1. Endocrine System Huiping Wang (王会平), PhD Department of Physiology
Rm C516, Block C, Research Building, School of Medicine
Tel:

2. RECOMMENDED TEXTBOOK: Widmaier EP, Raff H, Strang KT (2006) Vander’s Human Physiology: The Mechanisms of Body Function, Tenth Edition. McGraw-Hill.
SUPPLEMENTARY READING: Stephan Sanders (2003) Endocrine and Reproductive systems, Second Edition. Mosby.
COURSE WEBSITERS:

3. Endocrine System General Principles of Endocrine Physiology
Hypothalamus and pituitary gland
Thyroid gland
Endocrine Regulation of Calcium and Phosphate Metabolism
Adrenal gland
Pancreatic hormones

4. General Principles of Endocrine Physiology

5. Outline Endocrine system and Hormone Hormone types
Hormone synthesis, storage, release, transport, clearance and action modes
Characteristics of hormones
Regulation of Hormone Secretion
Mechanisms of hormone action

6. Endocrine System
One of the two major communication systems in the body
Have much longer delays
Last for much greater lengths of time
Integrate stimuli and responses to changes in external and internal environment
crucial to coordinated functions of highly differentiated cells, tissues and organs

7. Endocrine Glands Hypothalamus Pituitary (Anterior and Posterior)
Thyroid / Parathyroid
Endocrine Pancreas (islets)
Adrenal Cortex and Medulla
Gonad (Ovary and Testis)
Endocrine gland (ductless) is a group of cells that produce and secret a hormone

8. Endocrine System
The endocrine system broadcasts its hormonal messages to target cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

9. What is a hormone?
Chemical messenger synthesized by specific endocrine cells in response to certain stimuli and secreted into the blood
Travel via the circulation to affect one or more groups of different cells (target cells) to elicit a physiological response
Hormones are primarily information transferring molecules

13. Types of Hormones Types Amines Steroids Protein and peptides Example
T4, T3,
catecholamine
Hormones from adrenal cortex
and gonads
Most of hormones
insulin, oxytocin, GH
Synthesis
Tyrosine
Cholesterol
DNA – mRNA –
Preprohormone -
Prohormone
Feature
lipid insoluble
lipid soluble

14. Synthesis of peptide hormones
NUCLEUS
The DNA code is “transcribed” into mRNA.
RIBOSOMES
The mRNA is “translated” to give instructions for proteins synthesis.

16. Typical synthesis of peptide hormones
Preprohormones- larger hormones produced on the ribosomes of the endocrine cells
Prohormones- cleavage of preprohormones by proteolytic enzymes in rER
Prohormones- packaged into secretory vesicles by the Golgi apparatus
Prohormones- cleaved to give active hormone and pro-fragments
pre-pro-insulin pro-insulin insulin

17. Synthesis of steroid hormones

18. Hormone Storage and Release
Thyroid and steroid hormones
Not stored as secretory granules
Transferring through plasma membrane
Protein and catecholamine hormones
Stored as secretory granules
Released by exocytosis

19. Hormones are not secreted at a uniform rate
In a pulsatile pattern
Diurnal (circadian) rhythm:
linked to sleep-wake cycles (cortisol, growth hormone)
Be aware of the pulsatile nature and rhythmic pattern of hormone secretion when relating the serum hormone measurements to normal values

20. Hormones are not secreted at a uniform rate
Rhythmic secretion
Cyclic
oestrogen, progesterone, LH

21. Modes of Action
Endocrine – transmission of a signal from a classic endocrine cell through bloodstream to a distant target cell e.g. testosterone
Neurocrine – hormone is released from a neuron down its axon and then travels via the bloodstream to target cell
Paracrine - hormone acts on adjacent cells e.g. histamine released at site of injury to constrict blood vessel walls and stop bleeding
Autocrine – hormone is released and acts on the cell that secreted it. e.g. norepinephrine itself inhibits further release by that cell in the adrenal medulla

22. A secretion may have several sites of action simultaneously
Example:
Norepinephrine
- Autocrine action causes negative feedback on secretion.
- Simultaneously, endocrine action causes respiration rate to increase, peripheral blood vessels to constrict, etc.

23. Hormone Transport Peptides and catecholamine
water soluble
dissolve in blood
circulate in blood mainly in free form
Steroid and thyroid hormones
circulate in blood mainly bound to plasma proteins
the free form is biologically active
the greater binding, the longer half-life

24. Hormone Clearance The half-life of a hormone in blood
is the period of time needed for its concentration to be reduced by half.
Free: min
Binding: mins, hrs, days
e.g. T4 (6 days); Insulin (0.006 days)
Hormone concentration in blood is determined by
secretion rate
clearance rate
Ways of Clearance
target cell uptake
metabolic degradation
urinary or biliary excretion

25. The “metabolic fate” of a given hormone molecule in the blood

26. Characteristics of Hormones
Regulates rate of reaction
Do not initiate
Very specific
Amplification effect
Present in very small quantity
pg/mL ~ g/mL

27. Characteristics of Hormones
Interaction between hormones
Synergistic action
Antagonistic action
Permissive action
Hormone A must be present for the full strength of hormone B’s effect.
Up-regulation of one hormone’s receptors by another hormone
the facilitation of the action of one hormone by another
e.g. the ability of TH to “permit” epinephrine-induced release of fatty acids from adipose tissue cells (TH causes an  no. of epinephrine receptors on the cell)

28. Regulation of Hormone Secretion
Three types of inputs to endocrine cells that
stimulate or inhibit hormone secretion.

29. Regulation of Hormone Secretion
Negative feedback
Most common
Occurs when a hormone produces a biologic effect that, on attaining sufficient magnitude, inhibits further secretion
Positive feedback
Less common
Amplify the initial biological effect of the hormone

30. Negative Feedback
Characteristic of control systems in which system’s response opposes the original change in the system.
Hormone itself feeds back to inhibit its own synthesis.
Regulated product (metabolite) feeds back to inhibit hormone synthesis.
Important for homeostatic control.
Example: Control of blood glucose by insulin

32. Positive Feedback
Characteristic of control systems in which an initial disturbance sets off train of events that increases the disturbance even further.
Amplifies the deviation from the normal levels
Example: Oxytocin (suckling)
Important for amplification of level for action

33. Mechanisms of hormone actions
Hormone action mediated by the specific receptors
Most hormones circulate in blood, coming into contact with essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.

34. Hormone Receptors Structure Location Receptor capacity
The receptor provides link between a specific extracellular hormone and the activation of a specific signal-transduction system
Structure
Recognition domain binds hormone
Coupling domain generates signal
Location
cell membrane (e.g. for insulin)
cytoplasm (for steroids)
nucleus (e.g. for thyroid hormone)
Receptor capacity
exposure to excess hormone down-regulates capacity
low hormone concentration up-regulates capacity

35. Two general mechanisms of hormone action
Second messengers – enzyme activity ↑↓(rapid, cytosolic effects)
Gene expression - enzymes synthesis ↑↓(slow, nuclear effects)

37. Mechanisms of Peptide Hormone Action
G proteins
are GTP-binding proteins
couple hormone receptors to adjacent effector molecule
have intrinsic GTPase activity
have three subunits: α, β, γ
α subunit bound to GDP → inactive G protein
α subunit bound to GTP → active G protein
the effect can be either stimulatory (Gs) or inhibitory (Gi)
Second messengers
cAMP second message system
IP3 mechanism
Ca2+-calmodulin mechanism

38. Signal transduction pathway involving adenylate cyclase

39. Cyclic AMP signaling-sequence of events
The hormone (1st messenger) binds to the membrane receptor; the membrane receptor changes shape and bind to G protein (GTP-binding protein)
G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and release GDP
Activated G protein moves to membrane and binds and activates adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)
Activated adenylate cyclase converts ATP to cAMP (second messenger) (if inhibited, no catalysed reaction by AC)
cAMP is free to circulate inside the cell; triggers activation of one to several protein kinase molecules; protein kinase phosphorylates many proteins
The phosphorylated proteins may either be activated or inhibited by phosphorylation

40. Adenylyl cyclase forms cAMP,
a “second messenger”
that activates enzymes
used in cellular responses.
The phosphodiesterase
enzymes “terminate” the
second messenger cAMP.

41. Amplification effect
Each protein kinase can catalyse hundreds of reactions
The cAMP system rapidly amplifies the response
capacity of cells: here, one “first messenger” led
to the formation of one million product molecules.

42. PIP-calcium signaling mechanism
This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels.

43. PIP-calcium signaling mechanism
A hormone (first messenger) binding to its receptor causes the receptor to bind inactive G protein
G protein is activated; binds GTP & releases GDP
Activated G protein binds & activates a membrane-bound phospholipase enzyme;
G protein becomes inactive
Phospholipase splits phosphatidyl inositol biphosphate (PIP2) to diacylglycerol (DAG) & inositol triphosphate (IP3);
DAG activates protein kinases on the plasma membrane; IP3 triggers calcium ion release from the ER
Released calcium ions (second messengers) alter activity specific enzymes’ activity and ion channels or bind to the regulatory protein calmodulin;
Calmodulin also activates specific enzymes to amplify the cellular response

44. Ca-calmodulin system

45. Mechanisms of steroid Hormone Action
Modulation of gene expression
Steroid hormones bind to intracellular receptors
The steroid-receptor complex binds to DNA, turning specific genes on or off
Steroid hormone receptor

46. Sequence of events for steroid hormone binding
Steroids are lipid-based and can diffuse into cells easily
No need for intracellular second messenger
Mobile receptors
Some steroids bind to a cytoplasmic receptor, which then translocates to the nucleus
Other receptors for steroids are located in the nucleus or are nuclear receptor proteins
In both cases, the steroid-receptor complex formed can then bind to specific regions of DNA and activate specific genes
Activated genes transcribe into messenger RNA and instruct the cell to synthesize specific enzyme proteins that change the metabolism of the target cell

50. Radioimmunoassay (RIA)
(from the Nobel lecture by Dr. Rosalyn Yalow, 1977)

52. QUIZ
The main difference between the modes of action of peptide hormones and steroid hormones is that
a. peptide hormones bind to intracellular receptors whereas steroid hormones bind to receptors on the cell surface. b. peptide hormones bind to receptors in the nucleus whereas steroid hormones bind to receptors in the cytosol. c. peptide hormones bind to receptors on the cell surface whereas steroid hormones act as second messengers. d. peptide hormones bind to receptors on the cell surface whereas steroid hormones bind to intracellular receptors. e. there are no differences; both act by binding to receptors on the cell surface.

53. QUIZ
The main difference between the modes of action of peptide hormones and steroid hormones is that
a. peptide hormones bind to intracellular receptors whereas steroid hormones bind to receptors on the cell surface. b. peptide hormones bind to receptors in the nucleus whereas steroid hormones bind to receptors in the cytosol. c. peptide hormones bind to receptors on the cell surface whereas steroid hormones act as second messengers. d. peptide hormones bind to receptors on the cell surface whereas steroid hormones bind to intracellular receptors. e. there are no differences; both act by binding to receptors on the cell surface.

54. QUIZ
In the absence of thyroid hormone, epinephrine stimulates release of a small amount of fatty acids from adipose cells. In the presence of thyroid hormone (which has no effect by itself), epinephrine causes a much more substantial release of fatty acids from the cells. The effect of thyroid hormone on epinephrine's actions is called
a. antagonistic. b. agonistic. c. permissive. d. direct. e. paracrine.

55. QUIZ
In the absence of thyroid hormone, epinephrine stimulates release of a small amount of fatty acids from adipose cells. In the presence of thyroid hormone (which has no effect by itself), epinephrine causes a much more substantial release of fatty acids from the cells. The effect of thyroid hormone on epinephrine's actions is called
a. antagonistic. b. agonistic. c. permissive. d. direct. e. paracrine.

56. Summary Hormone Hormone types Action modes of hormones
Primarily information transferring molecules
Transfer information from one set of cells to another
Travel via the circulation to affect one or more groups of different cells to elicit a physiological response
Hormone types
Protein and peptides
Amines
Steroids
Action modes of hormones
Endocrine
Paracrine
Autocrine
Neurocrine

57. Summary Regulation of Hormone Secretion Mechanisms of hormone action
Negative feedback
Positive feedback
Mechanisms of hormone action
Mechanisms of Peptide Hormone Action
Second messenger signaling pathway
cAMP second message system
IP3 mechanism
Ca2+-calmodulin mechanism
Mechanisms of Steroid Hormone Action
Modification of gene expression