fat synthesis- fat synthesis
- fat breakdown- fat breakdown
52. Absoptive (fed) state
- glucose is plentiful as used as main energy source
- anabolism of amino acids, fatty acids and extra glucose
- persists for about 4 hours following a meal
Postabsorptive (fasting) state
- glucose sparing at non-neural tissue
- gluconeogenesis is activated
- anabolism of amino acids and fatty acids is curtailed
53. Important constraints on fuel metabolism:
1) Food intake is intermittent.
2) Brain requires continuous supply of glucose from blood.
54. Pancreatic hormones insulin and glucagon regulate fuel metabolism
islets of Langerhans:
beta cell - insulin
alpha cell - glucagon
Effects of insulin on:
carbohydrate: insulin lowers blood glucose levels
- facilitates glucose transport into most cells
- stimulates glycogenesis
- inhibits glycogenolysis
- inhibits gluconeogenesis
fat: insulin lowers blood fatty acid levels and promotes triglyceride storage
protein: insulin lowers blood amino acid levels and enhances protein synthesis
56. Diabetes mellitus (too little insulin activity)
Most common endocrine disorder
Results from inadequate insulin action
Most prominent feature is elevated blood glucose levels,
leading to “sweetened” urine
Type I: lack of insulin secretion
- childhood onset
- treated with insulin injections
Type II: normal or increased insulin secretion but reduced
sensitivity of target tissue
- adult onset
- treated with diet control
57. Short-term consequences of insulin deficiency:
- hyperglycemia causes dehydration, can lead to
renal failure and/or circulatory failure
- switch to fats as main energy source, can lead to
ketosis and acidosis
Long-term consequences of insulin deficiency
- on average, reduced life span due to degenerative
disorders of the vasculature and nervous system
- heart disease, stroke, kidney and retinal lesions,
neuropathies and circulatory problems, sometimes
requiring amputation
58. Hypoglycemia (too much insulin activity)
- insulin shock in diabetics
- reactive hypoglycemia due to beta cell overactivity
62. The concentration of freely diffusible calcium found in ECF
is critical for:
Neuromuscular excitability
Excitation-contraction coupling in cardiac and smooth muscle
Stimulus-secretion coupling
Maintenance of tight junctions between cells
Clotting of blood
Three factors affect Ca metabolism
- parathyroid hormone
- calcitonin
- vitamin D
Calcium MetabolismCalcium Metabolism
63. ECF [Ca] is regulated by hormonal control of
Ca exchange between ECF and three compartments:
bone, kidney and intestine
Calcium homeostasis
- maintenance of constant ECF [Ca] on minute-to-minute basis
- primarily accomplished by exchange with bone
Calcium balance
- maintenance of constant total amount of Ca in body
- balance intake with excretion over long-term
64. Parathyroid hormone is essential for life – raises ECF [Ca]
Actions on bone:
- “bone bank” consists of Ca stored in hydroxyapatite crystals
- PTH induces fast Ca efflux into ECF from small labile Ca pool in bone fluid
- PTH promotes a slow transfer of Ca (and phosphate) to the ECF (bone
resorption)
Actions on kidneys: stimulates Ca conservation
Actions on intestine: indirect, by stimulating kidney enzymes that activate vitamin D
