L 1 Characters_Mechanisms_Pituitary Final

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Endocrine System

Lecture 1

Characters and mechanisms of actions of hormones

Pituitary hormones

Asso. Professor Dr Than Kyaw

17 September 2012

What is endocrinology?

Endocrinology

Study of:

- Intercellular Chemical Communication

- about communication systems & information transfer.

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?

PGF

2 α

- 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

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)

Gap junctions

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

Synaptic cleft

Between a neuron and a muscle fiber or

Between 2 neurons

Acetylcholine

Mode of transmission

3.

Paracrine transmission

- Hormones diffuse through interstitial fluid - PGF

2

α

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

Endocrine Functions

Maintain Internal Homeostasis

Support Cell Growth

Coordinate Development

Coordinate Reproduction

Facilitate Responses to External Stimuli

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 & 2 º Messengers

Amplifier = Transducer/Effector Enzymes

Effector = Effector Proteins

Response = Cellular Response

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 2 nd 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.

Classes of hormone

1. Amine hormones (can b lipophilic / hydrophilic)

thyroid hormones, catecholamines (aromatic amines)

- all derived from single amino acids

- thyroid hormones - from tyrosine (lipophilic)

- catecholamines - from tyrosine

- melatonin - from tryptophan

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

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

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, prostacyclin

Hormone Interactions

Responsiveness 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. (not directly involved in the action)

- 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.

Hormone Interactions

2. Synergistic effects when the effect of two hormones acting together is greater or more extensive than the sum of each hormone acting alone

3. 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

Enzyme amplification

One hormone molecule does not trigger

- the synthesis of just one enzyme molecule

It activates thousands of enzyme molecules through cascade 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

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

Metabolic Clearance Rate or

Half-life of some hormones

Hormone

Amines

Thyroid hormones: T4

T3

Polypeptides

Proteins

Steroids

Half-life

2-3 min

6.7 days

0.75 days

4-40 min

15-170 min

4-120 min

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.

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.

Hormone & Receptor in General

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.

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 (G

S

)

-- Inhibitory (G

I

)

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)

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

4. Guanyl cyclase –linked receptor

- Natriuretic peptide

1. A seven-transmembrane domain receptor

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

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.

Activation of receptor induced by binding of the hormone (1 st messenger).

Cytoplasmic tail of receptor activates

G protein

The activated G protein complex links to

2 nd messenger which is responsible for the effect associated with hormone action

G protein-linked hormone mechanism

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

Hormones and their receptors by classifying water soluble and lipid soluble

Hormone

Amine

(epinephrine)

Amine (thyroid hormone)

Peptide/protein

Steroids and

Vitamin D

Class of hormone

Water-soluble

Lipid soluble

Water soluble

Lipid Soluble

Location

Cell surface

Intracellular

Cell surface

Intracellular

Endocrine glands of animals

Hypothalamus and

Pituitary gland

(

hypophysis cerebri

)

Hypothalamic releasing hormones

Hypothalamic releasing hormone Effect on pituitary

Corticotropin releasing hormone

(CRH)

Thyrotropin releasing hormone

(TRH)

Growth hormone releasing hormone

(GHRH)

Somatostatin

Stimulates ACTH secretion

Stimulates TSH and Prolactin secretion

Stimulates GH secretion

Inhibits GH (and other hormone) secretion

Stimulates LH and FSH secretion Gonadotropin releasing hormone

(GnRH) a.k.a LHRH

Prolactin releasing hormone (PRH) Stimulates PRL secretion

Prolactin inhibiting hormone

(dopamine)

Inhibits PRL secretion

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

Pituitary gland (hypophysis cerebri)

Anterior lobe (adenohypophysis)

Posterior lobe (neurohypophysis)

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

Hypophyseal portal 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.

Anterior Pituitary

Hormone

Corticotropin

,

Adrenocortic otropin

Thyrotropin,

Thyroid

Stimulating

Hormone

Prolactin,

Mammotropi n,

Luteotropin

Somatotropin

, Growth

Hormone

Follitropin,

Follicle

Stimulating

Hormone

Lutropin,

Luteinizing

Hormone

A

C

T

H n y m r o

A c

T

S

H

P

R

L

G

H

F

S

H

L

H

Hypop hysial

Cell

Type

Cortic otrope

Thyrot rope

Lactot rope;

Mam motro pe

Somat otrope

Gona dotro pe

Gona dotro pe

Melanotropin,

Melanocyte

Stimulating

Hormone

M

S

H

Melan otrope

Hypothalamic Regulator(s)

+Corticotropin Releasing Hormone,

Corticoliberin (CRH); + Interleukin 1 ; -

Glucocortical Steroids (via CRH); +

Vasopressin

-Thyroxine (T

4

(SS)

-Dopamine; + TRH; - SS; + Estrogens; +

Oxytocin

+ Growth Hormone Releasing Hormone,

Somatoliberin (GHRH); - SS

+ CRH

); +Thyroid Releasing

Hormone, Thyroliberin (TRH); -Somatostatin

+ Gonadotropin Releasing Hormone,

Luteinizing Hormone Releasing Hormone,

Gonadoliberin (GnRH, LHRH); - Inhibin; - Sex steroids (via LHRH)

+ GnRH (LHRH); - Sex steroids (via LHRH); +

Estradiol in near midcycle

Hormonal Function(s)

Stimulates glucocorticoid production by adrenal fasiculata & reticularis

Stimulates thyroxine production by thyroid

Stimulates milk synthesis by secretory epithelium of breast; supports corpus luteum function

Stimulates somatic growth, supports intermediary metabolism

Supports growth of ovarian follicles & estradiol production; Supports Sertoli cell function & spermatogenesis

Supports late follicular development, ovulation, & corpus luteum function

(especially progesterone synthesis); Supports testosterone synthesis, Leydig cell

Supports dispersal & synthesis of pigment in melanocytes; may alter adrenal response to

ACTH

STIMULUS

Hypothalamus

Releasing Hormone

(Release-Inhibiting Hormone)

Pituitary

Stimulating Hormone

Gland

Hormone

Target

Anterior Putuitary Hormones

Regulated by:

Releasing Hormones and Inhibiting hormones of hypothalmus

Cells of anterior pituitary and hormones

5 cell type; 7 hormones

1. Somatotrope cells (Growth hormone)

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

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.

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.

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

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

Adrenocorticotrophic hormone (ACTH)

Increase activity of the adrenal cortex

Glucocorticoids and mineralocorticoids

(aldosterone ) secretion

Similar effects of somatotropic hormone (STH)

-

↑ protein synthesis (mobilisation of AA for gluconeogenesis)

- ↑fatty acid uptake

- ↓ glucose uptake

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.

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

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.

Posterior Pituitary

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

Neurosecretions

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)

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

Release of ADH

Target cells

(collecting tubules &

Collecting ducts of kidney)

Retention of water

Oxytocin

Function related to the reproductive processes

Includes in parturition and lactation

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

Intermediate Lobe of Putuitary

 During development a transitional zone between the neural derived posterior lobe

& the epithelium derived anterior lobe forms.

 It is lost in adults of some species like humans but persists in others.

 It makes melanocortin (MSH).

Negative

Feedback

Mechanism

Simple example

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

• 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.

Thyroid Gland and

Thyroid Hormones

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

Bovine thyroid gland

Thyroid hormones

T3 = tri-iodothyronine; T4 = tetra-iodothyronine

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

Regulation of secretion

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

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

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

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

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

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

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

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

Hypothyroidism in man

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

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

1. Presentations

8 groups of students, each with 5 students

Presentation on Week 13

1. Hormone receptors and their regulations (G2)

2. Hyperthyroidism and hypothyroidism (G3)

3. Hyper- and hypo-secretion of Growth Hormone (G6)

4. Parathyroid gland and calcium metabolism (G1)

5. Factors that affect urine concentration (G8)

6. Renal function tests (G7)

7. Thyroid function test (G4)

8. Hormonal influence on the various stages of estrous cycle

(G5)

2. One Assignment

Diabetes in animals before midterm break

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