HORMONE

Hormone is a chemical messenger, secreted in trace amount by specific cells that carries a signal to generate some alternation at the cellular level

The endocrine (or) ductless glands secrete hormones directly into the blood stream

Systemic or general hormones

Hormones act on distant targets ( via the blood stream )

Local hormones

Local hormones act mainly in the tissues and sites in which they are produced eg. Eicosanoids, endothelin, nitric oxide, histamine etc

Tropic hormones

Stimulate the secretion of hormones from other endocrine glands or tissues

They also promote the synthesis of hormones and increase the vascularity and the growth of the target gland or tissue

Endocrine hormone

That arise in one tissue, or gland and travel a considerable distance through the circulation to reach a target cell

Paracrine hormone

Arise from a cell and travel a relatively small distance

Autocrine hormone

Are produced by the cells that are also a target cell

GENERAL CHARACTERISTICS OF HORMONE

1. Chemical nature of hormone

2. Types of synthesis and modification of hormones

3. Transport of hormones

4. Concentration of hormones in body fluids

5. Feedback control of plasma hormone level

6. Target cell

7. receptors

1.Chemical nature of hormone

lipid derivatives

Steroids: -------- adrenocortical hormone, sex hormones and 1.25 DHCC

Fatty acid------- prostaglandin

Retinols--------- retinoic acid

Protein and amino acid derivatives

Proteins ------------------ Insulin, growth hormone, parathyroid hormone, prolactin, chorionic somatotrophin

Peptides------------------- antidiuretic hormone, glucagon and adrenocorticotropic hormone, melanocyte stimulating hormone, endorphins, oxytocin, thyrotrophin releasing hormone

Glycoprotein-------------- thyroid stimulating hormone, follicular stimulating hormone, leutinizing hormone and human chorionic gonadotrophin

Amino acid (tyrosine) derivatives----------- catecholamine and thyroid hormones (T3, T4)

2.Types of synthesis and modification of hormones

1. Hormones synthesized and secreted as active form

estriol, aldosterone, cortisol, catecholamines

2. Hormones that are modified in the secreting cells prior to secretion

parathyroid hormone , insulin, pro-opiomelanocortin

3. Hormones that are converted to active form in the peripheral tissue

Target tissue --------- T4 to T3 in liver and pituitary , testosterone to dihydrotestosterone

Non-target tissue -------- DHEA to testosterone

Combination of target and non- target tissue -------------- Vitamin D to 1, 25 DHCC

3. Transportation of hormones

Hormones can be transported as free form or bound form

Lipid soluble hormones in plasma are bound to protein. T3 and T4 bound to thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA), Glucocorticoids are bound to a globulin (transcortin) or corticoticosteroid binding globulin (CBG) or albumin.

Only the free or unbound hormone have biologic activities. Hormones bound to proteins cannot be destroyed and therefore their half-life is long

4. Interactions of hormone

Inhibitory interaction --------2 hormones have opposite effects on target tissue

eg. Growth hormone and insulin

Synergistic interaction-------2 hormones administered simultaneously give an effect greater than the sum of either of them given alone

eg. FSH and LH on follicular growth, LH alone has no effect on follicular growth

Permissive interaction

A small quantity of one hormone allows full response to another hormone

5.Concentration of Hormones in the body fluid

Hormones are present at very low concentration in the ECF ( 10-15 to 10-9 mol/L)

6. Feedback control of plasma hormone level

When circulating hormone level is increased, the hormone can control its synthesis by negative feedback regulation When circulating hormone level is decreased, the hormone can control its synthesis by positive feed forward regulation

7.Target cell

It is the type of cell that able to recognize specific hormone due to presence of specific receptor

Target cells must distinguish not only between different hormones but also between a given hormone and related molecules

8. Receptors

Receptors are proteins that bind a specific extracellular signaling molecule (ligand) and initiate a response in the cell. They are located on the cell surface or in the cytosol/ nucleus of the target cell

Receptors have very high specificity and affinity to its hormone. Hormone receptors are protein in nature

All receptors whether for polypeptide or steroid hormones have at least 2 functional domains

1. a recognition domain binds the hormones

2. a second region generates a signal that couples hormone recognition to some intracellular function

RECEPTORS

The action of hormone starts by binding to cell associated recognition molecule called receptors. Receptors are proteins that bind a specific extracellular signal molecule (ligand) and initiates a response in the cell. They are protein or glycoprotein in nature. There are 2 types of receptors

1. Intracellular receptors2. Cell surface receptors.

1) Intracellular receptors

Receptors for lipophilic (steroid) hormones are present in the cytosol or nucleus of target cells. Their action is by mediating gene expression. Steroid hormone receptors have several functional domains---

1. Hormone binding domain2. Adjacent DNA binding domain3. Site that bind to specific DNA region4. Site that activate or repress gene expression5. Site for translocation of receptor from cytoplasm to nucleus.

2) Cell surface receptors

Receptors for hydrophilic hormones are present on cell surface and their actions are mediated by second messengers. These cell surface receptors act as signal transducer and generates signals that alter the behavior of target cell. Cell surface receptors have 3 functional domains---

1. Hormone binding domain2. Transmembrane domain3. Signal transduction domain

Most cell surface receptors belong to one of the three classes. They are

1. Ion-channeled linked receptors2. G-protein linked receptors3. Enzyme linked receptors

(1) Ion-channeled linked receptors Also known as transmitter gated ion channels. These receptors are concentrated in post synaptic cell membrane. Neurotransmitters transiently open or close the ion channel and alter the permeability of cell

membrane. They belong to homologous multi-pass trans-membrane proteins. E.g, receptor for acetylcholine

(2) G-protein linked receptors They act indirectly to regulate the activity of separate membrane bound target protein which can be

an enzyme or ion channel. The interaction between the receptor and target protein is mediated by G-protein. They belong to homologous seven pass trans-membrane protein. Example – receptors for catecholamine

(3)Enzyme linked receptors These receptors either function as enzymes or associated with enzymes. They are heterogenous single pass trans-membrane protein. Example , receptor for insulin

The number of receptors in cells are not static , they are dynamic in nature. When the hormone is present in excess, the number of active receptor is decreased by internalization, desensitization and repression(down regulation). If the amount of hormone is decreased, the number of receptor will increase by induction(up regulation)Biomedical importance.

Androgen receptor agonist enhances the development of lean muscle mass.Estrogen receptor antagonists (tamoxifen) are used in treatment of breast cancer.

CLASSIFICATION OF HORMONES BY THE MECHANISM OF ACTION

1. Hormones that bind to intracellular receptor

Androgens, estrogens, progestins

Calcitriol (1,25 DHCC)

Glucocorticoids

Mineralocorticoids

Retinoic acid

Thyroid hormones (T3, T4)

2. Hormones that bind to cell surface receptors

A. Hormones that use cAMP as a 2nd messenger

1. Angiotensin II

2. Antidiuretic hormone

3. a2 adrenergic catecholamines

4. Parathyroid hormone

5. Glucagon

6. calcitonin

B. Hormones that use cGMP as 2nd messenger

Atrial natriuretic factor (ANF)

Nitric oxide (NO)

C. Hormone that use Ca 2+or phosphatidylinositol derivatives as 2nd messengers

angiotensin II

Antiduretic hormone

a1 adrenergic catecholamines

Acetylcholine

D. Hormones that use kinase or phosphatase cascade

insulin

Insulin like growth factors

Epidermal growth factor

Erythropoietin

Fibroblast growth factor

Nerve growth factor

Growth hormone

Cell signaling

Signaling molecules

Signaling molecules can generate specific response in its target cell to adapt the changes in its environment. Signaling molecules are

1. Hormones (major factor)2. Growth factors3. Cytokines 4. Cellular antigens & extracellular matrix5. Special senses (sight, hearing, taste, smell, touch via neurotransmitters)6. Gases ( NO, CO & free radicals)7. Other physicochemical factors(pH, tension, temperature, osmolarity etc)

Signal transduction

Signal transduction is the process by which the message carried by signaling molecule is accepted by (specific cell associated molecule called) receptor, then transmitted via intracellular modulator and generate the appropriate responses of the cells

Mechanisms of Action of Hormones/ General mechanism of cell signaling

Depend on type of receptors which in turns on solubility, hormones can be divided into lipid soluble hormone & water soluble hormone

1. Mechanism of lipophilic signaling molecules

2. Mechanism of hydrophilic signaling molecules

A. that use ion channel linked receptors

B. that used G protein linked receptors

C. that used enzyme linked receptor

1. Mechanism of lipophilic signaling molecules

• Signaling molecules are steroid hormones, thyroid H & retinoic acids

• After secretion, hormone associates with transport proteins ( because of water insoluble) & long plasma half-life

• In plasma 2 forms--- bound & free form of Hormone

• Because of lipid soluble in nature, free hormone transverses cell membrane and binds to intracellular receptors (in cytoplasm or nucleus) of target cells.

• forms a hormone-receptor complex. It is assumed to be the intracellular messenger.

• This complex(HRC) undergoes a temperature & salt dependent activation results in size, conformation and surface charge changes

• HRC moves into the nucleus and binds to hormone response element (HRE) of a particular gene & activate or inactivate specific gene.

• By selectively affecting gene expressionà production of mRNAàspecific proteinàinfluence metabolic process

• HRE behave as enhancer or silencer

• Regulate the gene expression, both in transcription as well as in translation

2. Mechanism of action of hydrophilic signaling molecules

They are water soluble in nature, so, no transport proteins is required & have short plasma half-life

• Hormones cannot pass through the cell membrane. So they bind to cell surface receptor(membrane receptor). Their mechanism is mediated by intracellular signals (second messengers). Hormones act as the first messenger that carry information from endocrine gland to target cell and 2nd messenger carry information from cell membrane to metabolic processes.

• This signals include cAMP, cGMP, Ca and phosphoinositides

(A)Mechanism of signaling molecules that use ion channeled linked receptors

Neurotransmitters bind to transmitter gated ion channels and convert chemical signals into electrical potential at chemical synapse. Excitatory neurotransmitters( acetylcholine, glutamate) open cation channel--- sodium influx increases----- depolarization--- generate action potential.

Inhibitory neurotransmitters(GABA, glycine) open chloride channel and cause hyperpolarization.

Strychnine( a toxin) binds to glycine receptors and block the action of glycine. This may lead to muscle spasm, convulsion and death.

(B)Mechanism of signaling molecules that use G-protein linked receptors

• Many hormones act via second messenger bind to G protein (GTP-binding regulatory ) linked receptor. This mechanism needs 2nd messengers for signal transduction of the cell.

• Ligand binds to extracellular domain of receptor. Active receptor stimulates the G protein.

• Activated G protein activates membrane bound enzyme systems which generate the 2nd messengers.

• G protein is heterotrimeric (α,β and γsubunits). It couples the hormone receptor to their target enzymes or ion channel in the plasma membrane.

Types of G protein (Depends on alpha subunit;

• - Gs (αs) - stimulates adenylyl cyclase

• - Gi (αi) - inhibits adenylyl cyclase

• - Gq (αq) - stimulates phospholipase C

• - G12 (α12 )- Cl- channel.

Gs system - α s-GTP stimulates adenyl-cyclase and cause increased in production of cAMP which then activate protein kinase A. PKA phosphorylates target protein and initiate a response in the cells. E.g ADH, calcitonin

Gi system - α i-GTP inhibits adenyl cyclase and makes decreased in production of cAMP. E.g α2 adrenergic , somatostatin

G α q-GTP activates phospholipase C. Phospholipase C (PLC) cleaves PIP2 to IP3 and DAG. IP3 stimulates opening of Ca2+ channel in ER and generates Ca2+ signaling. DAG stimulates PKC for cellular responses. E.g TSH, GnRH.

(C) Mechanism of Hormone Action through Enzyme linked Cell Surface Receptor

• Intracellular domain of receptor have intrinsic protein kinase action or is associated with membrane bound protein kinase.

• Signal is transmitted throughout the cell via protein kinases.

• Cellular responses are related to growth and differentiation.

i)Enzyme Linked Receptor by guanylate cyclase

• ANP or NO signaling

• The receptor has gaunylate cyclase activity.

• Stimulation of receptor generate cGMP .

cGMP activates PKG then generate cellular responses (e.g. vasodilation, smooth muscle relaxation

ii)Actions through Tyrosine Kinase Receptor

• Insulin, EGF & IGF-1 receptors have intrinsic tyrosine kinase activity. Binding of hormone to receptor causes dimerization and cross phosphorylation on tyrosine residue.

• Then phosphorylated receptor phosphorylates the insulin receptor substrates (IRS)

• Phosphorylated IRS binds to the variety of proteins containing SH2 domain

iii)Mechanism of Action through Tyrosine-Kinase Associated Receptor

• GH, erythropoietin and cytokines bind to tyrosine kinase associated receptor

• Hormone receptor interaction promotes the binding and activation of cytoplasmic protein tyrosine kinases . Then phosphorylation mechanism is propagated

iv)Mechanism of Action through Tyrosine phosphatases

Activator protein-1

v)Mechanism of Action through serine threonine kinases

Transforming growth factor-β

- 2ND MESSENGERS

• 2nd messengers are small intracellular molecules which are generated as consequences of ligand receptor interaction and initiate a response in the cell.( the hormone itself is the first messenger).

• Second messenger concept-proposed by Earl W Sutherland in 1961.” Epinephrine bind to plasma membrane of pigeon RBC and increase intracellular cAMP”

2nd Messengers are ----1)cAMP 2)cGMP 3)IP3 (inositol 1,4,5 triphosphat) 4) DAG (1,2 diacyl glycerol)(5) Ca++

1. cAMP(cyclic adenosine monophosphate)

Formation --- when some hydrophilic hormone bind to G-protein linked receptor, membrane bound G protein is activated which then activate membrane bound adenylate cyclase that catalyzed the conversion of ATP to cAMP. Increased cAMP activates cAMP dependent protein kinase(PKA) which further phosphorylate target proteins and initiate cellular responses. In some animal cells an increase in cAMP activates the transcription of specific gene through cAMP response element binding (CREB) protein. Hormones such as ADH, glucagon, epinephrine(β-adrenergic),etc exert their action via cAMP. cAMP is degraded to 5’ AMP by phosphodiesterase enzyme.

2.cGMP(cyclic guanosine monophosphate)

Formation ---when hormone bind to enzyme linked receptor, membrane bound guanylate cyclase is activated which then convert GTP to cGMP. Increased cGMP activate cGMP dependent protein kinase(PKG). PKG phosphorylates a number of smooth muscle protein that result in smooth muscle relaxation and vasodilatation. Hormones in this group include ANF and NO(nitric oxide).

3.Inositol triphosphate, DAG and Calcium.

• TRH, TSH, GnRH, angiotensin,etc. bind membrane receptor and activate Gq protein and then activate membrane enzyme phospholipase C .This enzyme cleaves PIP2 to IP3 and DAG

• IP3 stimulate the endoplasmic reticulum to release calcium

• Calcium and calmodulin (Ca++ binding protein) complex activate Ca-M kinase & DAG activate protein kinase C

• CaM-kinase and PKC also phosphorylate target proteins and regulate the cellular functions

• CaM kinase activation can function as a molecular memory devices because it remain active even after Ca++ is withdrawn.

G PROTEIN

• It is GTP binding regulatory protein in cell membrane. G protein is heterotrimeric protein composed of α, β & γ subunits.

• G-protein is inactive when GDP is bound to α subunit and active when GTP is bound to α subunit.

• When hormone binds to a G-protein linked receptor, the receptor changes its conformation and switches to active form ( to eject their GDP and replaces it with GTP)

• a subunit which binds GTP dissociate from b and g subunits

• The membrane bound enzyme is stimulated by a -GTP . Stimulated enzymes generate 2nd messengers (cAMP, IP3 ,DAG & Ca2+) and initiate response in the cell.

• The intrinsic GTPase activity of α subunit converts the GTP to GDP which inactivates the protein.

• Alpha-GDP subunit is reassociated with b & g subunits

Types of G protein (Depends on alpha subunit)

• - Gs (as) - stimulates adenylyl cyclase

• - Gi (ai) - inhibits adenylyl cyclase

• - Gq (aq) - stimulates phospholipase C

• - G12 (a12 )- Cl- channel.

Gs & Gi System

• Gs system - αs-GTP stimulates adenyl-cyclase and cause increased in production of cAMP

• Gi system - αi-GTP inhibits adenyl cyclase and makes decreased in production of cAMP.

•

Gq system

• Gq-GTP activates phospholipase C which cleaves PIP2 to IP3 and DAG.

• IP3 stimulates opening of Ca2+ channel in ER and generates Ca2+ signaling.

• DAG stimulates PKC for cellular responses.

• The responses are rapidly turned off by removal of external signal and break down of GTP to GDP by GTPase

Biomedical Importance

- Cholera toxin causes ADP-ribosylation to α subunits of Gs and inhibit the GTPase activity of αs allowing adenylate cyclase in active state and enhances cAMP production. This result in opening of electrolyte(Cl) channels in intestinal mucosa and loss of water and NaCl from GIT.

• Pertussis toxin catalyzed ADP-ribosylation to α subunits of Gi. Retains in inactive state and unable to inhibit cAMP production.

- G protein and Cancer

- ras proteins (member of GTPase family ) that cycle between GTP and GDP forms

- GTP forms stimulate cell growth and differentiation–lead to cancer

BIOCHEMISTRY OF INSULIN

Insulin gene is located at short arm of chromosome 11

Synthesized as preprohormone

Pre or leader sequences (23 amino acid) is removed in ERProinsulin is transported to the Golgi apparatus

Site specific peptide cleavages and form mature insulin and C- peptide

Zn2+ forms complex with insulin and proinsulin

Proteolysis and packaging into secretory granules

Upon appropriate stimulation, the mature granules fuse with plasma membrane & discharge into blood by exocytosis

Insulin is a heterodimeric protein

Composed of 2 chains, A chain (21 amino acids) and B chain (30 amino acids)

Two chains are linked by 2 interchain disulfide bridges ( A7 to B7 and A20 to B19)

Third intrachain diulfide bridge ( A6 to A11)

Regulation of insulin seceretion

Increase insulin secretion

After ingestion of glucose or CHO rich meal leads to rise blood glucose( glucose is most important stimulant) . After ingestion of protein( amino acids level in plasma). Hormone like Secretin , release after the ingestion of food

Decrease insulin secretion

Scarcity of dietary fuel and trauma because of release of epinephrine

Transport and metabolism of insulin

Insulin has no plasma carrier protein. Metabolism occurs in liver (50%), kidney and placenta.2 enzymes systems degrade insulin,1. insulin specific protea 2. glutathione insulin transhydrogenase

Mechanism of insulin action

Insulin actions begin when the hormone binds to a specific glycoprotein receptor on the surface of the target cell. The insulin receptor is a heterodimer (2a2b), glycoprotein in nature.

2a 2b linked by disulfide bonds

a subunit is entirely extracellular and it binds insulin via a cystiene-rich domain

b subunit is transmembrane protein that performs signal transducer . b subunit has tyrosine kinase activity and an autophosphorylation site.

When insulin binds to the receptor

When hormone binds receptor, tyrosine subunit of receptor is autophosphorylated. The phosphorylated receptor next phosphorylates insulin receptor substarte(IRS).

Phosphorylated IRS binds to the SH2 domains of a variety of proteins

These proteins are docking proteins, kinases and phosphatases. The effect of insulin on membrane transport, enzyme activity, gene expression and growth are well known.

The action of insulin is terminated by dephosphorylation of receptor

Metabolic effects of insulin

1.Effect on carbohydrate metabolism

Liver - decrease production of glucose

Muscle & adipose tissue ------ increase glucose uptake

2. Effect on lipid metabolism

Adipose tissue – inhibit lipolysis

3. Effect on protein metabolism -----Increase protein synthesis

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Glucagon

Small peptide (29 amino acid)

Binds specific G protein linked receptor & cAMP is intracellular mediator of action

Metabolic effects of glucagon

increase blood glucose

Activate lipolysis

BIOSYNTHESIS OF HORMONES

BIOSYNTHESIS OF THYROID HORMONE

Thyroid Hormone biosynthesis involves thyroglobulin and iodide metabolism. Thyroid hormones are synthesized from follicular cells of thyroid gland

Steps in biosynthesis

1. Concentration of iodide

2. Oxidation of iodide

3. Iodination of tyrosyl residues

4. Couplig of iodotyrosyls

5. Secretion

Biosynthesis of amino acid derivative hormones

Catecholeamine; - dopa, dopamine, norepinephrine and epinephrine

Thyroid hormones

1. Concnetration of iodide

Concentrate iodide against a strong electrochemical gradient

Energy-dependent process and linked to ATPase-dependent Na+/K+ pump (thyroidal I- pump)

The activity of pump is controlled by TSH

The ratio of iodide in thyroid to iodide in serum (T:S) ratio in human on a normal iodine diet is about 25. The transport mechanism is inhibited by 2 classes

Perchlorate , Perrhenate and pertechnetate – compete with iodide

Thiocyanate is a competitive inhibitor of iodide transport

2. Oxidation of iodide

Thyroid is only tissue that can oxidize iodide

An obligatory step in iodide organification and thyroid hormone biosynthesis

Involved a heme-containing peroxidase and H2O2

Iodide oxidation is inhibited by thiourea drugs

3. Iodiantion of tyrosyl residues

Oxdized iodide reacts with the tyrosyl residues in thyroglobulin. This reaction is catalyzed by thyroperoxidase

3 position of aromatic ring is iodinated first and then 5 position to form MIT (monoiodotyrosine) and DIT (diiodotyrosine) respectively, catalyzed by thyroperoxidase

Thyroglobulin is precursor of T3 and T4

4. Coupling of iodotyrosyls

Coupling of 2 DIT molecules to form T4

Coupling of one MIT and one DIT to form T3, catalyzed by thyroperoxidase

Thiourea also inhibit coupling

About 70% of iodide in thyroglobulin exists as MIT and DIT and 30% exist in T4 and T3

5. Secretion

iodinated thyroglobulin are stored in extracellular colloid

After TSH or cAMP stimulation, there is marked increase of microvilli on apical membrane

Microtubule-depedent process entraps thyroglobulin and pinocytose into the follicular cell

Phagosome fuse with lysosomes to form phagolysosomes

Proteases and peptidases hydrolyzes thyroglobulin and T3 and T4 are discharged from basal portion of cell into blood. About 50 mg of thyroid hormone is secreted each day

Mechanism of action of thyroid hormone

TH binds to intra nuclear receptor and HR complex binds to thyroid hormone response element binding region(TRE) of DNA and regulate gene expression.TH enhances the synthesis of sodium-potassium ATPase pump.

Biosynthesis of hormones of adrenal medulla

Catecholamines synthesized in chromaffin cells of adrenal medulla

Catecholamine (dopamine, norepinephrine and epinephrine)

80% is epinephrine

Biosynthesis of catecholamines ---------4 sequential steps

1. Ring hydroxylation

2. Decarboxylation

3. Side chain hydroxylation

4. N-methylation

1. Ring hydroxylation

Tyrosine is the immediate precursor of catecholamines

L- tyrosine converted to L-dopa(L-dihydroxyphenylalanine) by tyrosine hydroxylase using tetrahydropteridine as a cofactor. Tyrosine hydroxylase is rate limiting enzyme &feedback inhibition by catecholamines

This reaction is competitively inhibited by methyltyrosine

2. Decarboxyation

Dopa decarboxylase convert L-dopa to Dopamine (dihydroxyphenyl ethylamine ) and coenzyme is pyridoxal phosphate.

Methyldopa is competitive inhibitors of this reaction

3. Side chain hydroxylation

Dopamine β-hydroxylase (DBH) catlayzes conversion of dopamine to norepnephrine

DBH uses ascorbate ,copper and fumerate for this reaction.

4. methylation

Phenylethanolamine N-methyltransferase (PNMT) catalyzes the N-methylation of norepinephrine to form epinephrine

PNMT is induced by glucocorticoid hormones

Catecholamines enter the chromaffin granules and stored

Neural stimulation of adrenal medulla results fusions of the membrane of the storage granules and catecholamines are secreted to blood .

BIOSYNTHESIS OF HORMONES OF ADRENAL CORTEX

Adrenal cortex synthesizes 3 classes of Steroid hormone

Glucocorticoids (adaptation to severe stress)

Mineralocorticoids ( water and electrolytes balance or Na+ and K+ balance)

Androgen

Free cholesterol is transported to mitochondria where cytochrome P450 side chain cleavage (SCC) enzyme (P450scc) covert it to pregnenolone (removal of 6 carbon). ACTH control this step

Glucocorticoids(cortisol) are synthesized in zona fasciculate. 3 key enzymes of glucocorticoids synthesis are 17-hydroxylase, 21-hydroxylase and 11-hydroxylase sequentially.

Mineralocorticoid(aldosterone) is synthesized in zona glomerulosa. 3 key enzymes of mineralocorticoids synthesis are 21-hydroxylase, 11-hydroxylase and 18-hydroxylase sequentially.

BIOSYNTHESIS OF GONADAL HORMONES

Gonads are bifunctional organs, produce germ cells and the sex hormones

Testes produce spermatozoa and testosterone

Testicular androgen are synthesis by the Leydig cells

Immediate precursor of gonadal steroid is cholesterol

Pregnenolone to testosterone require actions of 5 enzyme and 2 pathways

D 5 (or) dehydroepiandrosterone D 4 (or) progesterone pathway

zona glomerulosa zona fasciculata

zona reticularis

BIOSYNTHESIS OF OVARIAN HORMONES

Ovaries produce ova, and steroid hormones , estrogens and progestrone

HORMONES THAT REGULATE CALCIUM METABOLISM

Total calcium in the body: approximately one kilogram

99% is located in bone as hydroxyapatite crystal

Provide the inorganic and structural component of skeleton

Normal blood calcium level:

- 2.1 to 2.6 (mmol/L) or 9 – 11 gm/dl

Plasma calcium exists as three forms- 1-complex with organic acids-2- bound with albumin

3- ionized form (active form)

Hormonal regulation

- Parathyroid hormone

- Calcitriol (1,25 DHCC)

- Calcitonin

Parathyroid Hormone (PTH)

Decreased in plasma Ca2+ stimulates PTH synthesis

Protein in nature & synthesized as preprohormone 115 amino acid residues. Active hormone has 84 amino acids.

Mechanism of action

Cascade activation of adenylate cyclase . Increase cAMP level causing PTH response

Actions of PTH

It restored normal ECF calcium concentration by acting directly on bone and kidney and indirectly on the intestinal mucosa

Effects on bones

PTH promotes osteoclastic activity and formation of more osteoclasts ----Increase bone resorption

PTH increases calcium entry to osteocytes and osteoblasts. The osteoblast then pumps calcium into ECF. The pump is stimulated by 1,25 DHCC.

Effects on kidneys

increase reabsorption of Ca++ in the distal tubules and decrease reabsorption of phosphate in proximal tubules (phosphaturic action)

PTH also promotes formation of 1,25 DHCC in kidney by stimulating 1α-hydroxylase.

Intestine

PTH increase Ca++ absorption from intestine by promoting synthesis of 1,25 DHCC.

CALCITRIOL (1,25 DHCC)

ACTIONS OF CALCITRIOL

It is steroid hormone.

MOA---by binding to intranuclear receptor and regulates the expression of calcium binding protein(calbidin) synthesis.

Effects on intestine

Increases calcium absorption from intestine by increasing the synthesis of calbindin D

Effects on kidney

Facilitates Ca++ reabsorption in the kidneys

Effects on bone

It mobilizes Ca++ and increase the number of osteocalsts

stimulates osteoblast to produce osteoclastic resorption stimulating activity (ORSA) and neutral protease

ORSA stimulates osteoclast and protease digest unmineralized bone

Calcitonin

peptide hormone (32 amino acids),,, secreted from parafollicular C cells of thyroid gland.

Mechanism of action

By binding G-protein linked cell surface receptor and increases cAMP level.

Action of Calcitonin

Lowers circulating calcium and phosphate levels. It inhibits action of osteoclast and decreases bone resorption. It Increases excretion of calcium in the urine.