MM Tutorial Year 1 Endocrinology - PowerPoint Presentation

Slide1

MM TutorialYear 1 Endocrinology

Hussein ElghazalyHe315@ic.ac.uk

Thursday, 25

th

January 2018

Slide2

Slides available:https://muslimmedics.co.uk

/year-1/

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Introduction

Endocrine Gland: A group of cells which secrete “messenger” molecules directly into the bloodstream. The “messenger” then goes to act on a distant target organ.

Endocrinology:

Study of endocrine glands and their secretions

Hormone:

The bioactive “messenger” molecule secreted by an endocrine gland into the blood - i.e. not simply a metabolite or energy substrate.

Endocrine System

Nervous

System

Chemical

Hormone

Neurotransmitter

Site of Release

Into

the bloodstream

Across

a synapse

Site of Action

Target cells all over the body

Localised

system – innervated target cells

Duration of effect

Long

lasting (seconds to days)

Very quick (milliseconds)

Slide4

Blood

Endocrine:

The hormones act on target cells

at a distance

from source.

Paracrine:

The hormones act on

nearby target cells

(within immediate surroundings).

Autocrine:

The hormones have an effect on its

own immediate source.

Cryptocrine

:

A hormone can have an effect within its own cell of production, but this is “hidden”.

Slide5

Hormone Classification

We can generally classify hormones into one of 3 classes:

Protein/ Polypeptide Hormones

70

amino acids is the cut-off between a polypeptide and a protein.

Steroid Hormones

Miscellaneous Hormones

(Amines):

Amines

are

hormones derived from the amino acid tyrosine.

These include thyroid hormones (T3 & T4) and catecholamines (Adrenaline and Noradrenaline).

Slide6

Protein/ Polypeptide Hormones: Synthesis

1) Transcription (DNA to mRNA)

2) mRNA migrates to RER.

3) Translation of

Pre-

Prohormone

4) The Pre-

Prohormone

loses is broken down into a

Prohormone

.

5) The

Prohormone

is stored in a Golgi (storage) vesicle.

6) The

Prohormone

is broken down into a hormone.

7) Secretion via exocytosis.

Slide7

Protein/ Polypeptide Hormones: Signaling

Receptor:

a protein (on the cell membrane or within the cell cytoplasm/ nucleus) that:

Binds to a specific chemical messenger (ligand).

Initiates a cellular response to the ligand.

Receptors for peptide hormones and catecholamines are proteins located in the

plasma membranes

of the target cells, as protein and polypeptide hormones are generally unable to penetrate the cell membranes

(polar/hydrophilic).

Most receptors for peptide hormones are G-Protein Coupled Receptors (GPCR):

The hormone binds to the receptor on the cell membrane.

The G-Protein dissociates from the receptor.

The G-Protein activates the enzyme Adenylate cyclase (AC).

AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).

cAMP activates protein kinase A (PKA).

PKA acts as 2

nd

messenger producing an effect

Slide8

Steroid Hormones: Synthesis

Derived from cholesterol

LDL’s carry cholesterol to cell which stores it as fatty acid esters

Cholesterol Esterase liberates the cholesterol

Cholesterol taken to

mitochondria

by

Steroidogenic

Acute Regulatory (

StAR

) protein.

Hormone production occurs in mitochondria

and smooth endoplasmic reticulum (SER). Lipid soluble steroid immediately diffuses out of cell

Steroid binds to protein in blood Equilibrium:

Hormone + Plasma protein Protein bound hormone

The protein bound hormone is inactive.Only the unbound hormone is biologically active.

 

Slide9

Steroid Hormones: Signaling

Receptor: a protein (on the cell membrane or within the cell cytoplasm/ nucleus) that:

Binds to a specific chemical messenger (ligand).

Initiates a cellular response to the ligand.

Receptors for steroid and thyroid hormones are located mainly inside the target cells (intracellular receptors).

As steroids are lipid-soluble and can penetrate plasma membranes via simple diffusion.

For example, glucocorticoid receptor (GR) is the specific receptor for cortisol.

The hormone acts in the nucleus as a transcription factor to increase or decrease the rate of gene transcription.

Hormones can influence the transcription of the code from DNA to mRNA, and the translation of the mRNA code to the synthesis of the protein on the ribosomes.

Negative Feedback

Slide10

Hypothalamo-Adenohypophysial Axis

The pituitary gland is called the

hypophysis

Anterior lobe:

ADENOHYPOPHYSIS

Posterior lobe:

NEUROHYPOPHYSIS

Reason for division:

The anterior and posterior pituitary develop differently.

Slide11

Hypothalamo-Adenohypophysial Axis

Hypothalamic Neurons:

Send axons down pituitary stalk to the posterior pituitary.

Terminate (and release neurosecretions) at the median eminence

Portal System:

2 connected capillary networks.

Hypothalamic

Neurosecretion

occurs at the are of Median Eminence.

These neurosecretions then go to the anterior pituitary via the

hypothalamo

-pituitary portal system.

Slide12

Slide13

Hypothalamo-Adenohypophysial Axis

Hypothalamic nuclei send neurones to the median eminence which has a rich blood supply.

The blood system links the hypothalamus to the adenohypophysis.

Neurosecretion

into primary capillary plexus into long portal veins into secondary capillary plexus (fenestrated) to

adenohypophysial

cells.

The

neurosecretions

then ‘influence’ the function of the anterior pituitary

–

they can stimulate or inhibit hormone production.

The hormones released by the pituitary gland can then serve their functions around the body.

Slide14

Adenohypophysial

Cell

Hypothalamic Neurosecretions

Adenohyophysial

Hormone

Site of Action

Physiological

Action

Somatotrophs

Growth

Hormone Releasing Hormone

Somatostatin

Somatotrophin

(Growth Hormone, GH)

Protein 191aa

General body tissues

. Especially the liver (

eg

IGF-I and IGF-II)

Important in growth and development. Also has lots of metabolic effects.

LactinotrophsDopamine

Thyrotrophin Releasing Hormone (TRH)Prolactin

Protein 199aa

Breasts of lactating women

Promotes

lactation in breastfeeding women.

Thyrotrophs

TRH

Thyrotrophin

Glycoprotein 92aa +110aa

Thyroid gland

Synthesis of

iodothyronines

(thyroid hormones).

Gonadotrophs

Gonadotrophin

Releasing Hormone (GnRH)

Gonadotrophins:

FSH and LH

Glycoprotein 92aa +115aa

Gonads (ovaries/testis)

Various

Corticotrophs

Corticotrophin Releasing Hormone (CRH)

Vasopressin (VP)

Corticotrophin/ACTH (

Adrenocorticotrphic

Hormone)

Polypeptide – 39aa

Adrenals

Various

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Somatotrophin –The Growth Axis:

Prolactin

–

Neuroendocrine Reflex Arc:

Effects of GH:

Stimulation of amino acid transport into cells

Stimulation of protein synthesis

Increased cartilaginous growth

Stimulation of lipid metabolism

Increased insulin resistance and therefore increased blood glucose

Effects of Prolactin:

Mainly:

Lactogenesis

in post partum women.

Renal Na (and water) Reabsorption

Immunological effects e.g. T-cell stimulation

Hyperprolactinaemia

is high level of prolactin inn the blood and has a

contraceptive effect as prolactin inhibits LH/FSH.

Slide16

Hypothalamo-Neurohypophysial Axis

There are 2 types of nuclei:

Paraventricular

(besides the 3

rd

ventricle) and

Supra-optic

(next to the optic

chiasm).

Supra-optic

nuclei have

magnocellular

neurons ONLY.Paraventricular nuclei have parvocellular

AND magnocellular neurons.

Magnocellular neurons pass through the median eminence and terminate in the posterior pituitary.Parvocellular neurons can either terminate in the median eminence, or in other parts of the brain.

Bothe supra-optic and paraventricular nuclei can be vasopressinergic or oxytocinergic.

The main hormones released by the posterior pituitary gland are: Vasopressin and

Oxytocin

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Vasopressin and Oxytocin are

both nonapeptides (9 amino acids).

They differ by only 2 amino acids.

Slide18

Hypothalamo-Neurohypophysial Axis

Hormone Synthesis:

Pre-

Prohormone

Prohormone

Hormone

Signal Peptide

Neurophysin

Glycoprotein

Vasopressin

Neurophysin

Glycoprotein

Vasopressin

Vasopressin

Same sequence for

oxytocin

synthesis, except that the

neurophysin

differs

slightly and the

glycopeptide

is absent

Principal Actions of VP:

(=ADH)

Water reabsorption in the Principal Cells within the Collecting ducts of the kidneys.

Control of the final concentration of urine.

Antidiuretic effect: Increase in concentration, and decrease in volume of urine.

Other actions:

Vasoconstriction of smooth muscle of arterioles.

CRH and ACTH release via

parvocellular

neurons.

CNS Effects: Neurotransmitters affect behaviour via receptors in the Hippocampus

Synthesis of blood clotting factors (Factor VIII and Von

Willbrandt

Factor)

Hepatic

Glycogenolysis

Regulation of VP:

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Vasopressin Receptors

V1: G

q

PCR

VP

V1R

G

q

-Protein

Phospholipase C

PIP

2

IP

3

+

DAG

↑ Ca

2+

+

Protein Kinase C (PKC)

V2:

G

s

PCR

VP

V2R

G

s

-Protein

Adenylate Cyclase

ATP

cAMP

AQP2

Protein Kinase A

(PKA)

V2:

Collecting duct cells

(water reabsorption)

Other effects

(endothelial cells, factor VIII and von

Willbrandt

factor)

(Vasodilation of blood vessels)

V1a:

Arterial/arteriolar smooth muscle

(vasoconstriction)

Hepatocytes

(

glycogenolysis

)

CNS neurones

(behavioural and other effects)

V1b:

Corticotrophs

(ACTH production)

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TUBULE

LUMEN

PLASMA

OSMOTIC GRADIENT

ACROSS CELL

V2

G

AC

VP

ATP

cAMP

AQP2 insertion

H

2

O

H

2

O

H

2

O

AQP 3

AQP4

Migration of

aggraphores

Activated

PKA

Other

intracellular

mediators

Synthesis

of AQP2

Apical

membrane

Basolateral

(

serosal

)

membrane

Physiological Action of VP:

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Oxytocin:

Physiological Action of Oxytocin:

Major:

Uterus

–

cotnraction

durin

childbirth

Mammary gland

–

milk ejection

Minor / Unwanted Effects:

Cardiovascular system

(Pharmacological)Kidney (Pharmacological)

Additional physiologicalCNS –Maternal behaviour, social recognition

‘Tend & Befriend’

Regulation of Oxytocin:

Clinical Uses of Oxytocin:

Induction of labour at term: controlled

i.v. infusionPrevention treatment of post-partum haemorrhage: Slow

i.v. injection/infusion. Local pressor action in uterus suppresses bleedingFacilitation of milk let-down: Intranasal spray

Autism: Intranasal spray

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Disorders of the Posterior Pituitary:

Lack of Neurohypophysial Hormones:

Oxytocin:

Not much

–

oxytocin can usually be replaced.

Vasopressin:

Diabetes Insipidus

Central/Cranial:

Lack of production of ADH

Nephrogenic

: Kidney resistance to ADH production

Diabetes Insipidus Signs and Symptoms:Polyuria (urinating too much)

Polydipsia (thirst)Very dilute urine (hypo-osmolar)

Too Much Neurohypophysial Hormones:

Oxytocin: Not much significance.Vasopressin: Syndrome of Inappropriate ADH (SIADH)

(Opposite of DI)Many things can cause SIADH, including tumours and infections.

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Insulin and Diabetes

Diabetes Mellitus: Blood glucose elevation and lack of control over the physiological feedback loop.T1DM:

Elevated blood glucose due to complete insulin deficiency. Insulin is required to prevent ketoacidosis.

T2DM:

Elevated blood glucose due to insulin resistance. Insulin is produced, but the receptors are resistant to its actions. It is related to hypertension and

dyslipidaemia

(part of the metabolic syndrome).

MODY: A single gene defect leading to diabetes. It behaves like T2DM and occurs in young people (15-30 year olds).

Diabetes Treatment:

To help symptoms, reduce complications and improve morbidity and mortality.

Diet

Insulin

Glucose Monitoring (Capillary glucose monitoring and HbA1C)

Glucose:

Very important energy substrate

–particularly for the brain.

The brain cannot metabolise fat. It can use ketone bodies but works best with glucose. This is useful, since the brain is made up of a lot of fat (to insulate axons) and so it can’t auto-digest. A decrease in blood glucose (<4mM) is called hypoglycaemia. This impair brain function.

Below 2mM, there is unconsciousness, coma and death.

Polyuria an

nocturiaThirst (Polydipsia)

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The Pancreas

98% of the pancreas is associated with exocrine secretions (lipases and other enzymes to digest food).

2%

are known as the

Islets of Langerhans

and have

endocrine

functions.

Islets of Langerhans:

Three types of cells, each with its own endocrine function.

⍺-Cells:

Glucagon:

Increases Blood Glucose.

β-Cells: Insulin: Stimulates growth and development

and decreases blood glucose.

𝛿-Cells: Somatostatin: Inhibits insulin and glucagon via paracrine actions.

Slide25

Insulin Production

The glucose sensor in

β-cells

is

Glucokinase

or

Hexokinase IV

.

GLUT2

transporter is responsible for the transport of glucose into the cell.

Glucokinase converts Glucose to

Glucose-6-Phosphate in a rate-limiting step. This G6P can go off and take part in metabolic pathways.

This allows the cell to ‘see’ the ambient glucose concentration so a rise in G6P causes insulin synthesis and release.G6P ultimately leads to ATP

production via metabolic pathways.The ATP-Sensitive K+ Channel is blocked by the ATP.

This leads to the opening of Voltage-Gated Calcium Channel.This causes an influx of Ca2+

.Ca2+ causes the vesicles containing insulin to migrate to the cell membrane and fuse with it, releasing pre-formed insulin.

Ca2+ also causes the synthesis of new insulin.

Pro-Insulin→ Insulin + C-Peptide

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GLP-1

Glucagon-Like Peptide 1: A GI hormone secreted in response to food.

Produced by the L-Cells in the small intestines.

Stimulates insulin release and inhibits glucagon release.

This stimulation of insulin is glucose-dependent. GLP-1 will only cause insulin release if there is enough glucose in the blood.

It also causes satiety by acting on the hypothalamus.

DPP4

(

Dipeptidyl

Peptidase 4)

breaks down GLP-1. Therefore, it has a short half-life.

GLP-1 analogues and DPP4 inhibitors are used to treat T2DM.

Insulin Secretion:

Insulin is secreted in a biphasic manner:

First Phase Insulin: Stored insulin, directly released after a meal. In T2DM, the patients lose their first phase insulin.

Second Phase Insulin: Newly-synthesised Insulin released over a couple of hours.

Incretin Effect: Oral glucose leads to greater insulin releas compared to IV glucose due to the effects of gut hormones (GLP-1)

Slide27

Action of Insulin

Glucose

Protein

Lipid

Decreases Hepatic

Glucose Output (Gluconeogenesis and

Glycogenolysis

)

Decreases proteolysis

Decreases lipolysis

Increases muscle uptake

Decreases

ketogenesis

In

muscles

and

adipose tissue

, insulin increases the expression of GLUT-4.GLUT-4 is a transmembrane transport protein

for glucose into the cell.Insulin recruits and enhances the expression of GLUT-4.This results in a 7-fold increase in the uptake of glucose into cells.GLUT-4 has an outer hydrophobic layer and an inner hydrophilic layer.

Insulin also has other effects like growth and energy expenditure.

Slide28

Proteins:

Protein metabolism is responsible for 20% of energy expenditure

Insulin inhibits Proteolysis (

Gluconeogenic

amino acids e.g. Alanine liberated from proteins)

Cortisol stimulates Proteolysis

Insulin, GH and IGF-1 stimulate Protein Synthesis (from amino acids)

Insulin also inhibits the conversion of Oxygen to carbon dioxide

Glucose:

Glycogen:

stored glucose in hepatocytes (liver cells), acting as an immediate energy store

Gluconeogenesis:

Synthesis of glucose from lipids and proteins.

Effects of Insulin:

Stimulates glycogenesis (the conversion of glucose to glycogen).Inhibits gluconeogenesis (the conversion of glycogen to glucose).

Inhibits hepatic glucose output (the release of glucose from the hepatocytes Effects of Glucagon: Increases uptake of

gluconeogenic amino acids into cells Stimulates glycogenolysis and gluconeogenesisIncreases hepatic glucose output

Slide29

Fat Metabolism:

Insulin and Lipoprotein Lipase stimulates the breakdown of Triglycerides into Glycerol and Non-Esterified Fatty Acids (NEFA).

Insulin also stimulates the uptake of glucose into Ad9pose tissue via GLUT-4

Effects of insulin within adipose tissue:

Stimulates the formation of triglycerides from Glycerol-3-Phosphate and NEFA.

Inhibits the breakdown of triglycerides into glycerol and NEFA.

NB: Catecholamines, cortisol and growth hormone stimulates the breakdown of triglycerides into glycerol and NEFA

Fatty Acids in the Liver:

NEFA

are taken up into hepatocytes, where they are converted to

Fatty Acyl-CoA

Fatty Acyl-CoA

à

Acetyl CoA

à

Acetoacetate

à

Acetone and 3-Hydroxybutyrate.

These are then released as Ketone bodies (An alternative source of fuel for the brain if hypoglycaemia occurs).

Insulin inhibits this process.

If insulin is completely

absent, this process will not be inhibited. Thus, ketone bodies will form. This occurs in type 1 diabetes, and therefore, there are ketones present in the blood and urine.

Slide30

Fasted State:

Fed

State:

Insulin is

inhibited, glucagon is stimulated.

There is a low Insulin: Glucagon ratio.

Blood glucose is maintained between 3.5-5

mM

(this is a relatively-fixed range, controlled by circulating hormones).

The low insulin level leads to increased lipolysis. This leads to increased production of NEFA.

There is also a decrease in amino acids in the blood, when prolonged (gluconeogenesis).

Prolonged Fasting:

Proteolysis: Protein is broken down so that amino acids can be used in gluconeogenesis.

Lipolysis: Adipocytes release glycerol and NEFA.

Increased HGO: From gluconeogenesis and

glycogenolysis.

Muscles will start using lipids for energy (to conserve glucose)The brain will use glucose, then ketone bodies.Ketogenesis: This is the formatin

of ketones. It will increase as the insulin levels get very low after prolonged fasting.Insulin is stimulated, glucagon is inhibited.There is a high Insulin: Glucagon ratio.

Blood glucose is maintained in the physiological range, by the circulating insulin.

1st Phase insulin –pre-formed insulin is released.2nd Phase insulin –

newly-synthesized insulin is slowly released.

Proteolysis is inhibited, and protein synthesis is stimulated.Lipolysis is inhibited, lipogenesis is stimulated

Decreased HGO: Decreased gluconeogenesis and glycogenolysis.Ketogenesis is inhibited.

Slide31

T1DM:

T2DM:

Absolute insulin deficiency (due to abnormal/lack of pancreatic function, caused by an autoimmune attack on the islets of Langerhans)

Increased hepatic glucose output; releasing glucose and ketones into the blood.

Increased proteolysis; releasing amino acids which leads to weight loss.

Increased lipolysis; releasing glycerol and fatty acids from adipocytes.

Glycosuria with osmotic symptoms; increased glucose in urine leads to increased water (osmosis) in urine which causes dehydration and increased thirst

Ketonuria

: Presence of ketone bodies in urine

Treatment:

Insulin

‘Hypos’:

Hypoglycaemia

is low glucose levels in the blood. This can be a

compllication

of T1DM treatment, if a patient takes too much insuln.

Treatment: Intramuscular glucagon –this will increase HGO, restoring blood glucose levels to normal.Insulin Resistance:

Resistance resides in liver, muscles and adipose tissue.

Resistance affects metabolism of glucose, lipids and proteins.

Glucose:

Impaired Glucose Tolerance and Hyperglycaemia, as glucose isn’t transported into cells.

Lipids:

Leads to increase in circulating NEFA due to the breakdown of triglycerides.

Lipoprotein metabolism effects:



VLDL;



Triglycerides;



Total Cholesterol;



HDL

Enough insulin to suppress

ketogenesis

and proteolysis. No ketones in T2DM.

Metaboli

c Syndrome

Presentation:

Centripetal Obesity:

60-80% of patients are obese

Dyslipidaemia:

High total cholesterol, TG and LDL; Low HDL.

Hyperglycaemia:

Initially due to insulin

resistence

and later due

to insulin deficiency

There are

less osmotic symptoms

(e.g. polyuria and polydipsia) than T1DM

They may present with complications.

Slide32

Insulin Receptor

Insulin Receptor is a Tyrosine Kinase-Linked receptor.

It has 2 ⍺-Subunits and 2 β-Subunits.

The β-Subunits have Tyrosine Kinase domains.

There is

autophosphorylation

and cross-phosphorylation when insulin binds to the receptor.

The receptor signals 2 intracellular pathways:

The MAPK pathway is responsible for growth and proliferation.

The PI3K-Akt pathway is responsible for the metabolic effects of insulin.

Insulin Resistance occurs in these intracellular pathways.

Metabolic Syndrome

Slide33

Hypothalamo-Adenohypophysial-Thyroid Axis

The thyroid gland is a bilobed endocrine gland that straddles the trachea in the neck and secretes thyroid hormones and calcitonin.

Thyroid hormones exert widespread and diverse effects throughout the body.

Within the thyroid gland are numerous follicles, each composed of an enclosed sphere of highly

specialised

follicular cells surrounding a core of protein-rich colloid.

Slide34

BLOOD

COLLOID

I

-

TSH

TSHR

R

nucleus

lysosome

I

-

NIS

I

-

I

-

1

5

P

3

TPO +H

2

O

2

I*

iodination

apical

membrane

basolateral

membrane

TG

T3

T4

coupling

reaction

4

TPO +H

2

O

2

TG

2

TG

TG

MIT

DIT

+

6

T4

T3

T4

T3

7

Slide35

Thyroid Hormones:

The thyroid gland produces two iodine-containing molecules of physiological importance: thyroxine (T4 because it contains four iodines

), and

triiodothyronine

(T3).

T4 is generally converted into the more bioactive T3 by enzymes known as

deiodinases

in target cells.

T3 is therefore considered the

major thyroid hormone

.

T4 is the major secretory product of the thyroid and T4 concentrations are higher in blood (80% T4, 20% T3).

T4 can also be deiodinated in a different position to produce the biologically inactive molecule known as reverse T3 (rT3).

Transport in the Blood: Mostly bound to

plasma proteinsa) Thyroid-binding globulin: TBG (70-80%)b) Albumin (10-15%)c)

Prealbumin (aka transthyretin)

Only 0.05% T4 and 0.5% T3 unbound (bioactive components

)

Effects of Thyroid Hormones:Increase Basal metabolic rate (BMR).Increase Protein, carbohydrate & fat metabolism

Potentiate actions of catecholamines [Adrenalne and noradrenaline] (e.g. tachycardia, lipolysis)Effects on the GI, CNS, Reproductive system

Fetal growth & development. Cretinism: Physical and mental developmental problems due to congenital hypothyroidism. There is a heel-prick test for newborns, testing for cretinism.

Slide36

Anatomy of the Thyroid:

The thyroid gland weighs about 20g.

It is a shield shaped gland composed of four lobes

Right lobe is the largest lobe

Found embedded within the thyroid are the parathyroid glands, which control the amount of calcium in the blood and within the bones.

The laryngeal nerve is a nerve originating from the

vagus

nerve and supplies the

vocal cords.

The

left recurrent laryngeal nerve

runs very close to the thyroid gland and supplies the vocal cords. Damage here will therefore result in changes in the quality of voice, or even difficulty in talking.

Thus all thyroid surgeons mention this when obtaining consent for

thyroidectomy

.

Embryology of the Thyroid:The origin of the thyroid is the back of the tongue –a midline outpouching of the floor of the pharynx. The outpouching forms a duct which elongates down the throat (thyroglossal

duct). It migrates down the neck and divides into two lobes. The structure is in its final position by week 7.

The thyroid gland then develops. The duct disappears, leaving the foramen caecum. The foramen caecum is a dimple at the back of the tongue that is the point of attachment of the

thyroglossal duct. TRH and TSH start being secreted from the foetal hypothalamus and pituitary at around 18 weeks gestation.

Developmental Problems:1- Agenesis

(complete absence)2- Incomplete descent (e.g. a lingual thyroid).

3- Thyroglossal cyst (Segment of duct persists and presents as a lump years later).

Thyroxine is essential for brain development.

Slide37

Thyroid Disorders

Primary Hypothyroidism (

Myxoedema

)

Hyperthyroidism

(Thyrotoxicosis)

Caused by primary thyroid failure:

Autoimmune

Surgery

The biochemical findings in an individual with primary hypothyroidism are that

thyroxine

levels drop and TSH levels are high

(no negative feedback).

Features:

Deepening, coarse voice

Depression and tiredness, lethargy, memory impairment Cold IntoleranceWeight gain with reduced appetiteConstipation and ascitesBradycardia

Treatment:Treatment of hypothyroidism is easy: simply replace thyroxine. This is usually in the form of one tablet (100μg) per day.Monitor TSH: If high, increase the dose; if low (zero) reduce the dose.

An overactive thyroid gland. The thyroid makes too much thyroxine and

TSH levels fall to zero. Features:Raised basal metabolic rateMyopathy, Mood swings

Feeling hot in all weatherDiarrhoeaIncreased appetite but weight lossTremor of hands

PalpitationsSore eyes, goitre (swelling of thyroid)Graves’ Disease: Autoimmune – antibodies bind to and stimulate TSH receptor.

Pretibial MyxoedemaExophthalmos (Grave’s

Opthalmopathy)

Slide38

The Adrenals

Blood Supply:

Many arteries; one vein

1- Arterioles to medulla.

2- Perfusion through cortical cells, until central vein.

Adrenal Cortex

Adrenal Medulla

Synthesises

Corticosteroids (derived from cholesterol). It is divided into 3 Zones:

G

lomerulosa

:

Aldosterone

F

ascicuata

: CortisolR

eticuaris: Sex Steroids (Androgend and Oestrogen)

Chromaffin CellsSynthesies Catecholamines (Adrenaline and Noradrenaline).Adrenaline: 80% and Noradrenaline 20%.

Also, trace amounts of Dopamine

Slide39

Corticosteroids

Corticosteroids are

lipophilic

, therefore can easily cross cell membranes where they bind with intracellular or nuclear membrane receptors.

Therefore these hormones cannot be stored, as this will result in excessive binding with receptors and hence over stimulation.

Because of this, the hormones can be produced

on demand

, or bound to

plasma proteins

in the blood to prevent their action

The plasma proteins act as a store and transport mechanism –they transport the hormone where the unbound-bound hormone

equilibrium

is unbalanced,

i.e. where the hormone needs to be released.

Cortisol:

CBG (Cortisol Binding Globulin): 75%

Albumin: 15% Bioactive/ Unbound: 10%.

Aldosterone: CBG: 60%Bioactive/ Unbound: 40%

To prevent Cortisol from over-activating the MR receptors in the body, there is a specific enzyme in the kidney called

11β-Hydroxysteroid Dehydrogenase 2. This converts Cortisol into the inacyive form Cortisone.

Slide40

=

Cyclopentanoperhydropenanthrene

Slide41

Kidneys

–

Juxtaglomerular Cells

Low Renal Perfusion Pressure

Sympathetic Activity acting on the Kidney

Low Sodium Load

Detected by the

Macula

Densa

Cells

of the Juxtaglomerular Apparatus

Renin

Angiotensin I

LIVER

Angiotensinogen

LUNGS

ACE

(Angiotensin Converting Enzyme)

Angiotensin II

ADRENALS

Aldosterone

Acts in the Kidneys (MR)

Stimulates Na+ Reabsorption

Stimulates H+ and K+ Excretion

RAAS

Slide42

ALDOSTERONE:

MECHANISM OF ACTION

P

Na

+

K

+

H

+

receptor

DNA

nucleus

Distal convoluted tubule

Tubular fluid

ECF (blood)

mRNA

New proteins

ALDOSTERONE

Na

+

Na

+

Na

+

K

+

H

+

Enzymes

Ion channels

Tubule lumen

apical membrane

Blood

basolateral (serosal) membranes

Slide43

Hypothalamo-Adenohypophysial-Adrenal Axis

Physiological Actions of Cortisol– Normal Stress Response

Metabolic Effects

Peripheral protein catabolism

Hepatic

gluconeogenisis

Increased blood glucose concentration

Lypolysis

in adipose tissue

Enhanced effects of glucagon and catecholamines

Mineralocorticoid effects

Renal and Cardiovascular Effects

Excretion of water load

Increased vascular permeability

Other effects

Bone growth

CNS effects

Pharmacological Actions of Cortisol (Supra-physiological):

Anti-inflammatory action

Immunosuppressive actionAnti-allergic actionAll associated with decreased production of molecules such as prostaglandins, leukotrienes, histamine, etc. as well as on the movement and function of leukocytes and the production of interleukins

Also, at high concentrations, will act o MR.

Slide44

CORTISOL:

MECHANISM OF ACTION

receptor

DNA

nucleus

mRNA

New proteins

e.g. Annexin 1

Arachidonic acid

Prostaglandin synthesis

Annexin 1

receptor

On

Neighbouring

Cells?

CORTISOL

Slide45

Addisons

Disease:

Primary adrenal failure.

Cause:

Autoimmune damage (most common cause in the UK).

Tuberculosis of adrenals (most common cause in the world).

Signs and Symptoms:

Increased ACTH production and as it is formed from POMC precursor with side product

melanocyte stimulating hormone (MSH)

(darkens skin), patients will look

tanned

.

Low blood pressure and low sodium

due to no aldosterone.

Biochemically, they have low sodium, high potassium and are acidotic (high H

+

).

Autoimmune damage also cause vitiligo

–

antibodies against the skin cause areas of depigmentation.Treatment of an Addisonian Crisis:

Rehydrate with normal salineGive dextrose (iv) to prevent hypoglycaemia (due to glucocorticoid deficiency).Give cortisol replacement: Hydrocortisone (and fludrocortisone to replace aldosterone).

Adrenal Disorders

Slide46

Cushing’s Syndrome:

A syndrome caused by excess cortisol/ glucocorticoids.

Cause:

Taking steroids by mouth (most common cause).

Ectopic ACTH (lung cancer)

Adrenal adenoma/ carcinoma

Pituitary adenoma (releasing ACTH)

Signs and Symptoms:

Thin skin, easy bruising

Striae

Proximal myopathy

Centripetal obesity (increased fat, loss of protein)

Moon face and buffalo hump

Diabetes (

inc

blood glucose )

Hypertension ( increased aldosterone)

Cushing’s Syndrome:

The clinical syndrome that results from glucocorticoid excess.

Cushing’s Disease:

Where cause is determined to be pituitary adenoma.

Adrenal Disorders

Aldosterone-Producing Adenoma:

Known as

Conn’s Syndrome.

Hypertension, Low Potassium and Oedema.

Slide47

The Gonads

Females:

Ovaries

Males:

Testes

SRY

(Sex Determining Region, Y) gene is on the

Y Chromosome

. It stimulates the development of stem cells into testes. In the absence of SRY, the stem cells will develop into ovaries.

Functions:

Gametogenesis:

Production of gametes for reproduction.

(Spermatogenesis in men; Oogenesis in women)

Steroidogenesis:

Production of steroid hormones.

In males: Androgens (with some oestrogen and progesterone)

In females: Oestrogen and progesterone (with some androgens)

Gametogenesis:

Slide48

Mitosis

Meiosis 1

Meiosis 2

Maturation

Some 1

0

spermatocytes return to the quiescent stage, regenerating

spermatogonia

Mitosis

Meiosis 1

Meiosis 2

Exist since before birth.

Exist as a

Primordial follicle

Most of these undergo atresia

Halted at Prophase

1

of Meiosis

From Puberty, under the

influence of FSH

Meiosis 1 continues

This last step of the cycle only occurs after fertilisation

OVULATION

Slide49

The Testes

Spermatogenesis occurs in the

coiled seminiferous tubules

The seminiferous tubules are lined with with

spermatogonia

.

Spermatozoa are eventually released into the lumen of the tubules, where they migrate to the

rete testis

via collecting ducts.

The spermatozoa are then drained from the rete testis via

the vasa

efferentia

into the

epididymis

.

They are stored and then mature in the epididymis, and are propelled to the urethra by the

vas deferens

which is surrounded by smooth muscle.

Coiled Seminiferous Tubules

Consists of a lumen surrounded by

Sertoli

cells

connected by tight junctions in the periphery.

Spermatogonia

are engulfed into the

Sertoli

cell

, where they develop in the cytoplasm into primary and secondary spermatocytes and are released into the lumen of the tubule as spermatozoa.

Sertoli

Cells

Form the seminiferous tubules

In response to FHS produce

Inhibin

Intimately associated with developing spermatocytes

They provide physical and metabolic support to developing spermatocytes.

Leydig

Cells:

Site of Testosterone Production

Lie outside the seminiferous tubules

Synthesise LH receptors

In response to LH, they produce androgens (mainly testosterone)

Slide50

The Ovaries

The Ovarian Stroma consists of:

Primordial Follicles

undergoing Atresia.

Graffian

Follicles:

A follicle ready for ovulation. It contains a maturing oocyte that is surrounded by fluid. 2 layers of cells surround the follicle: inner

granulosa

cells and outer

thecal

cells.

Remnants

of the last

corpus luteum (after ovulation).

The Menstrual Cycle

It is divided into:An ovarian cycleAn endometria cycle

These occur simultaneously, so it can be hard to get your head around it.The easiest way to remember it is to think about it as one process.

Slide51

The pituitary gland produces FSH. The concentration of the FSH increases.

Many follicles will develop in response to FSH (=Follicle Stimulating Hormone).

The Follicles will secrete oestrogen as they develop.

The oestrogen has a negative feedback on FSH.

Since FSH is inhibited, the follicles will stop producing oestrogen. They will undergo atresia.

However, one follicle will be dominant. It will have become independent of FSH.

The dominant follicle will develop further, continuing to produce oestrogen.

The oestrogen levels continue to rise.

High levels of oestrogen cause a ‘switch’ in the pituitary. There is no longer a negative feedback on FSH/LH; rather, there is a positive feedback.

This causes an LH surge, together with some FSH.

LH (=Luteinising hormone) causes Ovulation.

Progesterone is produced by the Corpus Luteum

Progesterone continues to rise.

This causes a negative feedback on FSH and LH (so their levels fall).

Since levels of FSH/LH fall, the progesterone levels fall as well.

The corpus luteum breaks down.

The falling levels of progesterone mean that there is less inhibition of

gonadotrophins

.

The pituitary gland produces FSH. The concentration of the FSH increases. The cycle restarts.

17 β-Oestradiol

Stimulates the

proliferative phase

of the Endometrial Cycle:

The thin endometrium thickens and moistens.

The endometrial glands go from straight to enlarged, coiled and increased blood supply.

Progesterone

Stimulates

the secretory phase

of the Endometrial Cycle:

Endometrium becomes secretory

Glands produce glycogen and

mucopolysacharides

.

The mucosa becomes engorged with blood.

MENSTRUATION

The endometrium becomes necrotic and sheds

Slide52

Sex Steroids

Testosterone:

Oestrogen:

Progestogens

:

Transport of testosterone and DHT:

In Blood:

bound to plasma proteins as the androgens are

lipophilic

therefore need to be bound to prevent excess effects.

Sex hormone binding globulin (SHBG)

: 60% bound (Specific for androgens and oestrogens)

Albumin:

38% bound

Free Bioactive Component:

2%

In seminiferous fluid:

Bound to

Androgen Binding Globulin

.

Principle Actions:Spermatogenesis

Growth and development

Protein anabolism

Pubertal growth spurt (along with growth hormone)

Feedback regulation

Behavioural effects (CNS) e.g. aggression, competitiveness

Definition: Any substance (natural or synthetic) which induces mitosis in the endometrium

 

Examples :

17



-

oestradiol

Oestrone (Precursor)

Oestriol

(Pregnancy)

 

Principal Actions:

Maturation of follicle

Induces LH surge resulting in ovulation

Stimulates growth

of the endometrium

Effects of vagina, cervix e.g. development of glands

Stimulates growth of ductile system of breast

Other

effects.

Bone

Metabolism

Behaviour

Feedback

(+ve and

–

ve).

Definition: any substance (natural or synthetic) which induces secretory changes in the endometrium

Examples:

Progesterone

17



-

hydroxyprogesterone

 

Principal Actions:

Stimulates secretory activity in the endometrium and cervix

Stimulates growth of alveolar system of breast

Decreases renal NaCl reabsorption (competitive inhibition of the aldosterone)

Associated with increases in basal body temperature (This is a useful marker of ovulation, as it results in a 0.1-0.2 degree increase)

All sex hormones are derived

from cholesterol.

Slide53

mRNA

New

proteins

ACTIONS

hormone

receptor

Sex Steroids

–

Mechanism of Action

Slide54

Androgen production (

Leydig

cells)

Stimulated by GnRH/

LH

system

Direct negative feedback to reduce LH release from anterior pituitary gland

Indirect negative feedback to slow hypothalamic GnRH pulse generator

2. Spermatogenesis (

Sertoli

cells)

Stimulated by GnRH/

FSH

systemAlso requires GnRH/LH/Testosterone

system for complete spermatogenesisLimited by inhibin negative feedback (direct and indirect)

The Hypothalamo-Pituitary-Testicular Axis

Slide55

Early

Follicular Phase

Early-Mid Follicular Phase

Mid Follicular Phase

Selective negative feedback loop by

oestrogen

and

inhibin

on the GnRH-FSH system results in

atresia

(regression) of all follicles that are still FSH dependent:

Graafian

follicle survives

Slide56

Late Follicular

Phase

If fertilization does not occur, progesterone,

oestradiol

and

inhibin

exert a negative feedback on LH and FSH release, leading to

luteolysis

and menstruation

Luteal Phase

Slide57

Disorders of the HPG Axis

1-

Amenorrhoea

:

Absence of menstrual cycles.

Primary

Amenorrhoea

:

Menstruation never occurs.

Secondary

Amenorrhoea

:

Menstruation occurs, but then stops. This can be physiological e.g. in pregnancy.2- Oligomenorrhoea: Irregular menstrual cycles.

3- Infertility: Couple cannot get pregnant following 12 months of regular unprotected sexCauses:Pituitary failure

Prolactinoma Testicular failure e.g. mumps, Klinefelter syndrome (XXY)Ovarian failure e.g. premature menopause, Turner syndrome (XO)

Slide58

Calcium Metabolism

Calcium is an important ion in the nervous system, and is involved in the release of neurotransmitters at the NMJ.

There are other roles for calcium as well.

In the Blood:

The concentration of calcium in the blood is 2.5mM:

This is controlled very precisely:

50% of calcium remained

unbound

– this is the

ionised

component which is biologically active

45% is bound to

plasma proteins

(1.13mM) 5% remain as diffusible salts

(approx 0.13 mM) – these include citrate and lactate are can readily diffuse through cell membranes.Calcium Regulation:

Increase

s Calcium:

Decreases Calcium:PTH: Parathyroid Gland

Calcitriol (1,25-dihydroxy Vitamin D3/ 1,25-dihydroxycholecalciferol)Calcitonin: Parafollicular

Cells in the Thyroid

Slide59

PTH

Initially synthesized as protein pre-

proPTH

Polypeptide of 84 amino acids

PTH Receptor is a

G

s

PCR

.

Increased Ca

2+

reabsorption (kidney)

Increased Ca

2+

absorption (gut)

Increased Ca

2+ mobilisation

(bones)(=

Phosphate Trashing Hormone)

Binds to PTH Receptors on osteoblastsInhibits osteoblasts

Osteoblasts release OAFs e.g. RANKLOAFs activate osteoclastsOsteoclasts resorb bone

BLASTS = BUILD

Slide60

Calcitriol

UV Light

Skin

7-Dehydrocholesterol

Cholecalciferol

Vitamin D

3

Liver

25-Hydroxycholecalciferol

25⍺-hydroxylase

Kidney

1⍺-hydroxylase

1,25-Diydroxycholecalciferol

Calcitriol

Actions:

Small Intestines:

Increased Ca

2+

Absorption

Increased Phosphate Absorption

Bones:

Increased Osteoblast Activity

Kidneys:

Increased Ca

2+

Reabsorption

Increased Phosphate Reabsorption

PTH

Renal Phosphate Reabsorption:

Calcitriol stimulates the production of FGF23 which stimulates the production of a sodium-phosphate co-transporter in the kidneys. This increases the reabsorption of phosphate.

Slide61

Calcitonin

It’s basically the exact opposite of PTH and calcitriol:

Stimulated by

high

serum calcium.

Results in a

reduction

of the calcium concentrations in the blood.

32 amino acid polypeptide.

Slide62

Hypocalcaemia

Causes:

Signs on Examination:

HYPOPARATHYROIDISM:

Idiopathic

Low

Magnesium

(Suppressed

Secondary to High Calcium)

PSEUDOHYPOPARAATHYROIDISM:

AKA

Albright’s Hereditary Osteodystrophy

PTH

is produced normally, but the receptors are resistant to it.

Features: PISAP

hysical appearance –short stature, round face.I

Q –Low

Short metacarpals; subcutaneous calcifications.

Associeated endocrine disorders e.g. hypothyroidism.VITAMIN D DEFICIENCY:

Rickets in ChildrenOsteomalacia in Adults

(Difference due to calcification in bone matrix with aging).Chvostek’s Sign

Trousseau’s Sign

Slide63

Hypercalcaemia

Causes of Hypercalcaemia:

Primary Hyperparathyroidism

Tertiary Hyperparathyroidism

Vitamin D Excess

Signs + Symptoms of Hypercalcaemia:

Bones, Stones, Abdominal Groans.

Bones:

Bone pain and fractures.

Stones:

Kidney stones, dehydration.

Abdominal Groans:

Abdominal pain, duodenal ulcers