Hormone ?? PROGRAM KEDOKTERAH HEWAN UNIVERSITAS BRAWIJAYA

Hormone ??PROGRAM KEDOKTERAH HEWANUNIVERSITAS BRAWIJAYA

Organism level Organ system level

Organ and Tissue levels

Cellular level

Macromolecular level

Molecular level

0.2 mm 20 µm 2 µm 200 nm 20 nm 2 nm 0.2 nm

Atoms

Molecules

Organelles

Cells

Biological function at each level of organization

Course Outline

Hormone: Definition ,classification dan Fungsi

Endocrine System

4

• Endocrine glands are ductless• Exocrine glands have ducts

• A specific chemical compound• Produced by a specific tissue of the body• Where it is released in the body fluids• And carried to a distant target tissue• Where it affects a pre-existing mechanism• And is effective is small amounts.

Definition

They are the chemical integrators of a multicellular existence, coordinating activities from daily maintenance to reproduction and development.

Hormone

• Substance produced by endocrine gland

• Acts on cells, tissues or organs at a place other than where produced

• Acts as a catalyst.

• Major Endocrine Organs are• Hypothalamus• Pituitary gland• Thyroid gland• Parathyroid gland• Thymus• Adrenal gland• Pancreas• Ovaries• Testes

Classification

Hormones can be classified by several properties

1. Classification by site of action.1.1. Autocrine secretion - substance released by cell

that affects the secreting cell itself(e.g. norepinephrine is released by a

neurosecretory cell in the adrenal medulla, andnorepinephrine itself inhibits further release by

that cell - this is also an example of direct negative feedback)

Endocrine Glands

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Endocrine glands• release hormones• hormones travel through blood to target cells

Paracrine secretions• act locally• affect only neighboring cells

Autocrine secretions• affect only the secreting cell

Testes(in bull)

Placenta

Uterus

OvaryAdrenalPineal

Hypothalamus

Pituitary

Pancreas

Thyroid

Endocrine Glands

Classification and Properties of Hormone

A. Site of Production

B. Type of action

1. Primary hormone of reproduction

2. Metabolic hormone

C. Chemical Structure

1. General structure• Proteins and polypeptides• Steroids• Fatty acids• Modified amino acid

2. Size

Paracrine secretion - substance released by cell that affects neighboring cells. - Not released into bloodstream (e.g. histamine released at site

of injury to constrict blood vessel walls and stop bleeding)Endocrine secretion - substance released by cell into bloodstream that affects distant

cells.

Types of cell-to-cell signaling

Classic endocrine hormones travel via bloodstream to target cells; neurohormones are released via synapses and travel via the bloostream; paracrine hormones act on adjacent cells and autocrine hormones are released and act on the cell that secreted them. Also, intracrine hormones act within the cell that produces them.

ANATOMICAL classification

Hypothalamus: Somatostatin Growth hormone releasing hormone

(GHRH)Thyrotropin releasing hormone (TRH) Gonadotropin releasing hormone (GnRH) Corticotropin releasing hormone (CRH) Prolactin releasing hormone (PRH)Dopamine (PIH)

Function of Hypothalamus• appetite• thirst• body temperature• vasomotor activity• emotion• use of body nutrient reserves• activity of intestine• sleep• sexual behavior• Production and release of releasing hormones

Cells of the Anterior Pituitary

• LH• FSH• Prolactin• STH• TSH• ACTH

HypothalamusHypothalamus

Nerve Cells

Nerve Cells

Superior hypophyseal

artery

Hypophyseal portal vessels

Capillary plexus

Posterior pituitary

Capillary plexus

Preoptic nuclei cell

Preoptic nuclei cell

Hypothalamus

Nuclei that produce posterior pituitary hormones

Nuclei that produce posterior pituitary hormones

Pituitary Gland Control

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• Hypothalamic releasing hormones stimulate cells of anterior pituitary to release hormones

• Nerve impulses from hypothalamus stimulate nerve endings in the posterior pituitary gland to release hormones

Anterior Pituitary HormonesA. Structure

1. glycoproteins or proteinsB. Hormones

1. gonadotropins• Follicle stimulating hormone (FSH)• Luteinizing hormone (LH)• Prolactin

Anterior Pituitary Hormones2.Other trophic hormones

• Adrenal Corticotropin (ACTH)• thyroid stimulating hormone (TSH) • growth hormone (GH or STH)

Anterior pituitary gland

Growth hormone (hGH)Thyroid stimulating hormone(TSH)Gonadotropins (FSH and LH)Adrenocorticotropic hormone (ACTH)Prolactin Melanocyte stimulating hormone (MSH)

Posterior pituitary gland:

Antidiuretic hormone (ADH, or: vasopressin) Oxytocin

Thyroid Gland

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Thyroid gland :

Thyroid hormones (T3 and T4)CalcitoninParathyroid glands : Parathyroid hormone (PTH)

Thyroid Gland Hormones

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Disorders of the Thyroid Gland

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Thyroid hormones

Adrenal cortex:

Cortisol AldosteroneDehydroepiandrosterone (DHEA)Adrenal medulla : Adrenalin (or: epinephrine)Noradrenalin (or: norepinephrine)

Kidney:

Erythropoietin1,25 Dihydroxy Vit D3Renin / angiotensin IPancreas: InsulinGlucagon

Liver:

Insulin-like growth factor (IGF I) or: somatomedinStomach: Gastrin Duodenum: SecretinCholecystokinin (CCK)

Gonads:

Sex hormones: Oestrogen, progesterone, testosterone.

Classification and Properties of Hormone

• Chemical Structure• Polypeptides - hypothalamic• Protein - pituitary, gonad• Steroids - gonad, adrenal• Fatty acid - many sources, prostaglandins• Modified amino acid - pineal

Chemistry of Hormones

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Steroid or Steroid-Like Hormones

• sex hormones• adrenal cortex hormones

Nonsteroid Hormones• amines• proteins• peptides• glycoproteins• most hormones

Chemical Structure of Hormones

polypeptide modified amino acid protein sex steroid fatty acidGnRh melatonin LH Estradiol PGFTRH FSH ProgesteroneCRH Prolactin TestosteroneGHRH ACTHSomatistatin TSHOxytocin GH or STH

RelaxinInhibin

2

Chemical Structure of Hormones

FSH 30,000 to 37,000LH 26,000 to 32,000Prolactin 23,000 to 25,000HCG 37,700eCG 28,000Inhibin >10,000Relaxin 6,500ACTH 4,500Oxytocin 1,007GnRH 1,200Estradiol 300Testosterone 300Progesterone 300PGF 300

Molecular size of hormones that regulate reproduction

Hormone Molecular Weight

2

Chemical Structure of Hormones Cont.

Polypeptide and protein hormonesare made of peptide bonds

NH 3

CH

C

HN

HC

C

NH

CH

COO-

R

O

R

O

R

Peptide Bond

These hormones can not be given orally!These hormones can not be given orally!

Chemical Structure of Hormones Cont.

SteroidsCHOLESTEROL

PREGNENOLONE

CORTISOL

ADRENAL OVARY OR TESTES

PROGESTERONE

OH-PROGESTERONE

ANDROSTEINDIONE ESTRONE

TESTOSTERONE ESTRADIOL

PROGESTERONE

CORTISOL

These hormones can be given orally!These hormones can be given orally!

Types of Hormones

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Structural Formulas of Hormones

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Hormones – chemical structure Hormones – chemical structure and synthesisand synthesis

1. Proteins and polypeptides –the anterior and posterior pituitary gland hormones, the pancreas (insulin, glucagon), the parathyroidal gland (parathyroidal hormone), etc.

2. Steroids – the adrenal cortex (cortisol, aldosterone), the ovaries (estrogen, progesterone), the testes (testosterone), the placenta (estrogen, progesterone)

3. Derivates of amino acid tyrosine – the thyroid gland (thyroxine, triiodothyronine), the adrenal medullae (epinephrine, norepinephrine)

Polypeptide and protein Polypeptide and protein hormoneshormones

Most of the hormones in the body.• Protein = 100 of more amonoacids• Peptides = less than 100 aminoacidsSynthesized in the rough endoplasmatic

reticulum as preprohormones prohormones transferred to Golgi apparatus secretory vehicles hormones (enzymatic fission) exocytosis

Water soluble – easy reaching the target tissue by circulatory system

Steroid hormonesSteroid hormones

• Usually synthesized from cholesterol• Not stored, but possible quick utilization

from cholesterol in the blood• Lipid soluble – diffuse across the cell

membrane interstitial fluid blood

Steroid hormonesAll steroid hormones are derived from cholesterol and differ

only in the ring structure and side chains attached to it.All steroid hormones are lipid soluble

Types of steroid hormones• Glucocorticoids; cortisol is the major representative in most

mammals • Mineralocorticoids; aldosterone being most prominent • Androgens such as testosterone • Estrogens, including estradiol and estrone • Progestogens (also known a progestins) such as progesterone

Steroid hormones

• Are not packaged, but synthesized and immediately released

• Are all derived from the same parent compound: Cholesterol

• Enzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ER

• Steroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells

Steroid hormones

• Steroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins.

• Corticosteroid binding globulin carries cortisol• Sex steroid binding globulin carries testosterone

and estradiol• In some cases a steroid is secreted by one cell

and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

Steroids can be transformed to active steroid in target cell

Steroidogenic EnzymesCommon name "Old" name Current name

Side-chain cleavage enzyme; desmolase

P450SCC CYP11A1

3 beta-hydroxysteroid dehydrogenase

3 beta-HSD 3 beta-HSD

17 alpha-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11 beta-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro CYP19

Steroid hormone synthesis

All steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates.

The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

Steroid hormone synthesis

•The cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol-containing low density lipoproteins.

•Lipoproteins taken up from plasma are most important when steroidogenic cells are chronically stimulated.

cholesterol

Extracellularlipoprotein

Cholesterolpool

LH

ATP

cAMPPKA+

Pregnenolone

Progesterone

Androstenedione

TESTOSTERONE

3HSD

P450c17

17HSD

acetate

Cholesterol is a 17 ketosteroid and an important precursor for all steroid hormones.

Actions of Steroid Hormones

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• hormone crosses membranes

• hormone combines with receptor in nucleus

• synthesis of mRNA activated

• mRNA enters cytoplasm to direct synthesis of protein

Actions of Steroid Hormones

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Actions of Nonsteroid Hormones

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• adenylate cyclase activated

• hormone binds to receptor on cell membrane

• ATP converted to cAMP

• cAMP promotes a series of reactions leading to cellular changes

Actions of Nonsteroid Hormones

59

Amino hormonesAmino hormones

Derivatives from tyrosine• The thyroid hormonesSynthesized and stored in follicules in the

thyroid gland as thyreoglobulin free hormone to the blood connection to plasma proteins (thyroxine-binding globulin)

• Adrenal medullary hormonesStored in vesicles exocytosis in the blood

as a free hormone or in combination with different substances

Amine Hormones

• Two other amino acids are used for synthesis of hormones: • Tryptophan is the precursor to serotonin and the pineal

hormone melatonin • Glutamic acid is converted to histamine

Fatty Acid Derivatives - Eicosanoids• Arachadonic acid is the most abundant

precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell.

• These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds.

Fatty Acid Derivatives - Eicosanoids

• Eicosanoids are a large group of molecules derived from polyunsaturated fatty acids.

• The principal groups of hormones of this class are prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Regulation of hormone secretionSensing and signaling: a biological need is

sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. Key features of this stimulus response system are: receipt of stimulus synthesis and secretion of hormone delivery of hormone to target cell evoking target cell response degradation of hormone

Prostaglandins

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• paracrine substances

• act locally

• very potent in small amounts

• regulate cellular responses to hormones

• can activate or inhibit adenylate cyclase• controls cAMP production• alters cell’s response to hormones

• wide variety of functions

Hormone secretion and Hormone secretion and blood concentrationblood concentration

• Norepinephrine, epinephrine -secreted within seconds after the gland is stimulated and develop full action within another few seconds to minutes

• Thyroxine or growth hormone – require months to full effect

• Rates of secretion: μg – mg / day• Concentration in the blood: pg - μg / ml

of blood

Feedback control of hormone Feedback control of hormone secretion - Negative feedbacksecretion - Negative feedback

• Prevents overactivity of hormone system• The control variable is often not the secretory

rate of the hormone itself but the degree of activity of the target tissue

• Feedback regulation of hormones can occur at all levels, including gene transcription and translation steps involved in processing the hormone or releasing the stored hormone

• HPA axis (hypothalamo-pituitary-adrenal axis) = complex negative feedback

Control of Hormonal Secretions

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• primarily controlled by negative feedback mechanism

Negative Feedback

69

Complex negative feedbackComplex negative feedback

Controlling centers of the CNS

Neural pathways

HypothalamusHypothalamic hormones

AdenohypophysisAdenohypophysal hormones

Peripheral glands

Hormones of peripheral glands

Tissue

Feedback control of hormone Feedback control of hormone secretion - Positive feedbacksecretion - Positive feedback

• Just in a few instances• Positive feedback occurs when the biological

action of the hormone causes additional secretion of the hormone

• Secretion of LH (luteinizing hormone) based of the stimulatory effect of estrogen before ovulation – LH stimulates ovaries to produce more estrogen and it stimulates again the pituitary gland to produce LH. When the LH reaches the appropriate concentration the negative feedback occurs

Hormone releaseHormone release

• Cyclical variation influenced by seasonal changes, stages of development and aging, circadial cycle, sleep etc.• STH (growth hormone) – development, ↑ during early

period of sleep, ↓ during later stages of sleep• Gonadal hormones - development and aging, seasonal

changes, lunar cycles• ACTH, glucocorticoids etc. – circadial cycle

• Reflex release influenced by stress and new situations• Stress hormones – corticoids, renin-angiotensin-

aldosterone system, prolactin

Transport of hormones in the Transport of hormones in the bloodblood

• Water-soluble hormones (peptides and catecholamines) – dissolved in the plasma, diffusion from capillaries to the interstitial fluid and to target cells

• Lipid soluble (steroid hormones) and thyroid hormones – circulate in the blood mainly bound to plasma proteins (less then 10% as free hormones). • Thyroxine – more than 99% bound to plasma proteins.• Hormones bound to proteins are biologically inactive

(reservoir) until they dissociate from plasma proteins

““Clearance” of hormones from Clearance” of hormones from the bloodthe blood

Clearance = rate of disappearance from plasma / concentration in plasma (measuring by radioactive hormone)

Ways to clear hormones from plasma:

• Metabolic destruction by the tissue (enzymes)

• Binding with the tissue (some hormones may be recycled)

• Excretion by the liver into the bile (steroid hormones), long-time life period because they are bound to plasma proteins – half-life of thyroid hormones = 1-6 days

• Excretion by the kidneys into the urine (peptide hormones and catecholamines = water soluble – short-time life period)

Hormone receptorsHormone receptors

• Location:• In or on the surface of the cell membrane – proteins, peptides,

catecholamines• In the cell cytoplasm – steroid hormones• In the cell nucleus – Thyroid hormones

• Hormonal receptors are large proteins• Each cell has 2 000 – 100 000 receptors• Receptors are usually highly specific for single

hormone• The number of receptors does not remain constant (from

day to day, even from minute to minute). Receptors are inactivated or destroyed (down-regulation) and reactivated or produced new ones (up-regulation).

Intracellular signaling after Intracellular signaling after hormone receptor activationhormone receptor activation

Different ways of hormone action:• Change of membrane permeability (ionotropic

receptors), opening and closing ion channels (Na+, K+, Ca2+)of postsynaptic receptors – acetylcholine, norepinephrine

• Activation of intracellular enzyme• Kinase promotes phosphorylation – insulin• Adenyl cyclase catalyzes the formation of cAMP (cyclic

adenosine monophosphate) or cGMP (cyclic guanosin monophosphate) = second messengers

• Binding with intracellular receptors – steroid and thyroid hormones – hormone-receptor complex activates specific portion of DNA and this initiates transcription of specific genes to form mRNA – protein synthesis (long-term process)

The adenylyl cyclase – cAMP The adenylyl cyclase – cAMP second messenger systemsecond messenger system

Hormones:• ACTH (Adrenocorticotropic

hormone)• Angiotensin II (epithelial cells)• Calcitonin• Catecholamines (β receptors)• CRH (Corticotropin-releasing

hormone)• FSH (Follicle-stimulating hormone)• Glucagon• HCG (Human chorionic

gonadotropin)• LH (Luteinizing hormone)• PTH (Parathyroid hormone)• Secretin• TSH (Thyroid-stimulating hormone)• Vasopressin (V2 receptor,

epithelial cells)

The cell membrane The cell membrane phospholipids second messenger phospholipids second messenger

systemsystemHormones:• Angiotensin II (vascular smooth

muscles)• Catecholamines (α receptor)• GRH (gonadotropin-releasing

hormone)• GHRH (Growth hormone-

releasing hormone)• Oxytocin• TRH (Thyroid-releasing hormone)• Vasopressin (V1 receptor,

vascular smooth muscle)

Hormones acting on the Hormones acting on the genetic machinery of the cell genetic machinery of the cell

(1)(1)• Steroids:

• Steroid hormone enters the cytoplasm of the cell and binds to receptor protein (HSP = heat-shock-protein)

• Receptor protein-hormone complex diffuses or is transported into the nucleus

• The complex binds to the DNA and activates the transcription process of specific genes to form mRNA

• mRNA diffuses into the cytoplasm, promotes translation process at the ribosomes and forms new proteins

Example: Aldosterone (mineralocorticoid from adrenal cortex) acting in renal tubular system. The final effect delays hours after aldosterone enters the cell.

Hormones acting on the Hormones acting on the genetic machinery of the cell genetic machinery of the cell

(2)(2)• Thyroid hormones:

• Hormones bind directly with receptor proteins in the nucleus

• Those proteins are probably protein molecules located within the chromosomal complex

• Function of thyroid hormones:• They activate the genetic mechanisms for the formation

of many types of intracellular proteins (100 or more) – many of them are enzymes that control intracellular metabolic activity

• Their function of this control may last for days or even weeks

Measurement of hormone Measurement of hormone concentration in the bloodconcentration in the blood

Radioimmunoassay• Hormone specific antibody is mixed

with:• Animal fluid (serum) containing the

hormone• Standard hormone marked by

radioactivity

• Hormones (animal’s and standard) compete for this antibody

• Result: • More radioactive hormone-antibody

complex (after separation) = little animal’s hormones

• Less radioactive hormone-antibody complex (after separation) = lot of animal’s hormones

Homeostasis – function of Homeostasis – function of hormones (1)hormones (1)

• Osmolality (280-300 mosm/l)• Aldosterone, antidiuretic hormone, insulin

• Acid-base balance (bases 145-160 mmol/l, bicarbonate 24-35 mmol/l, pH 7.4 ± 0.4)• Aldosterone, antidiuretic hormone, insulin

• Ions in blood• Na+ (130-148 mmol/l) – aldosterone, cortisol, atrial natriuretic peptide• K+ (3.8-5.1 mmol/l) – aldosterone, cortisol• Ca2+ (2.25-2.75 mmol/l) – parathormone, calcitriol, calcitonin• Phosphates (0.65-1.62 mmol/l) - parathormone, calcitriol, calcitonin• Mg2+ (0.75-1.5 mmol/l) - parathormone, calcitriol

• Cholesterolemia (4-6 mmol/l)• Gonadal hormones, thyroxine, trioidothyronine

• Proteinemia (64-82 g/l, albuminemia 35-55 g/l)• Gonadal hormones, growth hormone, trioidothyronine, cortisol

• Glykemia (3.9-6.7 mmol/l)• Insulin, glucagon, cortisol, adrenalin, growth hormone

Homeostasis – function of Homeostasis – function of hormones (2)hormones (2)

• Energetic and oxygen metabolism (basal metabolism = 1800 kcal/day, 7600 kJ/day)• ↑ - thyroxine, trioidothyronine, epinephrine,

norepinephrine, glucagon, cortisol• ↓ - insulin

• Blood pressure (120/80 mmHg)• ↑ - angiotensin, epinephrine, norepinephrine,

aldosterone, glucocorticoids• ↓ - Atrial natriuretic factor, NO, kinins, endothelial

relaxating factor

Hormone Receptors

A hormone receptor is a receptor protein on the surface of a cell or in its interior that binds to a specific hormone. The hormone causes many changes to take place in the cell.

Binding of hormones to hormone receptors often trigger the start of a biophysical signal that can lead to further signal transduction pathways, or trigger the activation or inhibition of genes

Types of Hormone Receptors

Peptide hormone receptors are often transmembrane proteins. They are also called G-protein-coupled receptors, sensory receptors or ionotropic receptors. These receptors generally function via intracellular second messengers (cAMP)

Steroid hormone receptors and related receptors are generally soluble proteins that function through gene activation. These are plasma membrane, cytosol and nucleus. They are generally intracellular receptors.

Types of receptors: Type I Receptors : Sex hormone receptors (sex hormones) ; Glucocorticoid receptor (glucocorticoids) ; Mineralocorticoid receptor (mineralocorticoids)

Type II Receptors: Thyroid hormone receptor