Endocrine System

Lecture 1Characters and mechanisms of actions of

hormonesPituitary 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?

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

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)

Modes of transmission

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

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

Mode of transmission

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 & 2º 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 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.

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

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

Classes of hormone

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.

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

Hormone Interactions

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 orHalf-life of some hormones

Hormone Half-life

Amines 2-3 min

Thyroid hormones: T4 T3

6.7 days0.75 days

Polypeptides 4-40 min

Proteins 15-170 min

Steroids 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 hormonefor 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 ProteinAny 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)

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

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

1. A seven-transmembrane domain receptor

4. Receptors dependent on guanylyl cyclase or adenylyl cyclase and synthesis of cGMP and cAMP.

3. Receptors with no intrinsic tyrosine kinase activity but activation by soluble transducer molecules.

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

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 receptorsby 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

Endocrine glands of animals

Hypothalamusand

Pituitary gland (hypophysis cerebri)

Hypothalamic releasing hormones

Hypothalamic releasing hormone 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

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 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

Gonadotrope

+ 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

STIMULUS

HypothalamusReleasing Hormone

(Release-Inhibiting Hormone)

PituitaryStimulating Hormone

GlandHormone 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

- 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.

Growth hormone (GH)

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

- 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)

Posterior pituitary and its hormones

Neurosecretions

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).

Simpleexample

Negative Feedback

Mechanism

Decreased hormone concentrationIn 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

NEGATIVE FEEDBACK MECHANISM

• 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 hormonesT3 = tri-iodothyronine; T4 = tetra-iodothyronine

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

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

- 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

Calcitonin

1. Presentations

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)

8 groups of students, each with 5 studentsPresentation on Week 13

2. One Assignment

Diabetes in animals before midterm break