1. Asso. Professor Dr Than Kyaw
Endocrine System
Lecture 1
Characters and mechanisms of actions of hormones
Pituitary hormones
Asso. Professor Dr Than Kyaw
17 September 2012

2. What is endocrinology? Endocrinology Study of:
- Intercellular Chemical Communication
- about communication systems & information transfer.

3. Hormones Definition (classical)
- Chemical substances produced by specialized ductless glands
- Released into the blood
- Carried to other parts of the body
- Produce specific regulatory effects.
Is that definition true?
PGF2α - produced by most of the body cells, transmitted by diffusion in interstitial fluid rather than by circulation in the blood.
Pheromones – transmission through olfaction (smell)
-- outside the body

4. Modes of transmission
Hormone transmission restricted only to blood – incorrect
1. Epicrine transmission
- Hormones pass through gap junctions of adjacent cells without entering extracellular fluid.
2. Neurocrine transmission
- Hormones diffuse through synaptic clefts between neurons. Neural – through neurons (neurotransmitters)

5. Gap junctions
- Pores connecting adjacent cells. Small molecules and electrical signals in one cell can pass through the gap junctions to adjacent cells.

6. Synaptic cleft
Between a neuron and a muscle fiber or
Between 2 neurons
Acetylcholine

7. Mode of transmission 3. Paracrine transmission
- Hormones diffuse through interstitial fluid - PGF2α
4. Endocrine transmission
- Hormones are transported through blood circulation. - Typical of most hormones
5. Exocrine transmission
- Hormones are secreted to the exterior of the body.
E.g - Somatostatin secreted into the lumen of GI tract (and inhibit intestinal motility and absorption)
- Pheromones

8. Endocrine Functions Maintain Internal Homeostasis Support Cell Growth
Coordinate Development
Coordinate Reproduction
Facilitate Responses to External Stimuli

9. Elements of an endocrine system
Sender = Sending Cell (where hormone is produced)
Signal = Hormone
Nondestructive Medium = Serum & Hormone Binders
Selective Receiver = Receptor Protein (Target cells)
Transducer = Transducer Proteins & 2º Messengers
Amplifier = Transducer/Effector Enzymes
Effector = Effector Proteins
Response = Cellular Response

10. What are transducers? Transducers
- proteins that convert the information in hormonal signals into chemical signals understood by cellular machinery.
- They change their shape & activity when they interact directly with protein-hormone complexes.
- Usually enzymes or nucleotide binding proteins, they produce 2nd messengers, or change the activity of other proteins by covalently modifying them (adding or removing phosphate, lipid groups, acetate, or methyl groups), or they interact with other proteins that do these things.
- They begin amplifying the energy content of the original hormone signals.

11. Classes of hormone 1. Amine hormones
- thyroid hormones, catecholamines
- all derived from single amino acids
- thyroid hormones - from tyrosine
- catecholamines from tyrosine
- melatonin - from tryptophan

12. Classes of hormone 2. Peptide hormones
- Peptides, polypeptides and proteins
- Hydrophilic/Lipophobic
- short half life
- hormones of hypothalmus (releasing and inhibiting)
- pituitary hormones
- Insulin, glucagon

13. Classes of hormone 3. Steroid hormones
- adrenocortical and reproductive hormones
- derived from cholesterol
- Hydrophobic/lipophilic
- long half life
- travel with a protein carrier
- bind to cytoplasmic/nuclear receptor

14. Classes of hormone 4. Eicosanoids (Lipid hormones)
- produced from 20 carbon fatty acids (arachidonic acid)
- produced in all cells except RBCs
- prostaglandin, leukotrienes (smooth m/s contraction
in trachea), thromboxanes

15. Hormone Interactions
Responsivenss of a target cell to a hormone depends on:
- The hormone concentration
- The abundance of the target cell’s hormone receptors
- influences exerted by other hormones
1. Permissive effect: when the action of a hormone on target cells requires a simultaneous or recent exposure to a second hormone.
- e.g: Epinephrine – alone, weakly stimulates lipolysis but presence of a small amounts of thyroid hormones - the same amount of epinephrine stimulates lipolysis much more powerfully.

16. Hormone Interactions Synergistic effects
when the effect of two hormones acting together is greater or more extensive than the sum of each hormone acting alone
Antagonistic effects
when one hormone opposes the activation of another hormone.
E.g, Insulin promotes glycogen synthesis by the liver
cells and glucagon stimulates glycogen breakdown

17. Enzyme amplification One hormone molecule does not trigger
- the synthesis of just one enzyme molecule
It activates thousands of enzyme molecules through a cascade of called enzyme amplification
This enables a very small stimulus to produce a very large effect
Hormones are therefore needed in very small quantities
circulating concentration very low compared to other blood substances: on order of nanograms per deciliter of blood
Because of amplification target cells do not need a great number of hormone receptors

18. Hormone clearance
- Hormone signals, like nervous signals, must be turned off when they have served their purpose
- Most hormones are taken up and degraded by the liver and kidneys and then excreted in bile or urine
- Some are degraded by the target cells
Rate of hormone removal (metabolic clearance rate – MCR)
Halflife – the length of time required to clear 50% of the hormone from the blood
- the faster the MCR – the shorter half life

19. Metabolic Clearance Rate or Half-life of some hormones
Amines
2-3 min
Thyroid hormones: T4 T3
6.7 days
0.75 days
Polypeptides
4-40 min
Proteins
min
Steroids
4-120 min

20. Modulation of target cell sensitivity
- Hormones affect only target cells
- cells that carry specific receptors that bind the recognized hormone
- Down regulation: when receptor quantity decrease
when hormone is in excess
- Decreases responsiveness to hormone
for example, in response to obesity when cells become less sensitive to insulin.
Up regulation: when receptor quantity increases when hormone is deficient
- Make target cell more sensitive to hormone
for example, in response to regular exercise when cells become more sensitive to insulin.

21. Hormone receptors (Cell surface receptor, membrane receptors, transmembrane receptors)
Cellular proteins that bind with high affinity to hormones & are altered in shape & function by binding.
exist in limited numbers.
- Binding to hormone is noncovalent & reversible.
- Hormone binding will alter binding to other cellular proteins & may activate any receptor protein enzyme actions.

22. Hormone & Receptor in General

23. Hormone receptors - Specialized integral membrane proteins
Communication between the cell and the outside world.
Extracellular signalling molecules (usually hormones, neurotransmitters, cytokines, growth factors or cell recognition molecules)
Attach to the receptor, trigger changes in the function of the cell.
This process is called signal transduction: The binding initiates a chemical change on the intracellular side of the membrane. In this way the receptors play a unique and important role in cellular communications and signal transduction.

24. G Protein
Any of a class of cell membrane proteins that function as intermediaries between hormone receptors and effector enzymes and enable the cell to regulate its metabolism in response to hormonal changes.
2 Types -- Stimulatory (GS)
-- Inhibitory (GI)

25. Surface Hormone Receptors
4 types or 4 domains of Surface hormone receptors
1. Seven-transmembrane domain receptors
- β adrenergic
- Parathyroid hormones (PTH)
- Luteinizing hormone (LH)
- Thyroid-stimulating hormone (TSH)
- Growth hormone-releasing hormone (GHRH)
- Thyrotropin releasing hormone (TRH)
- Adrenocorticotropic hormone (ACTH)
- MSH (melanocyte-stimulating hormone)

26. Surface Hormone Receptors
2. Single transmembrane receptors
- Insulin
- Insulin like growth factor I (IGF I)
- Epidermal growth factor (EGF)
- Platelet derived growth factor (PDGF)
3. Cytokine receptor super family
- GH, Prolactin,
- Erythropoietin
- Interleukin
- Leptin
Guanyl cyclase –linked receptor
- Natriuretic peptide

27. 1. A seven-transmembrane domain receptor
2. A single-ransmembrane domain receptor with kinase activity typical of many growth factors

28. 3. Receptors with no intrinsic tyrosine kinase activity but activation by soluble transducer molecules.
4. Receptors dependent on guanylyl cyclase or adenylyl cyclase and synthesis of cGMP and cAMP.

29. G protein-linked hormone mechanism
Activation of receptor induced by binding of the hormone (1st messenger).
Cytoplasmic tail of receptor activates
G protein
The activated G protein complex links to 2nd messenger which is responsible for the effect associated with hormone action

30. Second messenger systems cyclic AMP
- Hormone travels in blood plasma - Hormone binds to its receptor in the plasma membrane GPCR (G-protein coupled receptor) - Hormone-receptor binding activates a G protein (in plasma
membrane) - Activated G protein in turn activates the enzyme adenyl cyclase - Adenyl cyclase causes ATP to lose two P, becoming cAMP
(cyclic AMP [adenosine monophosphate]) - cAMP activates protein kinases (enzymes that activate other
proteins/enzymes), producing the hormonal effect

31. Hormones and their receptors
by classifying water soluble and lipid soluble
Hormone
Class of hormone
Location
Amine (epinephrine)
Water-soluble
Cell surface
Amine (thyroid hormone)
Lipid soluble
Intracellular
Peptide/protein
Water soluble
Cell surface
Steroids and Vitamin D
Lipid Soluble
Intracellular

33. Endocrine glands of animals

34. Hypothalamus
and
Pituitary gland
(hypophysis cerebri)

36. Hypothalamic releasing hormones
Effect on pituitary
Corticotropin releasing hormone (CRH)
Stimulates ACTH secretion
Thyrotropin releasing hormone (TRH)
Stimulates TSH and Prolactin secretion
Growth hormone releasing hormone (GHRH)
Stimulates GH secretion
Somatostatin
Inhibits GH (and other hormone) secretion
Gonadotropin releasing hormone (GnRH) a.k.a LHRH
Stimulates LH and FSH secretion
Prolactin releasing hormone (PRH)
Stimulates PRL secretion
Prolactin inhibiting hormone (dopamine)
Inhibits PRL secretion

38. Putuitary gland = Master gland
Because pituitary gland produces many hormones –k/s master gland
Pituitary extracts – obtained from pituitary glands from slaughter houses
Laborious and low yields
- 340 g/100 cattle; 30 g/100 pigs
- Pituitary extracts are used for research or commercial purposes

39. Pituitary gland (hypophysis cerebri)
Anterior lobe (adenohypophysis)
Posterior lobe (neurohypophysis)

40. Location of the pituitary gland
Just below the hypothalmus
Provide direct delivery of releasing and inhibiting hormones from the hypothalmus to the anterior lobe
direct entry of secretory neurons from the hypothalmus to posterior lobe
Hypophysioportal circulation
The venous blood drained from the hypothalmus is redistributed by another capillary system within the anterior lobe. Shortages of hormones in arterial blood are directed by specific cells within the hypothalmus, which are stimulated to secrete releasing hormones. The hormones produced are distributed by the second capillary bed to their appropriate cells in the anterior lobe.

41. Anterior Pituitary

42. Hypothalamic Regulator(s) Hormonal Function(s)
Hormone
Acronym
Hypophysial Cell Type
Hypothalamic Regulator(s)
Hormonal Function(s)
Corticotropin, Adrenocorticotropin
ACTH
Corticotrope
+Corticotropin Releasing Hormone, Corticoliberin (CRH); + Interleukin 1 ; - Glucocortical Steroids (via CRH); + Vasopressin
Stimulates glucocorticoid production by adrenal fasiculata & reticularis
Thyrotropin, Thyroid Stimulating Hormone
TSH
Thyrotrope
-Thyroxine (T4); +Thyroid Releasing Hormone, Thyroliberin (TRH); -Somatostatin (SS) 
Stimulates thyroxine production by thyroid
Prolactin, Mammotropin, Luteotropin
PRL
Lactotrope; Mammotrope
-Dopamine; + TRH; - SS; + Estrogens; + Oxytocin
Stimulates milk synthesis by secretory epithelium of breast; supports corpus luteum function
Somatotropin, Growth Hormone GH
Somatotrope
+ Growth Hormone Releasing Hormone, Somatoliberin (GHRH); - SS
Stimulates somatic growth, supports intermediary metabolism
Follitropin, Follicle Stimulating Hormone
FSH
Gonadotrope
+ Gonadotropin Releasing Hormone, Luteinizing Hormone Releasing Hormone, Gonadoliberin (GnRH, LHRH); - Inhibin; - Sex steroids (via LHRH) 
Supports growth of ovarian follicles & estradiol production; Supports Sertoli cell function & spermatogenesis
Lutropin, Luteinizing Hormone LH
+ GnRH (LHRH); - Sex steroids (via LHRH); + Estradiol in near midcycle
Supports late follicular development, ovulation, & corpus luteum function (especially progesterone synthesis); Supports testosterone synthesis, Leydig cell 
Melanotropin, Melanocyte Stimulating Hormone
MSH
Melanotrope
+ CRH
Supports dispersal & synthesis of pigment in melanocytes; may alter adrenal response to ACTH

43. (Release-Inhibiting Hormone)
STIMULUS
Hypothalamus
Releasing Hormone
(Release-Inhibiting Hormone)
Pituitary
Stimulating Hormone
Gland
Hormone
Target

45. Anterior Putuitary Hormones
Regulated by:
Releasing Hormones and Inhibiting hormones of hypothalmus

46. Cells of anterior pituitary and hormones
5 cell type; 7 hormones
1. Somatotrope cells (Growth ormone)
2. Corticotrope cells (adrenocorticotropic hormone and beta-lipotropin hormone)
3. Mammotrope cells (prolactin)
4. Thyrotrope cells (thyroid stimulating hormone)
5. Gonadotrope cells (Follicle stimulating hormone and luteinizing hormone)
Nature of anterior pituitary hormones
Polypeptides to large proteins
Different structures among species
- Replacement therapy from one spp to another not uniformly successful

47. Growth hormone (GH) Somatotropic hormone (STH)
Stimulatory effect of increase in body size
Growth of all tissues of the body
Both cell numbers and cell size
Epiphyseal bone plates are more sensitive to GH
Increases mitotic activity
Stimulate the liver to form several small proteins, somatomedins (Insulin-like growth factors 1 and 2, IGF 1 and IGF2)
Somatomedins act on cartilage and bone growth. Therefore bone and cartilage are not stimulated directly by GH but indirectly by this intermediate compound.

48. GH Several specific metabolic effects
because of this, GH is necessary throughout life
Metabolic effects
Increases
- rate of protein synthesis in all body cells
- mobilization of fatty acids from fat
- use of fatty acids for energy
Decreased rate of glucose uptake throughout the body
Use of fats for energy conserves glucose and promotes glycogen storage – the heart can endure emergency contraction more effectively whereby glycogen stored in the heart is converted to glucose.

49. GH
Milk production
Increasing milk yield in lactating cows by growth hormone is not stimulation on mammary gland but by partitioning of available nutrients from body tissues towards milk synthesis

50. Abnormal GH production
Excessive production of GH
Before puberty:
– increase growth of long bones (prolonged proliferation of growth plate chondrocytes)
After puberty – closure of epiphyseal plates
- acromegaly
- enlargement of extremities and facial bones
Gigantism – frequently seen in human
Failure to produce sufficient GH
– stunted growth
- dwarfism

51. Adrenocorticotrophic hormone (ACTH)
Increase activity of the adrenal cortex
Glucocorticoids and mineralocorticoids (aldosterone ) secretion
Similar effects of somatotropic hormone (STH)
- ↑protein synthesis
- ↑fatty acid uptake
- ↓ glucose uptake

52. Thyroid stimulating hormone (TSH)
Stimulate
- Synthesis of colloids by thyroid gland
- Release of thyroid hormone
Associate functions
- accumulation of iodine
- organic binding of iodine
- formation of thyroxine within the thyroid gland
- No extrathyroid activity as for STH and ACTH.

53. Gonadotropic hormones and prolactin
Follicle stimulating hormone (FSH) and luteinizing hormone (LH) have specific roles in male and female reproduction
FSH stimulates oogenesis and spermatogenesis
LH assists ovulation and development of functioning corpus luteum in female
LH stimulates secretion of testerone in male
Prolactin helps to initiate and maintain lactation after pregnancy
Maintenance of CL in ewe

54. Beta-lipoprotein hormone (β-LPH)
Secreted by adrenocorticotropic cells
Exact physiologic role unknown
Assumed to be involved in the pain relief and response to stress.

55. Posterior Pituitary

56. Posterior pituitary and its hormones
An outgrowth of hypothalmus
Contains terminal axons from two pairs of nuclei
- supraoptic nucleus and paraventricular nucleus
These nuclei synthesize
- Antidiuretic hormone (ADH)
- Oxytocin
Transported to axon terminals in the posterior pituitary, stored in secretary granules
An action potential generated by the need for each of stored hormones causes the release of the hormone and subsequent absorption into the blood – distributed to the receptor cells
Both hormones – peptides (nona-peptides – nine amino acids)
Neurosecretions

57. Collecting ducts of kidney)
Antidiuretic hormone (Vasopressin)
Normally outloaded water of the body – excreted by diuresis (increased output of dilute urine)
Diuresis can be prevented by administration of ADH
Dehydration
(osmoconcentration) ↓
osmoreceptors ↓
Posterior putuitary ↓
Target cells
(collecting tubules &
Collecting ducts of kidney) ↓
Release of ADH
Retention of water

58. Oxytocin Function related to the reproductive processes
Includes in parturition and laction
Neuroendocrine reflexes
- Suckling by young or similar teat stimulation
- Release of oxytocin
- Milk letdown
Myometrial contraction at parturition
Transport of sperm in the oviduct at copulation

59. Intermediate Lobe of Putuitary
During development a transitional zone between the neurally derived posterior lobe & the epithelially derived anterior lobe forms.
It is lost in adults of some species like humans but persists in others.
It makes melanocortin (MSH).
Get histology of the intermediate lobe.

60. Negative
Feedback
Mechanism
Simple
example

61. NEGATIVE FEEDBACK MECHANISM
Decreased hormone concentration
In the blood (e.g. Thyroxine)
Pituitary gland
Release of stimulating hormone (e.g. TSH)
Stimulation of target organs to produce &
release hormone
(e.g. Thyroid gland release of Thyroxine)
Return of the normal
Concentration of hormone

62. Most hormonal regulatory systems work via negative feed back
Occasionally, a positive feed back system contributes of regulation
- E.g. At parturition, where oxytocin stimulates contractions of the uterus and the uterus in turn stimulates more oxytocin release.

63. Thyroid Gland and
Thyroid Hormones

64. Thyroid glands Located - on the trachea just caudal to the larynx
- 2 laterally placed, flattened lobes joined by isthmus
- No isthmus in dog and cat
- pig has a large medial lobe instead of isthmus
Thyroid gland
- composed of numerous follicles lined by simple cuboidal epithelial cells filled with fluids (colloids)
Colloids - gel-like substances
- consists of a protein–iodine complex, thyroglobulins
- hormones T3 and T4 are stored in the colloids

65. Bovine thyroid gland

67. Thyroid hormones
T3 = tri-iodothyronine; T4 = tetra-iodothyronine

68. Regulation of secretion
Thyrotropin-releasing hormone (TRH) from hypothalmus controls the secretion of thyroid stimulating hormone (TSH) from the anterior pituitary
TSH stimulates the synthesis of thyroxine (T4) and triiodothyroxine (T3)
T4 and T3 inhibit TRH by negative feedback
There is no thyrotropin inhibiting hormone

69. Regulation of secretion

70. Thyroid hormones: Synthesis and release
Iodine containing compounds
Belong to the amine classification of hormones
derived from tyrosine
Iodine trapping and iodination are unique features of the thyroid gland
Synthesis of thyroglobulin
Iodination of tyrosine
Coupling of T1 and T2 to form T3 and T4
T3 and T4 are attached to the thyroglobulin in the colloids
Lysosomes - release proteolytic enzymes that separate T3 and T4 from the thyroglobulin

71. Thyroid hormones: Synthesis and release
About 90% of thyroid hormones released is T4
Released T3 and T4 immediately combined with plasma protein (mainly thyroxine binding globulin – TBG) for transport in the blood
TBG – greater affinity to T3 than T4
Therefore, T3 is released more to the tissues
Once in the tissues, T3 is more potent than T4 but short duration of action

72. Functions of thyroid hormones
Increase internal heat
increased rate of O2 consumption
Stimulate metabolic activities of most tissues of the body except brain, lungs, retina, testes and spleen
Increased metabolic activity and O2 consumption are through activation and stimulation of key enzymes
- alpha glycerophosphate dehydrogenase
- hexokinase
- diphosphoglycerate mutase
- cytochrome b and c
Thyroid hormones also markedly potentiate lipolytic effect of epinphrine
It is suggested that heat generated is secondary to protein synthesis stimulated by thyroid hormones

73. Thyroid deficiency and antithyroid compounds
Typical deficiency
Result from iodine deficiency and consequently inability of the thyroid gland to produce T3 and T4
Lack of circulating hormones causes feedback mechanisms so that TSH is produced
This causes thyroglobulin accumulation without effective output of T3 and T4
Thyroid gland enlarges because of colloid accumulation
- a condition k/s goiter

74. Thyroid enlargement (goiter) may be caused by
Hypothyroidism (iodine deficiency) or
Hyperthyroidism (increased thyroxine demands, tumour)
Goiter caused by iodine deficiency – rare in animals
Other causes of thyroid disfunction
– relatively low in sheep, cattle and swine

75. Hyperthyroidism – common in dogs and cats - Signs of hyperthyroidism
- Fatigue
- weight loss
- Hunger
- nervousness
- sensitivity to heat
Signs of hypothyroidism
- lack of activity (lethargy)
- hair loss, dry and dull hair
- cold sensitivity
- anaemia

76. Antithyroid compounds
Goitrogens
Natural substances – inhibit thyroid function
Thyroxine is not produced in sufficient amounts and TSH continues to be secreted -- thyroglobulin accumulation
Goitrin
Produced in the intestinal tract after ingestion of progoitrin containing plants (cabbage, turnip)
Thiocyanate
- Another goitrogen in some plants; it interferes with iodine trapping
This can be overcome by feeding excess iodine
Antithyroid compounds are used in the treatment of hyperthyroidism
- thiourea, thiouracil, sulphonamides, chlorpromazine
- propylthiouracil or methimazole

77. Hyperthyroidism in man
Signs and symptoms
Increased heart rate
More forceful heartbeat or contractions
Increased blood pressure
Anxiety
Weight loss
Difficult sleeping
Tremors in the hands
Weakness
Bulging eyes (exophthalmos)
Remember - Hyperthyroidism - rare in animals except old cats and dogs

78. Hypothyroidism in man Cretinism Signs and symptoms Weight gain
Dry skin and puffy skin
Constipation
Cold intolerance
Hair loss
Fatigue and
Menstrual irregularity in women.
Cretinism
Congenital lack of thyroid hormone
Characterized by arrested physical and mental development

79. Calcitonin
- Produced by C cells (parafollicular cells) of thyroid gland
Peptide hormone
Lowers blood calcium level inhibiting the action of osteoclasts
Calcitonin release
– Hypercalcemia (lesser degree by hypermagnesemia)
– directly regulated by negative feedback of serum calcium concentration on C cells, NOT by TSH
physiological importance in overall regulation of calcium conc is minimal compared with the role of parathyroid hormones

80. Diabetes in animals before midterm break
1. Presentations
8 groups of students, each with 5 students
Presentation on Week 13
Hormone receptors and their regulations (G2)
Hyperthyroidism and hypothyroidism (G3)
Hyper- and hypo-secretion of Growth Hormone (G6)
Parathyroid gland and calcium metabolism (G1)
Factors that affect urine concentration (G8)
Renal function tests (G7)
Thyroid function test (G4)
Hormonal influence on the various stages of estrous cycle (G5)
One Assignment
Diabetes in animals before midterm break