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Table Of Contents:

What’s included: Ready-to-study anatomy, physiology and pathology notes of the endocrine system
presented in succinct, intuitive and richly illustrated downloadable PDF documents. Once downloaded,
you may choose to either print and bind them, or make annotations digitally on your iPad or tablet PC.

File List:

• Overview of The Endocrine System

• The Hypothalamo-Pituitary Axis
• Thyroid Function
• Insulin, Glucagon & Regulation of Metabolism
• Fluid & Electrolyte Balance
• Calcium & Phosphate Metabolism
• Physiological Response to Stress
• Reproductive Endocrinology
• ADH Disorders
• Adrenal Cortex Dysfunction
• Adrenal Medulla Dysfunction
• Calcium & Phosphate Imbalance Disorders
• Diabetes
• Diabetic Emergencies
• Gonadal Dysfunction
• Growth Dysfunction
• MENS Multiple Endocrine Neoplasia Syndrome
• Pituitary Dysfunction
• Thyroid Dysfunction
• Free bonus: ‘Endocrinology’ chapter of Toronto Notes for reference and further detailed reading.
 NotesByToppers.com exclusive

System: Endocrinology

Endocrinology:
- Endocrinology: The scientific study of Hormones (Chemical Messengers) and the endocrine organs.
- Endocrine system maintains Homeostasis in coordination with the nervous system.

Families of Chemical Messengers:

- Amino Acid Derivatives:
o Catecholamines (Eg. Adrenaline, Nor-Adrenaline & Dopamine) (Derived from Tyrosine)
o Histamine (Derived from Histidine)
o All Thyroid Hormones (Derived from Tyrosine)
- Proteins:
o All Pituitary Hormones
- Steroids:
o Sex Hormones (Derived from Cholesterol)
- Fatty-Acid Derivatives:
o Prostaglandins
o Thromboxanes
o etc.
- Purines
- Gases:
o Eg. Nitric Oxide.
- Acetylcholine

What is a Hormone?
Long distance chemical signals secreted by endocrine glands into the extracellular fluids
Travel in blood or lymph throughout the body.
ARE BIOLOGICALLY SPECIFIC: Interact with specific receptors of specific cells of specific target organs.
Either AMINO ACID BASED OR STEROIDS (cholesterol based) Mostly amino acid based.
o Only gonadal & adrenocortical hormones are steroids
Travel in blood or lymph throughout the body.

Synthesis of Chemical Messengers:

- Steroidogenesis:
o All steroid hormones are derived from Cholesterol.
o There are 5 Families of Steroids, each with their main physiological member:
Progestagens (Progesterone)
Androgens (Testosterone)
Mineralocorticoids (Aldosterone)
Glucocorticoids (Cortisol)
Oestrogens (Oestrogen)
- Protein/Peptide Synthesis & Processing:
o Synthesis of polypeptide hormones can be more complex than Transcription & Translation.
o Some Protein Hormones are initially synthesised as longer Pre-Prohormones.
o These Pre-Prohormones are then cleaved, leaving Prohormones.
o These Prohormones are then cleaved again, leaving active Hormones.

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R a P C a M
- Biological Specificity: Certain Chemical Messengers will only fit into certain receptors.
- Affinity: The degree to which a chemical is attracted towards a receptor.
- Efficacy: The degree of effectiveness of the binding of the messenger to the receptor.
- A Chemical Messengers with High Affinity & High Efficacy.
- A a Chemical Messengers with High Affinity but Low Efficacy.
NB: There are no Endogenous Receptor-Antagonists, Only Exogenous (Drugs)
- Hormone Binding Proteins: Proteins that inactivate hormones by binding to them, limiting Bioactivity.
- Epitope: An Immunologically active binding site on a protein to which an antibody can
attach.

Endocrine (diffuse) Glands:

- Endocrine Glands are Ductless and secrete by Exocytosis into the Extracellular Fluid Diffuses into Blood.

Classical Endocrine Glands:

Pineal gland
Hypothalamus
Pituitary gland
Thyroid gland
o Parathyroid glands (dorsal aspect of thyroid gland)
Thymus
Adrenal glands
Pancreas (has exocrine in parts)(endocrine part secretes insulin)
Gonads: Testes/Ovaries (also exocrine)

Long or Short Range?

Endocrine: Some signals are broadcasted thro gho t the entire bod ia bloodstream Hormones
(produced by endocrine cells) [TV]
Autocrine: Signals that affect only cells of the same cell type as the emitting cell. [doctor conference]
Paracrine: Signals (aka local mediators) that act on cells in the vicinity of the emitting cell but on different
cell types than the emitting cell. [Lecture]

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2 Main Receptor Types: (Intracellular & Membrane-bound Receptors)
Intracellular Receptors:
o Lipid-soluble hormones (steroid/thyroid hormones) & even gasses (nitric oxide-blood vessel
dilation)
Steroid hormones bind to receptor proteins in the cytosol or the nucleus that regulate
gene expression.

Plasma-Membrane-Bound-Receptors:
o Most signal molec les can t cross the plasma membrane of the target cell
o Most intracellular signalling proteins act as molecular switches activated by either
phosphorylation OR GTP-Binding (swapping a GDP for a GTP)
o 3 Types:
Ion-Channel-Linked Receptors
Resulting signal is a flow of ions across the membrane produces an electric
current.
Enzyme-Linked Receptors
o When activated act as enzymes or are associated with enzymes inside the
cell.
G-Protein-Linked Receptors (more common)
o Binds to a class of membrane-bound GTP-Binding-protein (G-Protein)
becomes activated and released to migrate across the membrane, initiating a
cascade of other effects.
o Some G-Proteins directly regulate ion channels in the plasma membrane.
o Other G-Proteins activate membrane-bound enzymes. Eg. adenylyl-cyclase
increases the [second messenger (cyclic-AMP)] activates an intracellular
signalling protein (eg. A protein kinase) OR turns on genes via activated
P K a A PKA .

Tissue Responsiveness:
- Receptor Downregulation:
o Where a decreased receptor density in the membrane decreases the responsiveness of that cell to
that receptor s stim li
o This is achieved by Internalising the receptor-ligand complex, dissociating the ligand, and recycling
the receptor back to the surface.

- Receptor Desensitisation:
o Where a change in receptor structure decreases the responsi eness of that cell to that receptor s
stimuli.
o Why? To prevent multiple, rapid stimulations.

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Regulation of Hormone Release:
- 3 Mechanisms:
o 1. Humoral:
Where the concentration of a solute in the blood (Eg. High Glucose/Low Calcium) is
detected by a specific gland, stimulating hormone release (Eg. Insulin/Parathyroid
Hormone)
o 2. Neural:
Where the Nervous System Directly stimulates hormone release.
Eg. Sympathetic NS Activated Stimulates Adrenal Medulla Secretes Catecholamines.
o 3. Hormonal:
Where one hormone stimulates the release of another hormone from a different cell.
Eg. The Hypothalamus secretes hormones Stimulate Ant. Pituitary Secretes
Hormones.
Eg. The Ant. Pituitary secretes Hormones Stimulate other organs to secrete hormones.

FEEDBACK:
Negative:
o Most common
o Maintains levels around a stable intrinsic/preset level.
o Involved in homeostatic control.
Positive:
o Uncommon
o Unstable mechanism
o Stopped by removal of initial stimulus.

Levels of Feedback Loops:

- Feedback ma occ r at man different le els ithin a single H pothalamo-Pituitary-Target a is
o Ultra-Short Loop:
Autocrine Feedback - The secreted hormone feeds back to the same tissue that secreted it.
Eg. A Hypothalamic Hormone feeds back to the Hypothalamus.
o Short Loop:
The secreted hormone feeds back to the tissue that stimulated its secretion.
Eg. The Hormone secreted by the Target Organ feeds back to the Pituitary.
Or. The Hormone secreted by the Pituitary feeds back to the Hypothalamus.
o Long Loop:
The hormone secreted by the target organ feeds directly back to the Hypothalamus.

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Endocrine Disorders:
- Level-Of-Function Disorders:
o Hypofunction Disorders:
Where the gland produces less than it should.
Common Causes:
Loss of reserve
Hypo-secretion
Agenesis failure to develop embryonicaly
Atrophy Wasting away due to injury/disease/lack of use.
Active Destruction
Tumour
o Hyperfunction Disorders:
Where the gland produces more than it should.
Common Causes:
Hyper-secretion
Loss of suppression
H perplasia Proliferation
Neoplastic Change (Tumour)
Hyperstimulation
Ectopic Sites of Secretion (Some far-off tumours secreting hormone)

- Hierarchical Classification of Hypothalamo-Pituitary Axis Disorders:

o NB: Endocrine disorders of the Hypothalamo-Pituitary Axis are often classified in a Hierarchical
Fashion depending on the origin of the disorder:
o Primary:
Disorder of the Target Gland
(eg. Primary Hypothyroidism the Thyroid Gland itself is under-responsive to TSH
stimulation)
o Secondary:
Disorder of the Pituitary Gland
(eg. Secondary Hypothyroidism the Pituitary Gland is under-producing TSH)
o Tertiary:
Disorder of the Hypothalamus
(eg. Tertiary Hypothyroidism the Hypothalamus is under-producing TRH)

Testing for an Endocrine Disorder:

- Basal Hormone Testing:
o A single snapshot measurement of the concentrations of specific hormones.
Eg. High [Thyroid-Stimulating Hormone] Therefore Primary Hypothyroidism.
o Problem Some secretions are Pulsatile meaning random meas rements don t acc ratel
diagnose a disorder of that gland. The Solution: Dynamic Hormone Testing.
- Dynamic Hormone Testing:
o Using exogenous chemicals/hormones to Stimulate/Suppress activity of a target gland. This tests
the responsiveness of a target gland to feedback stimuli.
Suppression Tests:
When Hyperfunction is suspected, an inhibitor is administered and then the
hormone concentration is re-measured to see if it has decreased. If not,
Hyperfunction is confirmed.
Stimulation Tests:
When Hypofunction is suspected, a stimulator is administered and then the
hormone concentration is re-measured to see if it has increased. If not,
Hypofunction is confirmed.

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 NotesByToppers.com exclusive

Typical Endocrine Symptoms:

- Diabetes (1 & 2):
o Weight Change
o Polyuria, Nocturia & Thirst
o Visual Disturbances
o Infections & Immunosuppression
o Constant Hunger
o Nausia + Vomiting
o Fatigue
o DKA (Diabetic Ketoacidosis) = Emergency Presentation
- Hyperthyroidism:
o Weight Loss
o Fatigue
o Suppressed TSH
o Elevated T4
- Hypothyroidism:
o Weight gain
o Pretibial Myxoedema
o Periorbital Oedema
o Bradycardia
o Bradypnoea
- PolyCystic Ovarian Syndrome:
o Weight Gain
o Hirtism
o Infertility
- Cushings Syndrome:
o Caused by Excess Corticosteroids
o Moon Facies (Fat, white, round faces)
o Muscle Wasting + Weakness
o Weight Gain (Truncal Obesity)
o Stretch Marks due to Weight Gain
- Pituitary Adenoma:
o Peripheral Vision Loss
o Compression symptoms or Secretory Symptoms
o Secretory eg. Prolactin Galactorhoea + Gynacomastia
eg. GH Gigantism (Pre-Purbety) Acromegaly (Post Puberty)
eg. ACTH: C shing s S ndrome
- Acromegaly:
o Soft-Tissue Swelling
o Arthritis
o Hyperhydrosis
o Headache + Visual Field Defect
- Addisons:
o Autoimmune
o Weight Loss
o Fatigue
o Hypotension
o Hyponatraemia
o Hyperkalaemia
o Hyperpigmentation
- Anorexia:
o Weight Loss
o Fatigue
o BMI
o FSH LH D e to no o lation
o GH
o Hypokalaemia (often due to vomiting) Arrhythmias

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 Week 2
Endocrinology Notes
The Hypothalamo-Pituitary Axis

General Location of the Hypothalamus & Pituitary Gland

Embryology of the Pituitary Gland:

- Q: Why is the Ant. Pituitary Endocrine, & the Post. Pituitary Neuronal?
- A: Because they have different embryonic origins.
o Anterior Pituitary:
§ Arises from an upward out-pouching of the Oral-Ectoderm from the roof of the oral cavity
called Rathke’s Pouch. This pouch pinches off from the oral cavity and is later separated by
the sphenoid bone.
§ Consists of Epithelial/Glandular Tissue, & therefore Manufactures & Secretes Hormones.
o Posterior Pituitary:
§ Originates from a downward out-pouching of Neuro-Ectoderm from the brain in the floor of
the 3rd ventricle.
§ Consists of Neural Tissue, & therefore Secretes Neurohormones.

1. 2.

3.

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The Hypothalamus & Pituitary Glands:
- Hypothalamus:
o Links the nervous system to the endocrine system via the pituitary gland.
o Controls body temperature, hunger, thirst, fatigue, anger, and circadian cycles.
o Secretes neurohormones (hypothalamic-releasing hormones) Stimulate/Inhibit Pituitary Gland.
Abbreviation Full Name Stimulated/Inhibited Hormone
GRH Growth-Hormone Releasing Hormone Stimulates Release of Growth Hormone
SS Somatostatin Inhibits Release of Growth Hormone & TSH
TRH Thyrotropin Releasing Hormone Stimulates Release of TSH & Prolactin
PRF Prolactin Releasing Hormone Stimulates Release of Prolactin
GnRH Gonadotropin Releasing Hormone Stimulates Release of Gonadotropins; FSH & LH
CRH Corticotropin Releasing Hormone Stimulates Release of ACTH
- Pituitary Gland:
o Has 2 Major Lobes:
Posterior Pituitary: (Neurohypophysis)
Nervous Tissue
Supraoptic & Paraventricular Nuclei in the hypothalamus synthesize Oxytocin &
ADH Transport them to their axon terminals in the Posterior Pituitary.
o Hormones released as needed via exocytosis in Post.Pituitary
ADH
Oxytocin
Normal Histology Just like normal brain tissue. (Neural Origin)
o NB: NO neurones, but plenty of axons.
o Many supporting cells (Astrocytes, oligodendrocytes)
o Plus Blood Vessels ( ei he a e ie ei b P al Ve el Ie. Blood
comes only from the hypothalamus carries the hypothalamic
hormones.)
Anterior Pituitary: (Adenohypophysis)
Glandular Tissue (adeno = gland)
Releasing-Hormones from Ventral Hypothalamus that stimulate Ant. Pituitary:
o CRF
o TRF
o GRH FSH/LH
o GHRH
o Prolactin Releasing Factor (PRF)
Normal Histology Glandular structure:
o Clusters of acini surrounded by blood vessels
o Acini - mosaics of different cells:
(acidophils red, basophils dark blue, chromophobes - colourless)
NB: Pituitary Tumours may be from any of the 3 cells
o PLENTY f bl d e el ei he a e ie ei b P al Ve el Ie.
Blood comes only from the hypothalamus carries the hypothalamic
hormones.)

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 o Blood Supply:
Arterial blood enters via Hypophyseal Branches of the Internal Carotid Arteries.
(BUT SHASHI SAYS NO ARTERIES...PORTAL SYSTEM)
o Venous Drainage:
Venous blood leaves via venules which drain into the Dural Sinuses.

- Pituitary Hormones & their Target Tissues/Organs

o NB: All these hormones are PROTEIN-based hormones.

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Secretory Setup of the Hypothalamus & Pituitary Gland:
- Anterior Pituitary:
o Neurons of the Ventral Hypothalamus terminate in the Primary Capillary Plexus within the
Infundibulum (Stalk).
o These Neurons secrete Releasing-Hormones into the Primary Cap. Plexus, which flow to the
Secondary Capillary Plexus, stimulating Endocrine Cells of the Ant. Pituitary to synthesize/secrete
hormones.
- Posterior Pituitary:
o Neurons of the Supraoptic & Paraventricular Nuclei synthesize Oxytocin & ADH in the
hypothalamus, then transport them as granules to their axon terminals which terminate in the
Posterior Pituitary.
o When one of the hormones is needed, it is released from the axon via exocytosis into the
bloodstream via the Inferior Hypophyseal Circulation.
- NB: Remember that the Ant. & Post. Pituitary don’t act entirely independently (there is some flow of
hormones from the Post. Pituitary à Ant. Pituitary via the ‘Short Portal Vein’)

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The Hypothalamus: A ‘Relay-Station’ for Higher Brain Centres:
- The Hypothalamus receives information from multiple higher brain centres, integrates it, decides on a
response, and orders the pituitary to secrete specific hormones to elicit the response.
- Inputs:
o RAS (Reticular Activating System/Substance) – Regulates drowsiness by releasing Serotonin.
o Thalamus – Plays a role in Pain Perception
o Neocortex & Limbic System – Emotional Centre
o Optical System – Vision
- Outputs:
o Anterior Pituitary
o Posterior Pituitary
o Brain-Stem (Autonomic NS)

Feedback Control:
- Negative:
o Where the Biological Response causes a Decreased Hormone Release.
o Maintains levels around a stable intrinsic/preset level.
- Positive:
o Uncommon (Lactation & Parturition)
o Where the Biological Response causes an Increased Hormone Release
o Are therefore Unstable mechanisms
o Stopped by removal of initial stimulus.

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Levels of Feedback Loops:
- Feedback may occur at many different levels within a single ‘Hypothalamo-Pituitary-Target’ axis.
o Ultra-Short Loop:
§ The secreted hormone feeds back to the same tissue that secreted it.
• Eg. A Hypothalamic Hormone feeds back to the Hypothalamus.

o Short Loop:
§ The secreted hormone feeds back to the tissue that stimulated its secretion.
• Eg. The Hormone secreted by the Target Organ feeds back to the Pituitary.
• Or. The Hormone secreted by the Pituitary feeds back to the Hypothalamus.

o Long Loop:
§ The hormone secreted by the target organ feeds directly back to the Hypothalamus.

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 Endocrine Regulation of Growth

Phases of Growth:
- NB: These Differ in their Rates of Growth and Regulators/Contributors:

Major Regulators/Contributors
Phase of Growth Nutrition Hormonal Genetics
Foetal Yes - #1 Insulin (Acts as a growth factor No
(In Utero) in this phase)
IGF-I
Infantile Yes - #1 GH & IGF is present, but in low Yes – (Only after a few months
(Birth 2yrs) amounts – NOT Imperative. after birth)
Pre-Pubertal -Ve influence only if - IGF Levels Increase Yes - #1
(Childhood) malnourished - GF Receptors Increase
NB: Growth Velocity progressively declines during this phase (Transition from Infant Child)
NB: Body Proportions start to change.
Pubertal -Ve influence only if Sex Hormones:
(Early Teens) malnourished - GH Release
- Epiphyseal Closure
GH Causes IGF Release
GH + IGF Bone Elongation
Post-Pubertal NB: Growth Velocity peaks & then stays same for yrs.
(Late Teens) - (The last 3 years mainly concern the Trunk)

Major Hormones involved with Growth:

- Growth Hormone, AKA: Somatotropin
- Insulin-like Growth Factors (Somatomedins) (IGF-I & IGF-II)
- Somatostatin (Inhibits secretion of GH from Ant. Pit.)
- Thyroid Hormone
- Cortisol – (Not Direct – has a ‘permissive’ role. Ie. Other growth hormones are more effective if it’s present
- Sex Hormones (Oestrogen/Testosterone)

The Growth Hormone Axis:

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Hypothalamic Hormones of Growth:
- (+) GRF (Growth-Hormone Releasing Factor)/GRH (Growth-Hormone Releasing Hormone):
o Produced Mainly in: Hypothalamus (But also in GIT, Pancreas & Placenta)
o Exerts Effects on: Somatotropes (Anterior Pituitary) Growth Hormone Release.

- (-) Somatostatin:
o What is it?:
Produced almost everywhere: (Hypothalamus, Gut, Pancreas, CNS)
Inhibits Somatotropes Growth Hormone.
o Actions of Somatostatin:
Inhibits some Hypothalamic-Releasing Hormones:
GH (Grow Hormone)
TSH (Thyroid Stimulating Hormone)
PRL (Prolactin)
ACTH (Adreno-Cortico Tropic Hormone)

Anterior Pituitary Hormone of Growth:

- Growth Hormone:
o Produced by: Anterior Pituitary After mths old
o Regulation of Release:
Stimulation Inhibition
GRH - (Growth-Hormone Releasing Hormone) Somatostatin
o Actions:
Growth-Promoter from Early Childhood Onwards
Longitudinal Bone Growth & Remodelling
Skeletal Muscle Growth
Liver Growth
Stimulates IGF-Binding Protein Synthesis (Important carrier for IGF)
Stimulates IGF Synthesis
Metabolic Effects:
Stimulates:
o Lipolysis
o Ketogenesis
o Gluconeogenesis
o Protein Synthesis
o Lactation
Inhibits Insulin Action.
Boosts Immune Function.

Defects in Endocrine Control of Growth:

- Hyper:
o Too Much Growth Hormone &/or Growth Factors (Rare):
Eg. Childhood Gigantism
Eg. Adults - Acromegaly
o Non-GH Causes:
Eg. Precocious Puberty
- Hypo:
o Defective Growth Hormone Axis:
GH-Deficiency:
Primary GH Deficiency:
o Hypothalamic Defect
o And/Or Pituitary Defect
Secondary Pituitary Deficiency:
o Eg. Tumour & other Destructive Diseases.
o Eg. Psychosocial Deprivation (Ie. Kids in abusive/non-supportive
environments GH-Deficiency exhibit slowed growth)

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 Liver
Insulin-Like Growth Factors (IGF’s):
- Both IGF-I & IGF-II are Structurally Similar to Proinsulin (The Insulin Precursor)
- IGF-I - Chromosome 12
- IGF-II - Chromosome 11
- Circulates bound to IGFBP (Insulin-like Growth Factor Binding Protein)
- Bind to Specific Receptors
- Stimulate Cell Division together with other Growth Factors.
- Foetal Life:
o Act in Paracrine Fashion
o IGF made by all foetal tissues (However, mainly by liver after birth)
o Absence of IGF-I in Foetal Life à Intra Uterine Growth Retardation

Long Bone Growth

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Thyroid Function

Anatomy of Thyroid Gland:

- A Bilobar Gland (2 Lobes L&R) connected in the middle by the I h of the Thyroid.
- Location:
o Immediately below the Larynx on each side of, and anterior to, the Trachea.
- Rich Blood Supply:
o Required for Building Blocks of Hormones.
o Required for Quick Release of Hormones.
o Flow - Regulated by the Sympathetic NS.

- C ed f M f Follicles
o Each contains a pool of Thyroid “Colloid” of stored Thyroid Hormones bound to Thyroglobulin.
Allows for a 2-3mth reserve of thyroid hormones.
o Each pool is lined by a layer of P i ci al F llicle Cell that secrete Thyroid Hormones (T3 & T4).
o There are also patches of Pa af llic la Cell that secrete Calcitonin.

Physiology of the Thyroid Gland:

o Iodine Balance:
NB: Iodine is essential for Thyroid Hormone Production.
Iodine is Actively taken up by Thyroid Gland via I di e T a i g .
TSH Th id I dine U ake
o Main Hormones:
T4 Thyroxine (93%) (Iodinated Tyrosine 4x Iodines) (Less Biologically Active)
T3 Triiodothyronine (7%) (Iodinated Tyrosine 3x Iodines) (Most Biologically Active)
Calcitonin (Polypeptide)
Secreted By The Parafollicular Cells of the Thyroid Gland
F c Plasma-Ca+ levels B O e cla Ac i i Osteoblast Activity)
Stimulated By: E acell la Ca+] (NB: Opposite of PTH)
o Effects of TSH on the Thyroid:

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 Thyroid Follicle Hyperplasia
I dine U ake f m he Bl d Iodine Trapping)
Th id H m ne S n he i
Relea e f T3 & T4
o Synthesis of Thyroid Hormone:
I dide U ake I dine T a ing
2. Iodide Activation via Oxidation
3. Secretion of Active/Oxidised Iodine into Colloid
4. Synthesis of Thyroglobulin from Tyrosines & Secretion into Colloid
5. Iodines stick to Thyroglobulin in Colloid DIT or MIT (Di/Mono-Iodo Tyrosine)
o Release of Thyroid Hormone:
Colloid is Endocytosed and Enzymatically Cleaved into T3 & T4.
Vesicles of T3 & T4 release contents into Cytosol
T3 & T4 Diffuse out of Follicle Cell & Into Bloodstream
Thyroxine-Binding Proteins (incl. Albumin)in Blood transport T3 & T4 to the rest of the body.
o Metabolic Effects of Thyroid Hormone:
NB: Because Thyroid Hormones act by Gene Activation, they are said to have a Long
La e Pe i d , during which they seem to have no discernible effect.
Skeletal - B ne T n e Re i n
Muscular - S eed f C n ac i n S eed f Rela a i n
Sympathetic NS - Ca ech lamine Sen i i i f Hea M cle Fa L m h c e
CVS - HR CO
GI - G M ili Sec e i n A e i e
Carbohydrate Metabolism - He a ic Gl c ne gene i He a ic Gl c l i
Lipid Metabolism - Li l i FFA in Pla ma
Metabolic Changes:
Ca b h d a e Fa P ein Me ab li m
Mi ch nd ial Ac i i N mbe
Na K-ATPase Activity
O2 Consumption
FFA in Plasma
Bodily Changes:
B d Tem Sweating
Me ab li m Ba al Me ab lic Ra e

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Thyroid Embryology:
- Forms from Pharyngeal Pouches (@4-5wks)
- Forms from the Endoderm germ layer.
- Once formed, it migrates downwards & becomes Bi-lobed.
o NB: Sometimes things go wrong during this migration, leaving a person’s thyroid gland between the
back of the tongue & where it normally sits. (See dotted red line on pic below)

Major Thyroid Hormones Produced (And Proportions):

- T3 – Triiodothyronine (7%) (Iodinated Derivative of Tyrosine – 3x Iodines) (Most Biologically Active)
- T4 – Thyroxine (93%) (Iodinated Derivative of Tyrosine – 4x Iodines) (Less Biologically Active)
NB: Because these hormones are stored in the ‘Colloid’, there is ≈2-3mths of ‘backup’ Reserve.
- Calcitonin (Polypeptide)

Iodine Balance:
- NB: Iodine is an essential component of the 2 major Thyroid Hormones & Is a Dietary Requirement.
- Of the Iodine ingested;
o 20% is Selectively Removed from blood by Thyroid Gland & used in Thyroid Hormone Synthesis.
o 80% is Excreted by the Kidneys
- NB: This process of Active Iodine Uptake by the Thyroid Gland is called “Iodine Trapping”.
- NB: The Rate of Iodine Uptake (Trapping) depends on TSH Concentration.

How TSH Stimulates Thyroid Hormone Synthesis/Secretion:

- Binding of TSH to Follicle Cell à Activates AdenylylCyclase à ↑cAMP à Activates pKa (Protein Kinase A)
à Phosphorylates Various Enzymes in Follicle Cell à Changes Activity of:
1. ↑Cleavage of Thyroglobulin in Lysosomes (Ie. ↑Release of T3 & T4)
2. ↑Activity of Iodine Pump (The Rate Limiting Step) à ↑Iodine Available for Synthesis
3. ↑Iodination of Tyrosine à ↑Synthesis of DIT’s & MIT’s à ↑Thyroid Hormone Synthesis
4. ↑Size & Secretory Activity of Follicle Cells
5. ↑# of Follicle Cells

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Synthesis of Thyroid Hormone: (Stimulated by TSH)
1. Active Uptake of Iodide by the Principal/Follicle Cells (Iodide “Trapping”):
a. Active Iodide uptake against massive Electrochemical Gradient.
b. NB: This is the Rate-Limiting Step of TH Synthesis.
2. Iodide Oxidation (by Peroxidase):
a. Oxidation of Iodide Ions (I-) à Iodine Molecules (I2).
3. Secretion of Active Iodine into Lumen of Colloid:
4. Synthesis of Thyroglobulin by Rough-ER+Golgi & Secretion into Lumen of Colloid:
a. Tyrosines – the basis of Thyroglobulin (A large poly-peptide of ≈70 Tyrosines)
5. Iodines stick to the Tyrosines on the Thyroglobulin in Colloid à DIT or MIT (Di/Mono-Iodo Tyrosine)

Hormone Release Mechanism:

6. Some of the Thyroglobulin Colloid is Endocytosed + Combined with Lysosome:
a. Lysosomal Enzymes cleave the T3 & T4 from the Thyroglobulin.
b. NB: In the process, many of the unpaired DIT’s/MIT’s are also released. These are De-Iodinised by
Deiodinase. Both the freed Iodines & Tyrosines are recycled.
7. Vesicle of Cleaved T3 & T4 Breaks Down, Releasing Hormones into Cytosol
8. Hormones in Cytosol Diffuse through Basement Membrane à Combine with Binding Proteins in the Blood
Stream (Thyroxine-Binding Protein/Albumin)

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Regulation of Thyroid Hormone Production/Release:
1. Hypothalamus Secretes “Thyrotropin-Releasing Hormone” (TRH) into portal circulation of Pituitary.
2. TRH Stimulates Anterior Pituitary to Secrete “Thyroid Stimulating Hormone” (TSH).
3. TSH Stimulates Thyroid Gland to Secrete:
a. *Primarily Thyroxine (T4) (The relatively inactive Thyroid Hormone à converted to T3)
b. And Some Triiodothyronine (T3) (The most active Thyroid Hormone)
4. T3 & T4 Circulate in the Bloodstream Eliciting their effects + Provide Neg.Feedback to Ant. Pituitary

Transport of Thyroid Hormones (Binding Proteins):

- NB: 75-100µg of Thyroid Hormone is secreted per day
- Thyroid hormone must be bound to carrier proteins when in bloodstream to avoid filtration by kidneys.
- Common Thyroid-Hormone Carrier Proteins:
o 70% - “Thyroxine-Binding Globulin” (TBG)
o 30% - Albumin
o NB: The minute %age of unbound Thyroid Hormones are those eliciting their effects.
§ Ie. TH must be unbound to be able to enter cells & bind to Intracellular Receptors.

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Mechanism of Action of Thyroid Hormone:
1. Thyroxine (T4) reaches target cell
2. Binding Protein releases Thyroxine (T4)
3. Thyroxine (T4) diffuses into cytosol à Converts to T3
4. T3 (The most active form) enters Nucleus à Binds to Nuclear Receptor on DNA à Alters Gene Transcription.
5. Activating Different Genes à leads to Change in Cell’s Protein/Enzyme profile à Change in Activity.

- Cellular Changes:
o ↑Carbohydrate/Fat Metabolism
o ↑Glucose Uptake
o ↑Protein Synthesis + Catabolism
o ↑Mitochondrial Activity & Number
o ↑Na/K-ATPase Activity
- Bodily Changes:
o ↑O2 Consumption à ↑Cardiac Output, HR & Respiration
o ↑Food Intake (↑Glucose Absorption from GIT)
o ↑Secretion of Digestive Juices
o ↑GIT Motility
o ↑Insulin Secretion
o ↑[FFA] in Plasma
o ↑Body Temp à Sweating
o ↑Metabolism (Basal Metabolic Rate)
o ↑Vitamin Requirements due to ↑Quantities of Enzymes (Of which vitamins are a vital component)

- NB: Because Thyroid Hormones act by Gene Activation, they are said to have a Long ‘Latent Period’, during
which they seem to have no discernible effect.
o Thyroxine: 2-3 Days
o Triiodothyronine: 6-12 Hours

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 Regulation of Metabolism Insulin, the Counter-Regulatory Hormones & Diabetes

NB: Insulin = the only Hypoglycaemic Hormone. (NB: Incretins I H I S

NB: The Counter Regulatory Hormones counter this G L H F

Blood [Glucose] Range:

- Basal: 4mMols/L
- Peak: 7-8mMols/L

Major Endocrine Organs that Regulate Metabolism:

- #1. Pancreas:
o 99% of Cells are A Exocrine Cells - (Secrete digestive enzymes into GIT via Pancreatic Duct)
o Therefore, only 1% are Endocrine I C - (Diffuse, Hormone-secreting). Of these:
25% are Alpha Cells Secrete Glucagon
60% are Beta Cells Secrete Insulin
10% are Delta Cells Secrete Somatostatin
(5% are PP Cells Secrete Pancreatic Polypeptide (Autoregulation of Pancreas))

- Anterior Pituitary:
o Responsible for Growth Hormone Secretion.
- Adrenal Gland:
o Responsible for Cortisol Secretion.

3 Insulin Dependent Tissues (Involved in Nutrient Processing/Storage):

- Liver
- Muscle
- Adipose Tissue

Insulin Independent Tissues:

- Blood Vessels (Endothelium)
- Myocardium of Heart
- Nervous System
- Red Blood Cells
- Kidneys
- Eyes

Hormones of Glycaemia:
- Hypoglycaemic Hormones:
o Insulin (By b-Cells of Pancreas) = the only Hypoglycaemic Hormone.
o NB: Also Incretins = Secreted by the Intestines Act to increase action of Insulin
- Hyperglycaemic Hormones (Counter-Regulatory Hormones):
o Glucagon (By a-Cells of Pancreas)
o Growth Hormone (By Ant.Pituitary)
o Cortisol (By Adrenal Cortex)
o Catecholamines (By Adrenal Medulla)
M I R -Cells of Pancreas:

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 1. B dG c e Insulin-Independent Uptake of Glucose into Pancreas (Via GLUT-2)
2. ATP P d c -Cell.
3. ATP C e he ATP-Gated-K+ Cha e -Cell Membrane De a e he -Cell
4. Depolarisation opens Voltage-Gated Ca+ Channels Influx of Ca+
5. Influx of Ca+ Ca+ Mediated Exocytosis of Insulin Vesicles (Similar to ACh Release in Muscles)

Mechanism of Insulin Action (Glucose Uptake):

- Insulin only affects Insulin Sensitive Tissues (Ie. Those that expresses GLUT-4 Transporters):
o Liver
o Muscle
o Adipose Tissue
- Insulin G U E GLUT-4 Transporters in the PM.
o Fasted State:
Some GLUT-4 Expression; But most will be imbedded in Cytoplasmic Vesicles within the
cell.
o Fed State:
Insulin Insulin Receptors Upregulation of GLUT-4 in PM G c eU a e

T F S Directly After a Meal:

- INSULIN
o Stimulates:
Nutrient Uptake from the Blood:
Glucose (Liver, Muscle & Adipose)
o V a GLUT-4 Receptors (Muscle & Adipose)
Amino Acids (Liver, Muscle & Adipose)
Fatty Acids (Liver & Adipose)
Macromolecular Synthesis (& Storage):
Glycogenesis (Liver & Muscle) (NB: Glucose Triglycerides in Adipose)
Proteingenesis (Liver, Muscle & Adipose)
Lipogenesis (Liver & Adipose)
Glycolysis In all body cells
o Inhibits:
Gluconeogenesis (Liver)
**Ketogenesis (Liver) (Therefore even Low Insulin (DM2) Prevents Ketoacidosis)
A problem for D1M due to NO insulin Diabetic Ketoacidosis
Macromolecular Breakdown:

- NB I E
o Incretins (Released by GIT after a meal) Further Stimulates Insulin Release from Pancreas.
o Hence The Insulin Response to Oral Glucose is much Greater & Quicker than IV Glucose.
o :. New Avenue for Diabetes Management:

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 Incretins:
Intestinal glucose intake Intestines release Incretins (glucagon-like peptide-1
[GLP-1] and Glucose-dependent Insulinotropic Polypeptide [GIP]) Stimulate
Cells to Insulin Release and Suppress -Cells and Glucagon
NB: Incretins are Destroyed by Dipeptidyl Peptidase-4 (DPP-4)
:. By Inhibiting DPP, you can Prolong the Action of Incretins.

T F S - A M
- GLUCAGON
o *Activates Glycogenolysis (Liver) Blood Glucose
o Activates Gluconeogenesis (Liver) Blood Glucose
o Activates Lipolysis (Adipose) Blood FA s NB Glucagon Powerful Lipol tic
o Stimulates Ketogenesis (Liver)
- NB: E F S T is still enough INSULIN to Prevent:
o Massive Lipolysis (As Glucagon is a powerful lipolytic)
o Massive Ketogenesis Normall Insulin Inhibits Ketogenesis Therefore Low Insulin allows
some Ketogenesis but Prevents Ketoacidosis.)
o Massive Proteolysis
o T T II D DON T D K DKA

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 INSULIN & GLUCAGON
The “Fed State” – Directly After a Meal:
- ↑INSULIN:
o Stimulates:
§ Nutrient Uptake from the Blood:
• Glucose (Liver, Muscle & Adipose)
o Via ↑GLUT-4 Receptors (Muscle & Adipose)
o Via ↑Glucose Utilisation (Liver)
• Amino Acids (Liver, Muscle & Adipose)
• Fatty Acids (Liver & Adipose)
o Via ↑Lipoprotein Lipase (LPL) Activity in Adipose Tissue.
§ Macromolecular Synthesis (& Storage):
• Glycogenesis (Liver & Muscle) – (NB: Glucose à Triglycerides in Adipose)
• Proteingenesis (Liver, Muscle & Adipose)
• Lipogenesis (Liver & Adipose)
§ Glycolysis – In all body cells
o Inhibits:
§ Gluconeogenesis (Liver)
§ Ketogenesis (Liver)
§ Macromolecular Breakdown:
• Lipolysis (Liver & Adipose)
• Glycogenolysis (Liver & Muscle)
• Proteolysis (Liver, Muscle & Adipose)

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 NotesByToppers.com exclusive

The “Fasted State” - ≈3hrs After a Meal:

- ↑GLUCAGON
o *Activates Glycogenolysis (Liver) à ↑Blood [Glucose] (NB: Glucagon = Powerful Glycogenolytic)
o Activates Gluconeogenesis (Liver) à ↑Blood [Glucose]
o Stimulates Amino Acid Uptake (Liver) à ↑Gluconeogenesis à ↑Blood Glucose
o Activates Lipolysis (Adipose) à ↑Blood [FA’s] (NB: Glucagon = Powerful Lipolytic)
o Stimulates Ketogenesis (Liver)
- ↓INSULINà “Glucose-Sparing” Effect:
o Increased Availability of Gluconeogenic Substrates:...due to:
§ ↓Inhibition of Gluconeogenesis – (↑Level of Gluconeogenesis)
§ ↓Inhibition of Lipolysis – (↑ Level of Lipolysis)
§ ↓Inhibition of Proteolysis – (↑ Level of Proteolysis)
o ↓Glucose Uptake by:
§ Muscle
§ Liver
§ Adipose.
o Glucose-Sparing à More Glucose for Brain & Nerves (Glucose = 1o Fuel)
- NB: Insulin is Low, but is still high enough to prevent:
o Massive Lipolysis (As Glucagon is a powerful lipolytic)
o Massive Ketogenesis (Normally, ↑Insulin Inhibits Ketogenesis) – Therefore Low Insulin allows
some Ketogenesis but Prevents Ketoacidosis.)
o Massive Proteolysis

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Regulation of INSULIN Secretion:
- Stimulators:
o Parasympathetic NS (Rest & Digest)
o ↑Blood [Amino Acids]
o ↑Blood [Glucose]
o Gastrointestinal Peptide (GIP)
o Glucagon – (Weak Stimulator)
- Inhibitors:
o Sympathetic NS (Acts to ↑Blood [Glucose] for Fight/Flight Response)
o Somatostatin

Regulation of GLUCAGON Secretion:

- Stimulators:
o ? Parasympathetic NS
o ? Amino Acids
o ↓Blood [Glucose]
o Cholecystokinin (CCK)
o Sympathetic NS (Acts to ↑Blood [Glucose] for Fight/Flight Response)
- Inhibitors:
o Insulin (NB: Inhibition of Glucagon Secretion in Hyperglycaemia requires a small amount of Insulin)
- Hence this can be a problem for Type 1 Diabetics (Insulin Deficiency)
o Somatostatin

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 Fluid & Electrolyte Balance

Why Maintain Fluid & Electrolyte Balance?:

- Critical for Normal Cell Function
- Critical for Chemical Stability (Homeostasis) of Surrounding Fluids
- *Electrolyte Balance (Particularly Na+ & K+) Critical for function of Excitable Tissues
- Critical for Blood Pressure Homeostasis

FLUID BALANCE:

Regulation of Water Intake (Thirst) Hypothalamic Triggers:

- 1. Decreased Plasma Volume Reduced Blood Flow to Salivary Glands Cellular Dehydration of
Salivary Gland Cells Dr Mouth Triggers Thirst Centre in Hypothalamus.
- 2. Increased Plasma Osmolarity Directly Causes Cellular Dehydration of Osmoreceptors in the
Hypothalamus Stimulates the Thirst Centre.

Regulation of Water Output:

- Anti-Diuretic Hormone (ADH) Wa e O :
o Acts to increase Blood Volume.
o Released from the Posterior Pituitary Gland
o Released in response to:
Plasma Osmolarit Na+]) Stimulation of Osmoreceptors in Hypothalamus
Plasma Volume.
o Works by INCREASING H2O Permeability of Distal & Collecting Ducts:
Distal Tubules & Collecting Ducts are Normally Impermeable to H2O.
However, the Presence of ADH of Aquaporins In Membrane Permeabilit to
H2O.
This Permeabilit to H2O + High [Solute] in Medulla H2O Reabsorption (From Collecting
Duct Interstitium Blood)

Absence of ADH Presence of ADH (+Aldosterone)

- Atrial Natriuretic Peptide (ANP) Water Output:

o Acts to:
↓blood volume
Blood Na
o Secreted by Atrial Myocytes of the Heart
o Released in response to:
High Blood Pressure (Atrial Stretch)
o Works by:
Dilating Afferent Glomerular Arteriole
Constricting Efferent Glomerular Arteriole
Filtration Pressure Filtration H2O & Na Excretion.

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 - Atrial Natriuretic Peptide (ANP):
o Acts to:
§ ↓blood volume
§ ↓Blood [Na]
§
o Secreted by Atrial Myocytes of the Heart
o Released in response to:
§ High Blood Pressure (Atrial Stretch)
o Works by:
§ Dilating Afferent Glomerular Arteriole
§ Constricting Efferent Glomerular Arteriole
• ↑Filtration Pressure à ↑ Filtration à ↑H2O & Na Excretion.
§ Inhibits Renin Secretion à Inhibits Renin-Angiotensin System
§ Inhibits Aldosterone Secretion from Adrenal Cortex.
§ Inhibits ADH Release from Post. Pituitary

ELECTROLYTE BALANCE:

Significant Electrolytes:
- Na+ = Major Extracellular Cation Account for 80% of Osmolarity of Interstitial Fluid & Plasma.
- Cl- = Major Extracellular Anion
- K+ = Major Intracellular Cation - Accounts for 50% of Osmolarity of Intracellular Fluid

Why Maintain Electrolytes

- Na+ = Important for Heart & Nerve Function/Cellular Transport
- K+ = Important for Heart Function/Cellular Transport
o (NB: too high Extracellular K+ interferes with Cardiac Function = Fatal)
+
- Ca = Important for Muscle, Heart & Nerve Function/Bone Formation
- Mg+ = Important for AcetylCholine Release à Important for Neural & Cardiac Function
- HPO42- = Important for Bone Formation (Bone salts – primarily calcium & phosphates)

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 ELECTROLYTE BALANCE:

Adrenal (AKA: Suprarenal) Anatomy & Physiology:

- Anatomy:
o Endocrine Glands that sit on top of the Kidneys
o Retroperitoneal
o Two Layers:
1. Cortex (3 Zones) (Remember GFR)
1. Zona Glomerulosa (Outer) Mineralocorticoids (Aldosterone)
2. Zona Fasciculata Glucocorticoids (Cortisol)
3. Zona Reticularis (Inner) Adrenal Androgens (DHEA)
2. Medulla (Middle)
Chromaffin Cells Catecholamines (Adrenaline, Noradrenaline)

- Physiology:
o Stress Hormones:
Corticosteroids (Cortisol) Blood Glucose Immunosuppression Bone Formation
Catecholamines (Adrenaline) Blood Glucose HR BP Paras mpathetics
o Electrolyte Balance:
Aldosterone (A Mineralocorticoid) Na+ Retention K+ E cretion BP

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Significant Electrolytes:
- Na+ = Major Extracellular Cation Account for 80% of Osmolarity of Interstitial Fluid & Plasma.
-
- Cl = Major Extracellular Anion
- K+ = Major Intracellular Cation - Accounts for 50% of Osmolarity of Intracellular Fluid

Why Maintain Electrolytes

- Na+ = Important for Heart & Nerve Function/Cellular Transport
- K+ = Important for Heart Function/Cellular Transport
o (NB: too high Extracellular K+ interferes with Cardiac Function = Fatal)
+
- Ca = Important for Muscle, Heart & Nerve Function/Bone Formation
- Mg+ = Important for AcetylCholine Release Important for Neural & Cardiac Function
- HPO42- = Important for Bone Formation (Bone salts primarily calcium & phosphates)

Regulation of Na+ - (The Main Extracellular Electrolyte):

- Extracellular [Na+] is normally stable & is Regulated by levels of Aldosterone:
- Aldosterone Na Re i :
o Aldosterone = Steroid Hormone Released from The Adrenal Cortex.
o Released in response to:
*Angiotensin-II, Part of the Renin-Angiotensin System (Due to Renin Release by Kidneys)
*Hyponatraemia (Low Na+ in Blood)
*Hyperkalaemia (High K+ in Blood)
Stress

o Works by:
ACTIVATING the Na/K-ATPases in the Principal Cells of Distal & Collecting Ducts:
Increases Na+ & Cl- Reabsorption
Increases K+ Secretion
o Effects:
Increases Na+ Reabsorption of the Principal Cells of the Distal & Collecting Ducts of the
Nephron.
If Aldosterone is High All Na in Filtrate is reabsorbed
If Aldosterone is Low No Na in Filtrate is reabsorbed

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K+: The Primary Intracellular Electrolyte:
- Primary Roles in Normal Neuromuscular Function, Membrane Potentials & Membrane Transport.
- Deficient Intracellular K+:
o Cell membrane will be more Negative than normal (Ie. Hyperpolarised)
o Therefore it’ll be harder to initialize an action potential as it takes more to reach threshold.
- Excess Intracellular K+:
o Cell membrane will be more Positive than normal (Ie. Depolarised)
o Therefore it’ll be easier to initialize an action potential as it takes less to reach threshold.
- Affect on the Heart:
o The heart is particularly sensitive to K+ Levels.
o Both Too High & Too Low K+ Levels will Disrupt Electrical Conduction of the Heart à Can be Fatal.
- Regulating K+ Levels:
o Relies solely on K+ Secretion by the “Principal Cells” in the Collecting Ducts of the Kidneys.
o Principal Cells Detect [K+] in the Blood:
§ High Blood [K+] à K+ Secretion is Increased
§ High Blood [K+] à K+ Secretion is Decreased
o Adrenal Glands Detect [K+] in the Blood:
§ High Blood [K+] DIRECTLY Stimulates Aldosterone Release from Adrenal Cortex.
o Aldosterone à Activates Na+/K+-ATPase’s in the Distal Tubules & Collecting Ducts:
§ This Increases Reabsorption of Na+, Cl- & H2O from Distal TubuleàInterstitium
§ But ALSO causes Secretion of K+ into the Filtrate.

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Disorders of Fluid/Electrolyte-Regulating Hormones:
- Disorders of ADH:
o Diabetes Insipidus:
§ Condition characterised by Excessive Thirst & the inability to Concentrate Urine.
§ 2 Types:
• Neurogenic - ADH Insufficiency
• Nephrogenic – Insensitivity of the kidneys to ADH
§ Signs/Symptoms:
• Extreme Thirst
• Excessive Urination
• Risk of Hypokalaemia
§ Diagnosis Criteria:
• Normal Blood Glucose
• Normal Blood Bicarb To Rule out other causes of Excess Urination.
• Normal Blood Calcium
• Urinalysis – Low Osmolarity, Electrolytes & Specific Gravity
• Fluid Deprivation Test - No change in urine osmolarity
• Desmopressin Stimulation – Distinguishes between Neurogenic & Nephrogenic.
§ Treatment:
• Patients compensate by ↑H2O Intake.
• If Neurogenic – Desmopressin (Synthetic ADH) à ↓Urine Production.
• If Nephrogenic – Hydrochlorothiazide Diuretic à ↓Urine Output in patients with DI.

o SIADH (Syndrome of Inappropriate ADH secretion):

§ Condition characterised by Excessive ADH Release from Post. Pituitary Or Ectopic Source.
§ 5 Cardinal Signs/Symptoms:
• Fluid Overload (Without oedema or hypertension)
• Hyponatraemia (Dilutional) à
o Headache
o Nausea
o Vomiting
o Confusion
o Convulsions (If Severe)
o Coma (If Severe)
• Natriuresis (Excretion of Sodium in Urine – usually excessive)
• High Urine Osmolarity relative to Plasma Osmolarity.
• Normal Renal & Adrenal Function
§ Caused by:
• Insensitivity of Hypothalamic Osmoreceptors to ↓Plasma Osmolarity
• Therefore, ADH release isn’t inhibited by ↓Plasma Osmolarity
§ Treatment:
• Fluid Intake Restriction
• Drugs:
o Demeclocycline – Induces Nephrogenic Diabetes Insipidus as a Side Effect.
- Hence desensitises ADH receptors in the Nephron.
o Conivaptan – Inhibits 2 of the 3 ADH Receptors.
o Tolvaptan – Competitive inhibition of ADH Receptors.

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 - Disorders of Aldosterone:
o Aldosteronism:
§ Hypersecretion of Aldosterone
§ Signs/Symptoms:
• Hypertension
• Hypernatraemia
• Hypokalaemia
• Metabolic Alkalosis (Due to ↑H+ secretion by the kidney)
§ Aldosterone ‘Escape’:
• 1. Escape from sodium-retaining effects of ↑↑Aldosterone.
• 2. Inability of ACE-Inhibitor Therapy to suppress Aldosterone release.
§ Diagnosis:
• Very Low Renin-Aldosterone Ratio (Ie. ↓Renin & ↑Aldosterone)

o Addison’s Disease:
§ Hyposecretion of Aldosterone (Amongst other Glucocorticoids produced by the Adrenals)
§ Signs/Symptoms:
• Hyponatraemia
• Hyperkalaemia
• Metabolic Acidosis – due to Na+ Reabsorption being linked to H+ Secretion.
§ Addisonian Crisis:
• A crisis of multiple symptoms indicating severe adrenal insufficiency.
• Result of – Previously undiagnosed Addison’s Disease
- Acute disease affecting adrenal function

GLS Questions:
- Define the Term ‘Third Space’ in relation to body fluid & briefly describe how it can arise:
o When body fluids collect in a ‘third’ body compartment that isn’t normally perfused with fluids,
causing depletion of the fluids in the first & second compartments.
§ Eg. Ascites
§ Eg. Haemorrhage
§ Eg. Pleural Effusion
§ Eg. Joint Swelling
- What is Renin?
o A Protein Enzyme that converts Angiotensinogen to Angiotensin I
- Where is Renin Released:
o From the Juxtaglomerular Cells of the Kidneys
- What stimulates renin release:
o Decrease in renal perfusion
o Sympathetic Stimulation
- What are the major effects of Angiotensin II:
o Peripheral Vasoconstriction
o ↑BP
o ↑Sympathetic Stimulation
o ↑Aldosterone Release à ↑Na reabsorption & ↑K Secretion in Kidneys.

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 Calcium & Phosphate Metabolism

Parathyroid Anatomy & Physiology

- Anatomy:
o Macro:
4x small Endocrine Glands on the Posterior Surface of the Thyroid Gland.
2x on Left; 2x on Right
Size of a grain of rice.
o Micro:
Densely packed cells (As opposed to follicle structure of Thyroid Gland)
2 Cell Types:
Parathyroid Chief Cells:
o Secrete Parathyroid Hormone (PTH)
Oxyphil Cells:
o Unknown function.

- Physiology:
o Function (Via PTH):
Calcium Homeostasis in Blood & Bones
(Important for Excitable Tissues)
(Important for Bone Integrity)
(Also has effects on Phosphate)
o NB: Parathyroid Gland is NOT under Hypothalamic Control!!! Functions Autonomously.

- Parathyroid Hormone (PTH):

o Secreted by The Chief Cells of the Parathyroid Glands
o Release Stimulated By:
Extracellular [Ca+] – Very Sensitive
o Release Inhibited By:
Extracellular [Ca+] – Very Sensitive
o Aims to:
Pla ma-Ca+ levels (By Increasing Bone Ca+/P- Resorption Renal Ca+ Excretion)
Plasma-P levels (By Renal P Excretion so that it exceeds Bone P- Resorption )
- -

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 o Primary Effects:
Stimulates Osteoclasts Mobilises Ca from Bone Matrix Calcium in Blood
Activates Vit.D in Kidneys GI Absorption of Ca+ Calcium in Blood
Renal Calcium Reabsorption Renal Excretion Calcium in Blood
(Increases Renal Excretion of Phosphate Phosphate in Blood)

Functions of Calcium & Phosphate:

- Calcium:
o Structural Purposes:
Development & Maintenance of Skeleton
o Biochemical Purposes:
Mediates exchange between Intracellular & Extracellular Compartements (eg. ACh Release)
Role in Muscle Contraction & Nerve Impulses
Role in Blood Clotting
- Phosphate:
o Structural Purposes:
Development & Maintenance of Skeleton
Phospholipids are a major structural component of Plasma Membrane
o Biochemical Purposes:
Phosphate Release from Nucleotides (eg. ATP ADP) is the Major Source of Cellular
Energy.
The Phosphodiester-Bond Provides the backbone for RNA & DNA.
Phosphorylation provides a basis for Receptor Activation & Signal Transduction.

Bone Chemistry:
- Bone Consists of 2 Things:
o 30% (By Weight) = Organic Bone Matrix:
o 70% (By Weight) = Bone Salts:
The major salt = Hydroxyapatite ( Ca10(PO4)6(OH)2 ) (Mainly Calcium & Phosphate)

Serum Concentrations:
- Calcium:
o Intestinal Absorption/Renal Excretion/Bone Deposition - are Regulated by 3 Hormones:
PTH - Parathyroid Hormone

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Serum Concentrations:
- Calcium:
o Levels depend on 3 Processes:
§ Intestinal Absorption (Ie. To ↑ Serum Ca+)
§ Renal Excretion (Ie. To ↓ Serum Ca+)
§ Resorption/Deposition of Bone (Ie. To ↑ Serum Ca+)
o The Above Processes are Regulated by 3 Hormones:
§ PTH - Parathyroid Hormone
§ Calcitonin
§ Vitamin D (The Active Form)
o Calcium levels are tightly regulated - @ ≈ 9.4mg/dl OR 2.4mmol/L.
o NB: Only ≈1% of the Body’s Ca+ is Extracellular. The Rest is Stored in Bones.
§ Hence, the Bones = Ca+ Reservoir.
o Extracellular Ca+ exists in 3 Forms:
§ 50% Ionized = Ca+ NOT Bound to Anything (Diffusable)
• (NB: This is the functionally important form.)
§ 10% In Covalent Compounds (Diffusable)
§ 40% Bound to Plasma Proteins (Eg. Albumin) (Non-Diffusable)
- Phosphorus:
o Levels depend on:
§ Age
§ Gender
§ Dietary Intake.
§ Calcium-Controlling Hormones.
o NB: Only ≈1% of the Body’s Phosphate is Extracellular. The Rest is Stored in Bones.
o Phosphorus levels are loosely regulated - @ ≈ 2.4 - 4.1 mg/dl.

Regulation of Plasma Ca+ & Phos. Levels:

- Intestinal Absorption:
o Calcium:
§ Normally, Ca+ is poorly absorbed by the Intestines.
§ NB: Vitamin D Increases Ca+ Absorption by the Intestines (POTENT)
§ NB: PTH indirectly promotes Intestinal Ca+ Absorption by ↑Vit.D Activation by the Kidneys.
o Phosphate:
§ Absorption occurs very easily
§ (Ie. Almost all dietary Phosphate is absorbed into the blood, and later excreted in urine)
- Renal Excretion:
o Calcium:
§ Normally, 99% of Filtered Ca+ is Reabsorbed...
• 90% happens in PCT, Loop of Henle & early DCT.
• 10% happens in the late DCT – and is Very Selective (Depending on Blood-Ca+)
§ If Blood-Ca+ is Above Normal – All remaining Ca+ is expelled in urine.
• NB: Calcitonin weakly ↑ Calcium Excretion.
§ If Blood-Ca+ is Below Normal – All remaining Ca+ is reabsorbed
• NB: PTH Greatly ↓ Calcium Excretion in the Kidneys. (Ie. ↑Reabsorption)
o Phosphate:
§ Renal Phosphate excretion is via an ‘Overflow Mechanism’:
§ If Blood-Phosphate is Below 1mmol/L – All filtered Phosphate is Reabsorbed
§ If Blood-Phosphate is Above 1mmol/L – Phosphate is excreted @ a rate relative to its conc.
• NB: PTH Greatly ↑ Phosphate Excretion in the Kidneys.
- Resorption/Deposition of Mineralized Bone:
o PTH promotes Osteoclast Activity (Bone Resorption)
o Vitamin D promotes Bone Calcification (Deposition) (Mechanism Unknown)
o Calcitonin promotes Bone Calcification (Deposition) (By Inhibiting Osteoclast Activity)

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The 3 Major Hormones:
- 1. Parathyroid Hormone (PTH):
o Secreted by – The Chief Cells of the Parathyroid Glands
o Aims to:
§ ↑Plasma-Ca+ levels (By Increasing Bone Ca+/P- Resorption & ↓ Renal Ca+ Excretion)
§ ↓Plasma-P- levels (By ↑Renal P- Excretion so that it exceeds Bone P- Resorption )

o Primary Effects:
§ Mobilises Ca & Phos from bone Matrix (Bone Resorption) (By Stimulating Osteoclast Activity)
§ Stimulates Osteoblast & Osteoclast Proliferation à Promotes bone turnover.
§ Decreases Renal Excretion of Calcium (By Increasing Calcium Reabsorption in DCT)
• NB: PTH is essential here to prevent excess loss of Calcium & therefore prevent
calcium depletion in ECF & Bone.
§ Increases Renal Excretion of Phosphate (By Preventing Phosphate Reabsorption in PCT)
§ Increases Activation of Vit.D in Kidneysà Indirectly increases intestinal absorption of Ca+/P-.
o Stimulated By:
§ ↓Extracellular [Ca+] – Very Sensitive
o Inhibited By:
§ ↑Extracellular [Ca+] – Very Sensitive

o Regulators (According to Dr. Seive)

Stimulated By: Inhibited By:
↓ Calcium ↑ Calcium
↑Phosphate (Indirect) Vit D3
↓Magnesium
Cortisol

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- 2. Vitamin D:
o Aims to:
§ ↑Plasma-Ca+/P- levels (by Increasing intestinal Ca+/P- absorption)
o Primary Effects:
§ ↑ Intestinal Calcium Absorption
§ ↑ Intestinal Phosphate Absorption (Even better than usual)
§ Aids PTH in mobilizing Ca & Phos from bone Matrix.
§ (In Small Quantities, it can ↑ Bone Mineralization (Mechanism Unknown))
o Vit.D Activation:
§ Vit.D itself is not the active form that causes the above effects. It must first be Activated.
§ Vit.D is converted through a series of reactions in the Skin, Liver & the Kidneys to produce
the final active product = 1,25-dihydroxycholecalciferol aka. 1,25(OH)2D3.
§ See Below for Steps:
• NB: The conversion in the Liver has Neg.Feedback for 2 Important Reasons:
o 1. Prevents excessive 25-Hydroxycholecalciferol in the plasma, which in turn
prevents excessive activation by kidneys à maintains Ca+ ion concentration.
o 2. Conserves the Vit.D3 stored in the Liver for future use. (Because the
converted forms only last a few weeks, whereas Vit.D3 lasts for months)
• NB: The conversion in the Kidneys is controlled by PTH:
o Without PTH, none of the 1,25(OH)2D3 is formed.
o Therefore, PTH has a huge influence on the levels of body’s functional Vit.D.
§ Furthermore, since Plasma-Ca+ levels determine PTH levels, Plasma-
Ca+ has an Indirect, but STRONG Negative Feedback Effect as well.
(Even a slight increase in [Ca+] above 10mg/dL, sharply suppresses
PTH secretion à ↓25-Hydroxycholecalciferol – See Diagram)

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 - 3. Calcitonin:
o Secreted By – The Parafollicular Cells of the Thyroid Gland
o Aims to:
§ ↓Plasma-Ca+ levels (By ↓Osteoclast Activity so that Bone Deposition is Favoured)
• This effect is much greater in children due to rapid remodelling.
o Primary Effects:
§ Decreases the Activity & Proliferation of Osteoclasts à Favours Bone-Salt Deposition.
o Stimulated By:
§ ↑Extracellular [Ca+] (NB: Opposite of PTH) (See Below Diagrams)

Summary:

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 Week 6
Endocrinology Notes
Physiological Response to Stress (Nervous & Endocrine)

Stress & The Hypothalamo-Pituitary Axis:

- 1. Stressors (Internal or External) trigger Receptors.
- 2. Receptors inform the Hypothalamus
- 3. Hypothalamus - Activates Sympathetic Pathways
- Secretes Corticotropin-Releasing Hormone à Ant. Pituitary releases ACTH.
- 4. Both Sympathetic Activation & ACTH Release à Stimulate the Adrenal Glands.
- 5. Adrenal Glands - Secrete Catecholamines (Incl. Adrenaline)
- Secrete Cortical Steroids (Incl. Cortisol)

Adrenaline Cortisol

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The Body’s Responses to Stress:
- Dr. Hans Selye proposed the “General Adaptation Syndrome” as the Body’s Responses to Stress
- He also noticed 3 Universal Symptoms of Chronic Stress:
o Adrenal Cortex Enlargement
o Atrophy of Lymphoid Tissues
o Bleeding Ulcers in Stomach & GI Tract.
- General Adaptation Syndrome:
o Overview:
§ Stress à Causes Physiological Changes à Causes Symptoms
§ There are 3 stages. NB: If the stress is overcome during one of the stages, the ‘GAS’ will
terminate in that stage.
o 3 Stages of the General Adaptation Syndrome:
§ Stage 1: ALARM REACTION:
• When we are surprised or threatened à Immediate Physical Reaction.
• Fight or Flight Response
• Prepares the body for life-threatening situations, channelling resources away from
things like the Digestive & Immune Systems, to more immediate muscular needs.
• ↑Sympathetic Nervous System
• ↑Catecholamines from Adrenal Medulla
§ Stage 2: STAGE OF RESISTANCE:
• If stressors continue, the body enters the Resistance Phase, where we feel like we’ve
adapted to the stressors, but the body is working at abnormally high levels to keep
up with the ↑ demands.
• ↑ Cortisol Secretion
• Sustained Catecholamine Actions
§ Stage 3: STAGE OF EXHAUSTION:
• Eventually, the body gives up on maintaining a high level of stress. Parts of the body
literally start to break down à Sickness à Possible Death.
• ↓ Adaptive Endocrine & Neuroendocrine Functions

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More About Stage 1 of The ‘GAS’: ALARM REACTION:
- Physical/Visual Responses to Stress: (Fight/Flight Response)
o ↑Pupil Diameter
o ↑Sweat Glands
o ↓Other Glands (Nasal, Salivary, Gastric, Pancreatic)
o ↑Bronchial Dilation
o ↑Blood Flow to Heart & Skeletal Muscle
o ↓Blood Flow to Kidneys & Skin (Cold & Clammy skin)
- ‘Lay’ Descriptions of the Above:
o Bug Eyed
o Dry Mouth
o Pounding Heart
o Cold/Clammy Skin
o Sweaty skin
o Rapid Respiration
- Physiological Responses Caused by ↑Sympathetic Activity:
o ↑HR & SV à ↑CO
o Vasoconstriction (Skin, Kidneys, Most Viscera) ↑BP, ↑Perfusion Rate, Redistribution of Blood.
o Vasodilation in Skeletal Muscles

o ↓Digestive Gland Secretion ↓Digestion

o ↓Peristalsis

o ↑Adrenal Secretion à ↑Epinephrine Levels à Increased & Prolonged Sympathetic Activity.

o ↑Glycogenolysis (Liver) à ↑Blood-Glucose. ↑Energy Precursor

o ↑Lipolysis (Adipose) à ↑Free Fatty-Acids. Levels in Blood

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Overview of the Body’s Response to Stress:

Metabolic Actions of Adrenaline/Epinephrine (Fight/Flight Response Hormone):

o ↑Glycogenolysis (Liver) à ↑Blood-Glucose. ↑Energy Precursor
o ↑Lipolysis (Adipose) à ↑Free Fatty-Acids. Levels in Blood
o ↑Glycogenolysis (Muscle)
§ à Fuels Muscle Cells
§ à Provides Lactate à Liver converts back to Glucose (Gluconeogenesis) à ↑Blood-Glucose

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Stress & The Immune System:
- Studies have shown that Acute Stress ENHANCES the Immune System, but Chronic Stress SUPPRESSES the
Immune System.
- The Affect of Stress on the Immune System is ‘BIPHASIC’:
o 1. During Acute Stress – There is a shift towards ↑Innate Immune Responses.
§ (↑Granulocyte/Macrophage/NK-Cell Activity + ↑Complement & Acute-Phase Proteins)
o 2. If Stress Continues – There is a shift from Cellular Immunity to Humoral Immunity.
§ ↓Type-1 Helper T-Cell Activity (à Become Macrophages)
§ ↑Type-2 Helper T-Cell Activity (à Become Plasma Cells à Secrete Antibodies)
o 3. If Chronic Stress – There is a Decrease in almost all functional Immune Responses
Hence: Increase in Stressor Duration à Shifts from Adaptive to Detrimental.

Questions:
- Q. Given that Cortisol is released in response to stress & has a potent Hyperglycaemic action, Why is
Adrenaline Release Needed to Increase Blood-Glucose in Acute Stress?
o A. Cortisol is a steroid hormone, meaning it takes a long time to synthesize, can’t be stored (because
it diffuses through membranes) and takes a while to elicit its effects. Hence, Adrenaline, which can
be easily stored in vesicles and is more rapidly acting, is useful in Acute Stress where a more
immediate response is required.

- Q. Adrenalin has an Endocrine Action in the Pancreas. What is its affect on Insulin & Glucagon Release &
Why might this be important?
o A. Adrenaline à ↓Insulin & ↑Glucagon Release à ↑Blood-Glucose (Desired)

- Q. What are the Causes of the 3 Universal Symptoms of Chronic Stress Discovered by Hans Selye:
o Adrenal Cortex Enlargement:
§ Hypertrophy & Hyperplasia of the Gland due to the Prolonged Tropic Hormone Stimulation
(ACTH).
o Atrophy of Lymphoid Tissues:
§ Due to the Immunosuppressive Actions of ↑Cortisol (Caused by Chronic Stress)
o Bleeding Ulcers in Stomach & GI Tract.
§ Most ulcers have a microbial origin. Therefore some may be due to the ↓Immune System.
§ However, not all ulcers have a microbial origin. Ie. Some are purely due to stress.
• How? – Due to ↓Secretion of Gastric Mucous Glands à Imbalance between Mucous
& Acid in Stomach à Stomach Ulcers.
• And/Or – Due to ↓Secretion of Pancreatic Neutralisers à ↑Acid load in GIT +
↓Peristalsis à Intestinal Ulcers.

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 NotesByToppers.com exclusive

Reproductive Endocrinology:

Hormonal Regulation of the Ovarian Cycle:

1) Day 1 – Hypothalamus increases levels of GnRH (Gonadotropin-Releasing Hormone) and stimulates the
Anterior Pituitary to produce FSH (Follicle-Stimulating Hormone)& LH (Luteinising Hormone).
2) FSH & LH stimulate follicle growth, maturation & oestrogen secretion.
- FSH targets follicle cells
- LH targets the thecal cells – makes thecal cells produce androgen.
o Androgen diffuses through basement membrane, where the granulosa cells convert it to
oestrogens.
3) Medium oestrogen levels exert negative feedback to the Ant. Pituitary, inhibiting FSH & LH release.
- Inhibin released by granulosa cells also exerts negative feedback on FSH release.
4) At a critically high oestrogen level, positive feedback is exerted on the brain & Ant. Pituitary.
5) Midcycle This positive feedback causes the Ant. Pituitary to release a sudden burst of LH (and also some
FSH – role midcycle is currently unknown).
6) LH surge stimulates the primary oocyte of the dominant follicle to complete MEIOSIS I, forming a
secondary oocyte + first polar body.
- LH surge also triggers ovulation.
- After ovulation, oestrogen levels decline due to the damaged dominant oestrogen secretor.
7) LH Surge also transforms ruptured follicle into corpus luteum – stimulates it to produce progesterone
& oestrogen.
8) Corpus luteum secretes inhibin along with progesterone & oestrogen, exerting a strong negative feedback
signal to the Ant. Pituitary – Stops the release of LH & FSH.
- End of cycle – LH levels fall corpus luteum degenerates no oestrogen or progesterone production
by Corpus Luteum no negative feedback to the hypothalamus hypothalamus increases FSH & LH
levels Back to square #1.

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Neuroendocrine Control: Hormonal Regulation of Spermatogenesis:
1) Hypothalamus releases GnRH (gonadotropin-releasing hormone) which-
2) stimulates the release of gonadotropins: FSH (Follicle stimulating hormone) & LH (Luteinizing hormone).
3) FSH: stimulates sustentacular cells to release Androgen-binding protein (ABP) Makes spermatagonium,
spermatocytes, and spermatozoa receptive to the androgen: Testosterone.
4) LH: stimulates the interstitial (Leydig) cells [Basally external to Seminiferous tubules] to produce
testosterone which triggers & maintains spermatogenesis.
5) Testosterone produced by Leydig (interstitial) cells inhibits GnRH production; as does Inhibin, produced by
the sustentacular (sertoli) cells.

- When testosterone is at its peak sperm count is high (20Mil+) inhibin levels rise GnRH decreases FSH &
LH levels decrease Testosterone & ABP levels decrease spermatogenesis slows.

-When sperm count is low (20Mil -) inhibin & testosterone levels are low no negative feedback to
hypothalamus hyp. Releases GnRH Ant. Pituitary releases LH & FSH FSH stimulates sustentacular (sertoli)
cells to produce ABP; LH stimulates the interstitial (Leydig) cells to produce testosterone Testosterone + ABP
stimulates spermatogenic cells Spermatogenesis increases.

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 Male Reproductive Endocrinology
Functional Micro-Anatomy of the Testes:
- Leydig Cells (In Interstitium of the Testes):
o #1 Function = Produce Testosterone (Stimulates Spermatogonia to enter Spermatogenesis)
o Stimulated by LH (Luteinising Hormone)
- Seminiferous Tubules (In Lobules of Testes):
o Spermatogonia (Germ/Stem-Cells):
§ In Basal Lamina of Seminiferous Tubules
§ #1 Function = Are the precursors for Spermatogenesis
§ Stimulated by Testosterone.
o Sertoli/Sustentacular Cells:
§ Make up the Walls of the Seminiferous Tubules
§ Main Functions =
• Endocrine – Production of Androgen Binding Protein (ABP)
o – (Makes Spermatogenic Cells receptive to Testosterone)
• Endocrine – Production of Inhibin
o – (Provides negative feedback to the Hypothalamus)
• Blood-Testes Barrier (because spermatids are genetically unique & require
protection from autoimmunity)
• Nourish Sperm
• Phagocytosis – (mop up any dead/underdeveloped spermatids)
• Produce Tubular Fluid – (Help transport the sperm)
• Produce Plasminogen Activating Factor – (Help free the sperm from tubule
wall)

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The Important Androgens:
- #1 – Testosterone - Affects Mainly the Testes
o 40% - Bound to SHBG (Sex-Hormone Binding Globulin)
o 60% - Bound to Albumin
o 2% - Free (Active) – (Receptors are intracellular :. Must be able to enter the cell)
- Dehydroepiandrosterone (Sulphate) – DHEA(S) - Affects Mainly the Periphery
- Androstenedione - Affects Mainly the Periphery

- NB: Sex Hormone Binding Globulin is an Important Transporter:

o Secreted by the Liver
o Increased by ↑Oestrogen
o Decreased by ↑Androgen
o Constant in Males
o Cyclical in Females – (but During Pregnancy, ↑↑Oestrogen à ↑SHBG)

- Measuring Androgen Levels – “The Free Androgen Index”:

o Gives a measure of the “free” active fraction of Androgens.

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The Other Hormones:
- Gonadotropin-Releasing Hormone (GnRH):
o Peptide Hormone
o Pulsatile Release (≈90mins)
- Gonadotropins - FSH & LH:
o Are Glycoproteins
o Released by the Anterior Pituitary in response to Pulsatile release (90mins) of GnRH.
o Share a common α-Subunit
o Differ by unique β-Subunits
o Act on G-Protein-Linked Receptors.
- Inhibin:
o Produced by the Sustentacular/Sertoli Cells (Male) & Granulosa Cells (Female).
o Released in response to high FSH.
o Inhibits FSH release via Hypothalamic Inhibition.

Actions of Androgens:
- Primary Sex Characteristics:
o Growth & Maturation of Reproductive Tract @ Puberty
o Maintenance of Reproductive Tract in Adulthood
o Libido
o Enhance Spermatogenesis
- Secondary Sex Characteristics:
o Body Hair
o Deep Voice
o Thick, rough skin
o Bone Growth
o Androgen Binding Protein Synthesis (in Sertoli/Sustentacular Cells)
o ↑Musculature

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Male Hypogonadism:
- What is it?
o A deficiency in Testosterone due to problems with either:
§ 1) Testes, or - Primary
§ 2) Hypothalamus/Pituitary - Secondary

- Hypergonadotropic:
o Primary Hypogonadism
o Ie. Problem with the Leydig Cells in the Testes à ↓↓Testosterone Production à
↑↑Hypothalamo-Pituitary release of Gonadotropins (FSH/LH).
o Causes:
§ Trauma/Irradiation of Testes.
§ Mumps
§ Klinefelter’s Syndrome (Extra X-Chromosome)
§ Androgen Resistance
§ Autoimmune
§ Congenital

- Hypogonadoptropic:
o Secondary Hypogonadism
o Ie. Problem with the Hypothalamo-Pituitary Axis à ↓↓Gonadotropin Release (FSH/LH) à
↓↓Testosterone Production
o Causes:
§ Developmental
§ Pituitary Tumour/Trauma/Autoimmune
§ Genetic Syndromes

- Effects of ↓↓Testosterone:
o Infertility (Low Sperm Count)
o ↓Libido
o ↓Muscle Mass
o ↓Beard/Body Hair
o Erectile Dysfunction
o ↑Breast Tissue
o ↓Bone Mass
o ↑Body Fat
- Range of Treatments – Testosterone Replacement Therapy:
o Buccal
o Oral
o Trans-Cutaneous (patch/gel)
o IM Injection
o Implant

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Male Infertility:
- Normal Semen:
o 2-5mLs
o Sperm Concentration – At least 20 Million/mL
o Total sperm count – At least 40 Million (To be “fertile”)
o >75% should be Alive
o >30% should be of normal Shape/Form.
o >25% should be rapidly Swimming Forward
o >50% should be Motile
- Causes of Infertility:
o Problem with Sperm Production:
§ Chromosomal/genetic causes
§ Undescended Testes (Heat)
§ Infections
§ Torsion
§ Radiation
o Blockage of Sperm Transport (Basis of Vasectomy)
o Sperm Antibodies (Autoimmune reaction due to poor blood-testes barrier.)
o Sexual Problems
o Hormonal Imbalances (Hypogonadism – Primary/Secondary)

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 ENDOCRINOLOGY Pathology:
ADH DISORDERS

Disorders of Fluid/Electrolyte-Regulating Hormones:

- Disorders of ADH:
o Diabetes Insipidus (↓ADH):
Condition characterised by Excessive Thirst & the inability to Concentrate Urine.
2 Types:
Neurogenic (Neuro) - ADH Insufficiency
Nephrogenic (Renal) Insensitivity of the kidneys to ADH
Signs/Symptoms:
Extreme Thirst
Excessive Urination
Risk of Hypokalaemia
Diagnosis Criteria:
Normal Blood Glucose
Normal Blood Bicarb To Rule out other causes of Excess Urination.
Normal Blood Calcium
Urinalysis Low Osmolarity, Electrolytes & Specific Gravity
Fluid Deprivation Test - No change in urine osmolarity
Desmopressin Stimulation Distinguishes between Neurogenic & Nephrogenic.
Treatment:
Patients compensate by H2O Intake.
If Neurogenic Desmopressin (Synthetic ADH) Urine Production.
If Nephrogenic Hydrochlorothiazide Diuretic Urine Output in patients with
DI.

o SIADH (Syndrome of Inappropriate ADH secretion) (↑ADH):

Caused by:
Insensitivity of Hypothalamic Osmoreceptors to Plasma Osmolarity
Therefore, ADH release isn’t inhibited by Plasma Osmolarity
Condition characterised by Excessive ADH Release from Post. Pituitary Or Ectopic Source.
5 Cardinal Signs/Symptoms:
1. Fluid Overload (Without oedema or hypertension)
2. Hyponatraemia (Dilutional)
o Headache
o Nausea
o Vomiting
o Confusion
o Convulsions (If Severe)
o Coma (If Severe)
3. Natriuresis (Excretion of Sodium in Urine usually excessive)
4. High Urine Osmolarity relative to Plasma Osmolarity.
5. Normal Renal & Adrenal Function
Treatment:
Fluid Intake Restriction
Drugs – (ADH Inhibitors):

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 ENDOCRINOLOGY Pathology:
ADRENAL CORTEX DYSFUNCTION

Adrenal Disorders:

Adrenocortical Insufficiency (Hyporadrenal) Syndromes:

- ADDISON S DISEASE (Primary Chronic Adrenocortical Insufficiency):
o Aetiologies (Multiple Possible):
Most Common = Autoimmune Adrenalitis (70%)
o Pathogenesis (Autoimmune Adrenalitis):
Aldosterone
Cortisol
o Clinical Features:
Initially: Progressive Weakness, Fatigue, Lethargy, Depression
Later:
GI - Anorexia, Weight Loss, Vomiting, Diarrhoea
Skin – Hyperpigmentation (Esp. Sun-Exposed & Pressure Point Areas)
Electrolytes (↓Aldosterone) – Hyponatraemia & Hyperkalaemia
o Diagnosis:
Synacthen (Synthetic ACTH) Test (Measure Cortisol and Aldosterone 30mins after)
Adrenal-Autoantibodies
UECs K Na Urea Creatinine
o Treatment:
Cortisol Replacement (Hydrocortisone)
Correct Electrolytes
o Complication - Addisonian Crisis:
Why: Stress Adrenal Glands Cannot Respond Crisis
Clinical Features:
Fever
Intractable Vomiting
Abdominal Pain
Hypotension
Coma
Shock (Vascular Collapse)

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- WATERHOUSE-FRIDERICHSEN SYNDROME (Acute Adrenocortical Insufficiency):
o Aetiology:
Overwhelming Sepsis
o Pathogenesis:
Acute Haemorrhageic Infarction Adrenal Necrosis Acute Adrenal Hypofunction:
↓Aldosterone Salt & Water Loss Hypovolaemic Shock
o Morphology:
Macro:
Haemorrhagic Mass (Blood Clot) Completely Obscures the Adrenal Gland
Micro:
Acute Haemorrhagic Necrosis (Starts in Medulla Spreads to Cortex)
Islands of Recognizable Cortical Cells
o Clinical Features:
Abrupt & Severe Clinical Course (Death in Hours-Days unless Treated)
Typically Meningococcal Septicaemia
:. Neck stiffness
:. DIC
Hypovolaemic Shock (Due to ↓Aldosterone)
o Treatment:
Prompt Antibiotic Treatment
Fluids

- CONGENITAL ADRENAL HYPERPLASIA (CAH) - (Adrenogenital Syndromes/Virility Syndromes):

o Aetiology:
Autosomal Recessive 21-Hydroxylase Deficiency
o Pathogenesis:
↓Cortisol/Aldosterone Synthesis Androgen Synthesis
o Clinical Features:
Androgen Excess:
Masculinisation of Females (Clitoral Hypertrophy/Hirsutism/Oligomenorrhoea)
Masculinisation of Males (Penile Enlargement/Precocious Puberty/Oligospermia)
Neonate with Ambiguous Genitalia
Mineralocorticoid (Aldosterone) Deficiency:
Hypotension & Salt Wasting.

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Adrenocortical Hyperfunction (Hyperadrenal) Syndromes:
- CONN S SYNDROME (& other Primary Hyper-Aldosteronisms):
o NB: Aldosterone = Mineralocorticoid = Produced by the Zona Glomerulosa of the Adrenal Cortex.
o Aetiologies:
#1. Idiopathic Hyperplasia of Adrenal Glands
#2. Aldosterone-Producing Adenoma (Conn s S ndrome
#3.(Rare) Aldosterone-Producing Carcinoma
o Pathogenesis:
Chronic Excess ↑↑ Aldosterone Secretion Na+ Retention (& ↓K+) Fluid Retention
Hypertension
o Clinical Features:
**Universal Sign = Hypertension
Hypernatraemia (due to Renal Na Retention)
Hypokalaemia (due to Renal K Wasting):
o Diagnosis:
Very HIGH Aldosterone
o Treatment:
Idiopathic Hyperplasia: Spirinolactone (Aldosterone Antagonist)
Adenomas Conn s Surgical Resection

- CUSHING S DISEASE/SYNDROME (Hypercortisolism):

o Aetiology:
Cushing s S ndrome (Any cause of Excess Glucocorticoid Levels)
Cushing s Disease (Central – ACTH-Secreting Pituitary Adenoma)
o Pathogenesis Cushing s Disease ONLY
ACTH-Secreting Pituitary Adenoma ACTH Levels Cortisol
o Clinical Features:
Slow onset
Early Features (Hypertension & Weight Gain)

o Diagnosis:
Dexamethasone Suppression Test (Central Vs. Primary)
ACTH Levels
Cortisol Levels
CT/MRI Brain (Pituitary Adenoma)
o Treatment Depends on Aetiology:
If Exogenous Cortisol – Wean Pt. off Cortisol.
If Pituitary Tumour Cushing s Disease Surgical Removal + Temp Cortisol Replacement.
If Adrenal Tumour – Surgical Removal + Temporary Cortisol Replacement.

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 ENDOCRINOLOGY Pathology:
ADRENAL MEDULLA DYSFUNCTION

Phaeochromocytoma:
- Ad e ali e N ad e ali e
- Metabolites of Adrenaline & noradrenaline = Normetadrenalines
- Hypertensive crises
- Worsening pre-existing hypertension
- Episodic white flashes, palpitations
- Young
- diaphoretic

Adrenomedullary Hyperfunction:
- Phaeochromocytoma (Medullary Adenoma):
o Aetiology:
Idiopathic
May be familial (in MEN2 Syndrome)
o Pathogenesis:
Tumour of the Medullary Chromaffin Cells (Which produce Catecholamines)
Increased Catecholamines
Secondary Hypertension
o Clinical Features:
Young Age
10% Are Malignant
Symptoms:
#1. Paroxysmal Hypertension
Palpitations/Tachycardia
Headache
Sweating/Hot Flushes
Tremor
Anxiety
Nausea/Vomiting
(NB: Phaeos are a cause of Surgically-Correctable Hypertension)
(NB: Phaeos May be associated with MEN2 Syndromes)
o Diagnosis:
Increased Urinary Catecholamines & VMA (Vanillylmandelic Acid A Metabolite of
Adrenaline & NA)
o Treatment:
Preoperative Sympatholytic Drugs (To prevent hypertensive crisis)
Surgical Resection
o Complications:
- of Hypertension:
Congestive Heart Failure
Pulmonary Oedema
Myocardial Infarction
Ventricular Fibrillations
CVAs

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 ENDOCRINOLOGY Pathology:
CALCIUM & PHOSPHATE BALANCE DISORDERS

Disorders of Calcium & Phosphate Regulation:

- Hypercalcaemia:
o Caused By:
Hyperparathyroidism
Malignancy (Eg. BRCA, Multiple Myeloma)
Vit D Excess
Secondary Renal Hyperparathyroidism
- Hypocalcaemia:
o Caused by:
Vit.D Deficiency/Disorders of Vit.D Metabolism (Activation) Ac i e Vi D Rickets
Eg. Lack of sunlight
Eg. Lack of Dietary Vit.D
Eg. Chronic Kidney Failure
Hypoparathyroidism (Because PTH is required for Vit.D Activation in the Kidneys)
Aquired/Congenital
- Rickets:
o What is it?:
A Vit.D Deficiency Resulting in a Calcium/Phosphate Deficiency.
NB Clinical Sign occ af e a fe mon h Once he Bone Ca P Re e oi a e De le ed
o Effects:
Ma ked PTH Sec e ion Extreme Osteoclastic Activity:
Pla ma Calci m
Pla ma Pho ha e D e o Renal E c e ion
Tetany Once he Bone Ca+ Reservoir is Depleted, Plasma Ca+ falls to dangerous levels.
o Treatment:
Dietary Calcium Supplements
Exogenous Vit.D Administration.
- Hypoparathyroidism:
o What is it?:
When he Pa a h oid Gland don ec e e fficien PTH
o Effects:
Re o ion of e changeable Calci m Hypocalcaemia
When Ca+ falls too low, Tetany can develop. (Can occur in larynx obstructs respiration)
- Hyperparathyroidism:
o What is it?:
When the Parathyroid Glands secrete an inappropriate excess of PTH.
o Effects:
E eme O eocla ic ac i i in bone
Hypercalcaemia
H o ho ha aemia D e o Renal E c e ion
- Osteoporosis:
o What is it?:
Decreased Bone Matrix (Not decreased bone calcification)
o Possible Causes:
Usually due to poor Osteoblastic Activity O eoid De o i ion
Can be d e o Osteoclastic Activity O eoid Re o ion
Inactivity Lack of physical stress on bones
Malnutrition
Po meno a al Lack of Oe ogen Oe ogen no mall O eocla Ac i i
C hing S nd ome - Gl coco icoid ca e P o ein de o i ion h o gho he
body.

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 Parathyroid Disorders:

Hyperparathyroidism:
- What is it?:
o When the Parathyroid Glands secrete PTH
- Effec f PTH
o E eme O eocla ic ac i i in bone Hypercalcaemia
o Renal Pho ha e E c e ion Hypophosphataemia
- Types:
o Primary Hyperparathyroidism Autonomous, Spontaneous Overproduction of PTH:
Aetiologies/Pathogeneses:
Adenoma(Sporadic or MEN)/Hyperplasia/Carcinoma PTH
Clinical Features:
F>>M
Hypercalcaemia Triad Bones Moans Abdominal Groans :
o 1. Bone: Pain/Osteoporosis/Fractures
o 2. Moans: Depression/Lethargy/Seizures
o 3. Abdo: Constipation/Nausea/Ulcers/Gallstones
o + (Renal: Renal Stones)
o + (Heart: Aortic/Mitral Calcification)
Diagnosis:
PTH
Se m Calci m
Se m Pho ha e
Treatment:
Surgical Excision
o Secondary Hyperparathyroidism Secondary to Chronic Renal Insufficiency:
Aetiology:
Secondary to Renal Failure HypOcalcaemia
(Others incl. Dietary Calcium Deficiency, Vit.D Deficiency)
Pathogenesis:
Renal Failure Hypocalcaemia PTH o Compensate Hyperplasia
Clinical Features:
Symptoms of Chronic Renal Failure
Osteoporosis
Treatment:
Vitamin D + Calcium Supplementation
Partial Parathyroidectomy

Hypoparathyroidism:
- Effects:
o Re o ion of e changeable Calci m Hypocalcaemia
- Aetiologies:
o Iatrogenic Surgery (Eg. Thyroidectomy/Lymphadenectomy/Over-resection in 1oHyperPT)
o Genetic (Autoimmune/Familial/Congenital Absence of Gland)
- Clinical Features:
o *Hypocalcaemia
o *Hallmark = Tetany:
Neuromuscular Irritability
Distal Paraesthesias
Carpopedal Spasm
*Laryngospasm (Life-Threatening)
Seizures
o CNS: Confusion/Depression/Hallucinations/Psychosis
o Eyes: Cataracts (Calcification of Lenses)
o CVS: Characteristic Prolonged QT-Interval

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 ENDOCRINOLOGY Pathology:
DIABETES

Diabetes: General Information:

- Diagnostic Criteria (The “ - Rule”):
o Fa ing BSL mm l L (NB: For Non-Pregnant)
o Random BSL of >11 (NB: If Fasting BSL = 5.5-7.0 mmol/L Perform OGTT)
o OGTT – Oral Glucose Tolerance Test (Fasting) >11 @ 2hrs
o Autoantibodies (If Type 1 Diabetes):
+ Anti-Islet-Cell Antibodies (Anti-ICAs)
+ Anti-Glutamic Acid Decarboxylase Antibodies (Anti-GADs)
o (NB: HbA1c for monitoring only)
- Initial Presentation:
o PPP – Polyuria, Polydipsia, Polyphagia
o Unexplained Weight Loss/Fatigue/Lethargy
o Recurrent/Persistent Infections, Delayed Healing & Immunosuppression (Eg. Genital Thrush)
- Emergency Presentations:
o HYPERs:
DKA - Diabetic Ketoacidosis
HONC - Hyperosmolar Non-Ketotic Coma
o HYPOs:
Eg. Insulin Overdose/Overexercise/Missed Meal
- Treatment:
o Lifestyle (Diet + Exercise + Weight Loss)
o Medications:
Insulins – (Broad range of Rapid to Long-Acting)
Oral Hypoglycaemic Agents:
“Insulin Secretagogues” – (*Sulfonylureas):
Biguanides - (*Metformin)
Incretin Mimetics:
Incretin Analogues – (*Exenatide):
DPP-4 Inhibitors – (*Sitagliptin)

Different Types of Diabetes:

- Type 1 Diabetes – Insulin Deficiency, Juvenile, Rapid Onset:
o Aetiology – (Autoimmune Destruction of the β-Cells of the Pancreatic Islets)
o Clinical Features – (Juvenile Disease, Rapid Onset)
o Diagnosis – (+ Anti-GADs, Anti-Islet-Cell Antibodies (Anti-ICAs) & Insulin Auto Antibodies (IAAs))
o Treatment: - (Exogenous Insulin)
o Complications – (Diabetic Ketoacidosis)
- LADA – Latent Autoimmune Diabetes of Adults:
o Aetiology – (Delayed Autoimmune Type I in Adults)
o Clinical Features – (Slim Adults with Diabetes Symptoms)
o Complications – (HONC, DKA)
o Diagnosis – (Hyperglycaemia, + Anti-GADs, Anti-ICAs & Insulin Auto Antibodies)
o Treatment – (Insulin)
- Type 2 Diabetes – Insulin Resistance, Adults, Insidious Onset:
o Aetiology – (Insulin Resistance And/Or Relative Insulin Deficiency)
o Clinical Features – (Adults, Slow Onset +/- P e-Diabe ic S a e )
o Diagnosis – (Random BSL >11, OGTT >11 @2hrs)
o Treatment – (1. Diet & Lifestyle, 2. Orals [Metformin/Sulfonylureas/Incretins], 3. Insulin)
- MODY – Maturity Onset Diabetes of Youth:
o Aetiology – (Autosomal Dominant)
o Pathogenesis – (Essentially a Type II DM in a Child)
o Clinical Features – (Young, Non-Obese, Autosomal Dominant :. FamHx)
o Treatment – (1. Orals [Metformin/Sulfonylureas/Incretins], 2. Insulin)
o Complications – (Like Type II Diabetes (Ie. HONC rather than DKA))

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 Week 7
Endocrinology Notes
Diabetes

What is Diabetes:
- Diagnostic Criteria:
o Fasting BSL ≥ 7.0 mmol/L
o 2hr Post Prandial BSL ≥11.1 mmol/L
o NB: People who have Impaired Glucose Tolerance and/or Impaired Fasting Glucose have slightly
raised fasting & Post Prandial BSL’s, but not high enough for diagnosis of diabetes.
- Symptoms:
o Thirst
o Polyuria & Nocturia
o Weight Loss
o Fatigue
o Blurring of Vision
o Infections
o Nausea, Vomiting, Abdo. Pain.

Insulin & Glucagon in a Nutshell: (For more detail – see previous endo weeks)
- Insulin:
o Released Due to:
§ ↑Blood Glucose
§ ↑Blood Amino Acids
o Stimulates:
§ Glucose Uptake (Fat & Muscle)
§ Lipid Synthesis & Storage (Fat)
§ Protein Deposition (Muscle)
o Inhibits:
§ Ketogenesis
§ Macromolecular Breakdown
- Glucagon:
o Released Due to:
§ ↓Blood Glucose
§ ↓Blood Amino Acids (Ie. Fasting)
o Stimulates:
§ Glycogenolysis
§ Gluconeogenesis
§ Lipolysis
§ Ketogenesis
o Inhibits:
§ Macromolecular Synthesis/Storage.

Without Insulin:
- ↑Gluconeogenesis in Liver
- ↑Glycogenolysis in Liver
- ↑Plasma Glucose à ↑Urine Glucose
- Osmotic Diuresis (Due to ↑Filtrate-[Glucose]) à Dehydration à Circulatory Collapse
- Polydypsia (↑Thirst) due to dehydration.
- ↑Lpolysis
- ↑Ketogenesis à Acidosis à
o à Myocardial Dysfunction
o à Cerebral Dysfunction
o à Venoconstriction
o à Arterial Dilation
- Fatal if Untreated.

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Mechanism of Insulin Release from β-Cells of Pancreas:
1. ↑Blood Glucose à ↑ Uptake of Glucose into Pancreas (Via GLUT-2)
2. GLUT-2 + Glucokinase + ATP à ↑Glucose-6-Phosphate
3. G-6-P is metabolised via Glycolysis à ↑ATP Production in β-Cell.
4. ↑ATP Closes the ATP-Gated-K+ Channels in β-Cell Membrane à Depolarises the β-Cell
5. Depolarisation à opens Voltage-Gated Ca+ Channels à Influx of Ca+
6. Influx of Ca+ à Ca+ Mediated Exocytosis of Insulin Vesicles (Similar to ACh Release in Muscles)

- NB: “Incretin Effect”:

o Incretins (Released by GIT after a meal) Further Stimulates Insulin Release from Pancreas.
o Hence à The Insulin Response to Oral Glucose is much Greater & Quicker than IV Glucose.

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Mechanism of Insulin Action (Glucose Uptake):
- Insulin only affects glucose uptake in tissue that expresses GLUT-4 Transporters (Ie. Are Insulin Sensitive):
o Muscle
o Adipose Tissue
- Insulin increases Glucose Uptake in the above tissues by ↑ Expression of GLUT-4 Transporters in the PM.
- Fasted State:
o There will be some GLUT-4 Transporters expressed in the Plasma Membrane.
o However, most will be found in the membranes of Cytoplasmic Vesicles within the cell.
- Fed State:
o Binding of Insulin to Receptors à Initiates a Signalling Cascade à Movement of GLUT-4 Laden
Vesicles to the Cell Surface.
o Upon reaching the Plasma Membrane, the vesicles fuse with it à ↑Plasma Membrane-[GLUT-4].
o ↑Plasma Membrane-[GLUT-4] à ↑Glucose Uptake
o NB: Signalling Cascade also Causesà
§ Glucose Metabolism
§ Protein Synthesis
§ Glycogen Synthesis
§ Inhibition of Gluconeogenesis
§ Lipid Synthesis.
§ Cell Growth & Gene Expression

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Different Types of Diabetes:
- Type 1 – Insulin Deficient:
o Autoimmune attack on the β-Cells of the Pancreatic Islets.
o Results in a Physical Lack of Insulin Production
o Aetiology can be Genetic & Environmental
o Rapid Onset à Therefore Fewer Complications @ Diagnosis.
o Presentation:
§ Hyperglycaemia
§ Ketonuria (Ketoacidosis) à
• Hyperventilation
• Nausea
• Vomiting
• Abdo Pain
§ Rapid Significant Weight Loss
§ Excessive Hunger (Polyphagia)
§ Mental Fatigue
o Treated with Exogenous Insulin

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- Type 2 – Insulin Resistance:
o Results from Insulin Resistance sometimes combined with Relative Insulin Deficiency.
o NB: Obesity is the #1 Predisposer of Insulin Resistance:
§ Due to Change in Adipose-Release of ‘Adipokines’ – Hormones that Mediate Insulin
Resistance.
• Incl: Resistin/Leptin/Adipopectin.
o Peak onset @ ≈50yrs
o Gradual Onset à Therefore ≈1/4 have Complications @ Diagnosis (Eg. Vascular)
§ NB: Many people spend years in a ‘Pre-Diabetic State’ – where BSL is higher than normal but
not high enough for a diagnosis of Type 2 Diabetes
o Presentation:
§ Same as Type 1, Except:
• No Ketonuria
• Usually Overweight (Central Obesity)
§ Metabolic Syndrome (Due to Insulin Resistance):
• ↑Circulating FFA’s
• ↑Insulin
• ↑Glucose
• ↓HDL’s
• ↑BP
o Treated with Diet / Tablets / Exogenous Insulin
§ NB: Over time Insulin Resistance Increases & β-Cell Function Decreases à
• Therefore the later stages require ↑Amount of Treatment.

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 NotesByToppers.com exclusive

Secondary Diabetes:
- Ie. Diabetes caused by some other disease...For Example:
o Endocrine Disorders:
§ Cushings (↑Cortisol)
§ Acromegaly (↑GH)
o Pancreatic Disorders:
§ Pancreatitis
§ Surgery
§ Cystic Fibrosis
§ Tumour
o Genetic Disorders:
§ Down’s Syndrome
§ Prada Willi
o Drugs That Antagonise Insulin’s Action:
§ Some Steroids
§ Some Diuretics
§ β-Blockers

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 Complications of Diabetes:

Acute Complications – (METABOLIC):

- Diabetic Keto-Acidosis (DKA):
o Acute life threatening
o Caused By – (Type I Diabetes - Lack of Insulin (Eg. Forgotten to take insulin))
o Diagnosis:
Hyperglycaemia: High Glucose (>15 mmol/L)
Ketoacidosis: Low pH, Low Bicarbonate (< 15 mmol/L), Sweet Breath, Ketonuria
o Symptoms:
– of Underlying Diabetes – (Polyuria, Polydipsia, Weight loss)
– of Hyperglycaemia – (Glycosuria/Osmotic dieresis, Severe Dehydration)
– of Hyperketonaemia KetoAcidosis – (Vomiting, Acetone Breath, Hyperventilation)
- of Electrolyte Disturbances Na K – (Cardiac Arrhythmia / Bradycardia)
o Treatment:
1. IV access Correct Dehydration
2. Insulin Infusion Correct Hyperglycaemia
3. Monitor/Correct Electrolytes – Particularly Potassium
o Complications:
40% mortality – medical emergency
Severe Dehydration
- HONC – Hyperosmolar Non-ketonic Coma:
o Caused By – (Type II Diabetes - Relatively Low Insulin/Insulin Insensitivity + Precipitant)
o Diagnosis:
Hyperglycaemia
NO KetoAcidosis
o Symptoms:
Confusion/Coma
Marked Dehydration
Polyuria (Osmotic Diuresis)
Neurology – (Sensory/Motor Impairment, Focal Seizures, Hyporeflexia, Tremors)
o Treatment:
IV Fluids
Insulin + Potassium (Since Insulin causes K+ Shift Into Cells)
Electrolyte Replacement (Esp. Potassium)
o Complications:
Fatal if Untreated
- Hypoglycaemia (BSL < 6.0mmol/L):
o Aetiology – (**Diabetes + Insulin Overdose / Alcohol / Sepsis)
o Diagnosis – (BSL < 3.5 mmol/L)
o Symptoms:
Autonomic – (Sweating, Anxiety, Hunger, Tremor, Palpitations, Dizziness)
CNS – (Confusion, Drowsiness, Visual Disturbances, Seizures, Coma)
o Treatment:
#1 – Oral/IV Glucose (Jellybeans/Juice/Biscuits/etc.)
OR – IM/IV Glucagon

Chronic Complications:
- Macrovascular (Atherosclerosis) IHD / CVA / PVD
- Microvascular (arteriolosclerosis) Retinopathy, Nephropathy, Neuropathy
- Immunosuppression
- Poor Wound Healing

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Chronic Complications:
- Caused by chronic exposure to Hyperglycaemia & Dyslipidaemia in the Insulin Insensitive Tissues.
- Vascular:
o Macrovascular:
§ Heart Disease/Coronary Artery Disease/Atherosclerosis
§ Stroke
§ Peripheral Vascular Disease
o Microvascular:
§ Retinopathy
§ Neuropathy
§ Nephropathy

- The ‘Somogyi’ Effect:

o Where Circadian Elevations in Counter-Regulatory hormones (GH & Cortisol) cause Hyperglycaemia
early in the morning à Patient Increases Insulin Dose @ Bedtime à Sustained Hypo all night à
Body releases Glucagon, Adrenaline & Cortisol à Hyper @ Dawn.

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Possible Causes of Chronic Complications:
- The ‘Polyol Pathway’:
o Hyperglycaemia à ↑Glucose Accumulation in Insulin Independent Tissues.
o Much Glucose à Converted to Sorbitol à Slowly converted to Fructose.
o However, Sorbitol is Osmotically Very Active à Sorbitol Accumulation à
§ Osmotic Cell Injury
§ Affects Ion Pumps
§ Affects Some Cellular Secondary Messenger Pathways

- Hyperglycosylation of Proteins:
o ↑Glucose à ‘Glycosylation’ of proteins (Ie. Linkage of Glucose to Free Amino Groups in Proteins)
§ Eg. HbA1C (Glycosylated Haemoglobin)
o Affects proteins in Blood Vessel Walls & Basement Membranes à Can stimulate Inflammation.
§ Includes Collagen, Fibronectin, etc.
o Leads to formation of ‘Advanced Glycosylated End-Products’ (AGE’s):
§ Can form cross-linkages between peptides à Forms a “Mesh” à Traps Other Molecules:
• Eg. LDL Trapping à Cholesterol Deposition à Atherosclerosis
• Eg. Immunoglobulins & Complement à Inflammation
§ Can form binding-sites for other proteins (eg. Albumin)
§ Inactivate Nitric Oxide à Reduce Vasodilation
§ Stimulate Growth-Factor & Cytokine Secretion
§ ↑Vascular Permeability
§ ↑Clotting Activity à Stroke/Embolus/etc.
§ ↑Extra-Cellular Matrix Deposition.

- Reactive Oxygen Species:

o ↑Hyperglycaemia à ↑O2 Free-Radical Production.
o Compounded by ↑Immune Cell Activation

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 Diabetes Qs

Lecture Keypad Questions:

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 Endocrine Emergencies:
Focus on Diabetic Emergencies

Diabetic Emergencies:
Diabetic Ketoacidosis:
o Acute life threatening
o Pathology Combination of:
Insulin Deficiency
Cell unable to absorb & metaoblis glucose
Excess Counter-Regulatory Hormones (Eg. Glucagon/Adrenaline)
Glycogen Breakdown
Lipolysis Ketogenesis
Protein Catabolism
Resultant Hyperglycaemia
Osmotic dieresis Dehydration
o Presentation:
of Underlying Diabetes:
Polyuria
Polydipsia
Weight loss
of Hyperglycaemia:
Glycosuria/Osmotic dieresis
Salt & Water Depletion
of Hyperketonaemia Metabolic Acidosis:
Acetone Breath
Hyperventilation (Respiratory Compensation)
Peripheral Vasodilation Hypotension
K+ Depletion

o Treatment:
Supportive (ABCs)
Rehydration
Replace ½ fluid deficit in 1st 12 hrs
Insulin infusion
Close monitoring of Electrolytes

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- Hyperosmolar Non-Ketotic Coma:
o Pathophysiology:
Relative Insulin Deficiency
Enough to Prevent Lipolysis;
NO Ketosis
But Not enough to Prevent Hyperglycaemia
Hyperglycaemia
o Presentation:
Confusion/Coma
Marked Dehydration
o Treatment:
Supportive ABCs
Rehydration
Insulin Infusion

- Hypoglycaemia:
o D E e F ge G c e
Because severe or prolonged hypoglycaemia can cause Brain damage/death.
o Causes:
**Diabetic:
Insulin Overdose (Accidental/Suicide Attempt)
Missed Meal
Exercise
Alcohol
Alcohol Excess
Sepsis
o Symptoms:
CNS Glucose Deficiency
Confunsion/Coma/Seiure
Drowsiness
Incoordination
Autonomic
Anxiety
Sweating
Tremors
Palpitation
Non Specifics
Nausea
Headache
Fatigue
o Diagnosis:
Hypoglycaemia
Clinical Symptoms
Response to Glucose Administration
o Treatment:
Supportive:
ABCs
Suspect the Diagnosis:
D e e f e c e
Correct serum Glucose:
Glucose Oral/IV
Glucagon f IV G c e t possible)
Disposition
Oral Hypoglycaemics (Admit to all patients)

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Other Endocrine Emergencies:
- Alcoholic Ketoacidosis:
o Cause:
Alcoholic with recent decreased food intake
o Presentation:
Abdo pain, nausea & vomiting
Metabolic Acidosis & Possible Ketoneuria
o Treatment:
Supportive ABCs
Rehydration

- Thyroid:
o Hyperthyroidism:
Cause:
High free T4 & low TSH
o Eg. Graves Disease: goitre, exopthalmos, pretibial myxoedema
Presentation:
Nervousness, irritability, mental disturbance, tachycardia,
palpitations, heat intolerance, weight loss, goiter
Treatment:
Supportive ABCs
Block Effects of T4 (Thyroid Blocking Drugs)
o Hypothyroidism:
Cause:
Low free T4 & high TSH
Presentation:
Fatigue, weakness, constipation, cold intolerance & depression
Goitre, menstrual irregularities
Treatment:
Supportive ABCs
T4 Replacement (Thyroxine)

- Adrenocortical Insufficiency:
o Causes:
Primary:
Adrenal Failure
Secondary:
Pituitary Failure
Adrenopituitary Suppression by Steroids
o Presentation:
Hypotension, abdominal pain, confusion, weakness, & pigmentation
Hyponatraemia
Hyperkalaemia
o Treatment:
Corticosteroid Replacement (Hydrocortisone)

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 ENDOCRINOLOGY Pathology:
GONADAL DYSFUNCTION

Male Hypogonadism:
- What is it?
o A deficiency in Testosterone due to problems with either:
1) Testes, or - Primary
2) Hypothalamus/Pituitary - Secondary
- Primary Hypogonadism (Hypergonadotrophic)
o Ie. Problem with the Leydig Cells in the Testes Testosterone Production
Hypothalamo-Pituitary release of Gonadotropins (FSH/LH).
o Causes:
Trauma/Irradiation of Testes.
Mumps
Klinefelter’s Syndrome XXY)
Androgen Resistance
Autoimmune
Congenital
- Secondary Hypogonadism (Hypogonadotrophic)
o Ie. Problem with the Hypothalamo-Pituitary Axis Gonadotropin Release FSH/LH
Testosterone Production
o Causes:
Developmental
Pituitary Tumour/Trauma/Pituitary Irradiation/Autoimmune
Genetic Syndromes

- Effec of Te o e one
o Infertility (Low Sperm Count)
o Libido
o Muscle Mass
o Beard/Body Hair
o Erectile Dysfunction
o Breast Tissue
o Bone Mass
o Body Fat
- Range of Treatments Testosterone Replacement Therapy:
o Buccal
o Oral
o Trans-Cutaneous (patch/gel)
o IM Injection
o Implant

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 ENDOCRINOLOGY Pathology:
GROWTH DYSFUNCTION

Defects in Endocrine Control of Growth:

- Hyper:
o Too Much Growth Hormone &/or Growth Factors (Rare):
Eg. Childhood Gigantism
Eg. Adults - Acromegaly
o Non-GH Causes:
Eg. Precocious Puberty
- Hypo:
o Defective Growth Hormone Axis:
GH-Deficiency:
Primary GH Deficiency:
o Hypothalamic Defect
o And/Or Pituitary Defect
Secondary Pituitary Deficiency:
o Eg. Tumour & other Destructive Diseases.
o Eg. Psychosocial Deprivation (Ie. Kids in abusive/non-supportive
environments GH-Deficiency exhibit slowed growth)

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 ENDOCRINOLOGY Pathology:
MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

Familial Endocrine Neoplasias – MEN Syndromes:

- Multiple Endocrine Neoplasia = Genetic Disorders where 2/More Tumours are found in Endocrine Glands
(Parathyroid, Pituitary, Thyroid, & Adrenal Medulla).
- MEN Disorders G ea he i k f de e i g i e cancerous and noncancerous tumors in glands
such as the parathyroid, pituitary, and pancreas.

Multiple Endocrine Neoplasm Classifications

Type Aetiology Organs Involved Clinical Features
MEN1: Autosomal 1. Pituitary 60 of Wermer’s Pts have >2x of the Following:
Wermer’s Domimant Genetic 2. Parathyroid -Pituitary Adenoma Eg. Prolactinomas/GH
Syndrome Mutation in MEN1 3. Pancreas - Can also Bilateral Hemianopia
Tumour Suppressor (Top 2/3 of Body) -Parathyroid Adenomas Hyperparathyroidism
Gene on -Pancreatic Gastrinoma Peptic Ulcer Disease
Chromosome 11 -Pancreatic Insulinoma Hypoglycaemia
-Pancreatic VIPomas VIP Secretory Diarrhoea
MEN2a: Autosomal 1. Thyroid 100% of Pts Medullary Thyroid Cancer
Sipple’s Domimant Genetic 2. Parathyroid 50% of Pts Phaeochromocytoma Ad e a i e
Syndrome Mutation in MEN2 3. Adrenal 30% of Pts Parathyroid Hyperplasia PTH
Tumour Suppressor Medulla
Gene on (Lower 2/3 of Body)
Chromosome 10
MEN2b: Autosomal 1. Thyroid 100% of Pts Medullary Thyroid Cancer
Domimant Genetic 2. Adrenal 50% of Pts Phaeochromocytoma Ad e a i e
Mutation in MEN2 Medulla (Other: Mucosal Neuromas, Marfanoid Features)
Tumour Suppressor (Lower 2/3 of Body)
Gene on
Chromosome 10

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 ENDOCRINOLOGY Pathology:
PITUITARY DYSFUNCTION
Hyperpituitarism:
- Anterior Pituitary:
o C hing Di ea e Alread Co ered
o Primary Central Hyperthyroidism (Already Covered)
o Gigantism/Acromegaly:
Aetiology:
Pituitary Adenoma
Pathogenesis:
Pituitary Adenoma Secretes Excess GH
Morphology:
Clinical Features:
Insidious Onset
Mostly Middle-Aged Adults
Symptoms:
o Severe Disfigurement
o Soft-Tissue Swelling (Hands, Feet, Nose, Lips, Ears, Skin, Carpal Tunnel)
o Prominent Jaw & Supra-Orbital Ridges
o Hypertension
o Compressive Pituitary Adenoma Headache + Visual Field Defect
Diagnosis:
IGF1 & GH Levels
Brain MRI
Treatment:
Surgical Removal of Pituitary Adenoma
Somatostatin Analogues
Complications:
Hypertrophic Cardiomyopathy & Heart Failure
Hypertension & Kidney Failure
Hyperglycaemia & Diabetes Mellitis
Accelerated Osteoarthosis
Possible Malignancy

- Posterior Pituitary:
o SIADH (Syndrome of Inappropriate ADH Secretion):
Hypopituitarism:
- Anterior Pituitary:
o Sheehan Di ea e AKA Postpartum Hypopituitarism (Pituitary Infarction):
- Posterior Pituitary:
o Diabetes Insipidus:

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 ENDOCRINOLOGY Pathology:
THYROID DYSFUNCTION

Abnormalities of Thyroid Function:

- Classic Common symptoms;
o Weight change
o Sleep change
o Mood change
o Bowel function change
o Skin change
o Menstrual bleeding change
o Infertility

Hypothyroidism (Most Common):

- Under-Secretion of Th roid Hormone
- Causes:
o **Autoimmune Hashimoto s Disease
Anti-Thyroid Peroxidase Antibodies (Anti-TPO-Abs) T T Production
- or Anti-Thyroglobulin Antibodies Destroy T3/T4.
Classically Women >60yrs
o **Dietary: - Insufficient Iodine intake (Worldwide greatest cause)
o Hypothalamic-Pituitary Disorder
- Effects of Hypothyroidism:
o Me abolic Ra e
o Bod Teme a e & Cold Intolerance
o S m a he ic Sen i i i
o If Extreme Cretinism Severely stunted physical growth & mental development.

Hyperthyroidism:
- E cessi e Secretion of Th roid Hormone
- Causes:
o **Auto-Immune: Gra e s Disease where TsAb s Th roid-Stimulating Antibodies) mimic TSH
T T P od c ion
o **Toxic Multinodular Goitre
o *Post-URTI Subacute De-Q er ain s Thyroiditis ( Transient Eu-Thyroid)
- Effects of Hyperthyroidism:
o Me abolic Ra e
o Bod Tem e a e Hea In ole ance Ie can and ho en i onmen
o S m a he ic Sen i i i
o If Gra e s Disease Exophthalmos (Eye Protrusion) & Goitre (Thyroid Enlargement)

Goitre:
- Enlarged Th roid Gland
- Occurs in the Following Conditions:
o Normal Physiological Conditions (Adolescence, Pregnancy, Lactation):
ie Condi ion e i ing Me aboli m
o Hyperthyroidism:
Why? Increased stimulation (eg. From T Ab Hypertrophy
o Hypothyroidism:
Why? Increased stimulation (eg. From Pituitary due to Iodine deficiency) Hypertrophy
o Dietary:
Eg. Iodine Deficiency
o Tumours:
Those secreting Thyroid Hormones regardless of TSH Levels.

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Where is the Problem?
- Primar -Thyroidism (Glandular Level)
o Eg. Primary Hyperthyroidism = Graves Disease
o Eg. Primar H poth roidism Hashimoto s Disease
- Secondar -Thyroidism:
o Problem with the Pituitary Gland or H pothalamus Ie TRH TSH

Diagnosing Thyroid Problems:

- TFTs Interpretation:

- Thyroid Autoantibody Assays:

o Gra e s Presence of TsAb s Th roid-Stimulating Antibodies)
o Hashimoto s Presence of Anti-Thyroid Peroxidase Antibodies (Anti-TPO-Abs)
o or Anti-Thyroglobulin Antibodies
- TRH Stimulation Test (Dynamic Testing)
o Investigates Pituitary-TSH Deficiency
- Imaging:
o Ultrasound for sizing.
o RadioIsotope Methods (Nuclear Medicine) (Radioactive Iodide) to measure activity of the gland.
Can distinguish Inactive (Cold) & Overactive (Hot) Nodules.

- Histopathology:
o Ie. Biopsy.

Treatment of Thyroid Problems:

- Hypothyroidism:
o Thyroid Hormone Replacement:
*Thyroxine/levothyroxine (T4)
- Hyperthyroidism:
o Surgery (Thyroidectomy):
Total Vs Partial
o Radioactive Iodine - Destroy Thyroid Follicular Tissue:
Radioactive Iodine (I125)
NB: Can kill too much thyroid tissue Hypothyroidism.
o Anti-Thyroid Agents:
*Carbimazole

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Hyperthyroidism Clinical Features:
- General:
o Fatigue
o Heat Intolerance
- CVS:
o Tachycardia
o Palpitations
AF (Suspect Thyrotoxicosis if New-Onset AF in elderly)
o Cardiomegaly
o Congestive Heart Failure (In Elderly)
- GI:
o Weight Loss Despite INCREASED Appetite
o Thirst
o H e mo ili F e enc of Bo el Mo emen Dia hoea
- Neuro:
o Overactive Sympathetic NS
Fine Tremor
Irritability
Anxiety
Insomnia
o Proximal Myopathy (Muscle Weakness) & Wasting.
- Eye:
o Exophthalmos (Wide, Staring Gaze)
o Lid Lag
o (NB: Proptosis only in Graves)
- Dermatology:
o Acropachy (Digital Clubbing & Swelling; Fingers & Toes)
o Hair: Fine, Allopecia
o Skin: Soft, Warm, Flushed, Sweaty.
o Vitiligo (Pigmentation)
o Sof Nail i h On chol i Pl mme Nail
- MSK:
o Bone Re o ion Osteoporosis
- Haem:
o Lymphadenopathy (esp. Graves Disease)
- Others:
o Menorrhagia
o Pretibial Myxoedema

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Complications:
- Thyrotoxic Storm:
o Aetiology:
Precipitated by Infection/Trauma/Surgery/etc. In a Hyperthyroid Patient.
o Pathogenesis:
Pre-existing Hyperthyroidism S m a he ic Sen i i i
+ Precipitant Ca echolamine Le el Sympathetic Symptoms.
o SEVERE Clinical Features 50% MORTALITY:
Extreme Fever
Tachycardia/Arrhythmias
Vascular Collapse (Hypotension)
Congestive Heart Failure/Pulmonary Oedema
Vomiting/Diarrhoea
Confusion/Delerium/Coma
o Differentials:
Sepsis
Phaeochromocytoma
Malignant Hyperthermia
o Lab Findings:
T T
TSH
(Leukocytosis, Hypercalcaemia, LFT
o Treatment:
Fluid & Electrolyte Maintenance
Vasopressors Regain Blood Pressure
Cooling Blanket/Paracetamol Control Fever
Dexamethasone Con e ion of T o T
& Treat Precipitating Factor

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Clinical Features:
- General:
o Fatigue
o Cold Intolerance
o Apathetic Face
o Droopy Eyes
o Hoarseness
o Menstrual Irregularities
o Muscle Weakness
- CVS:
o Bradycardia
o Pericardial Effusion
o Ca diac O
- GI:
o Weight Gain Despite Poor Appetite
o Constipation
- Neuro:
o Paresthesia
o Slow Speech
o Mental Sluggishness
- Dermatology:
o Skin:
Pale Cool D D e o Blood Flo
NON-Pitting Oedema (Due to Accumulation of Hyaluronic Acid & Glycosaminoglycans)
Face & Periorbital Oedema
o Hair: Dry, Coarse, Loss of Lateral 1/3 Eyebrow
- MSK:
o Muscle Cramps
o H ng Refle e Delayed Relaxation in deep tendon reflexes.
- Haem:
o Macrocytic Anaemia

Dx:
- TSH Levels
- T4/T3 Levels
- Hashimotos:
o + Anti-Thyroid Peroxidase Antibodies (Anti-TPO-Abs)
o + Anti-Thyroglobulin Antibodies

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Complications:
- Cretinism :
o Terminology:
H o h oidi m ha de elo in Infanc o Ea l Childhood Severely stunted physical
g o h men al de elo men
o Aetiology:
Maternal Hypothyroidism (Typically Iodine Deficiency)
o Clinical Features:
Short Stature
Severe Mental Retardation
Coarse Facial Features
Protruding Tongue
Umbilical Hernia
(NB: Severity of Disease depends on When Maternal Hypothyroidism occurred during
Pregnancy)
- Generalised Atherosclerosis:
o D e o Chole e ol LDL T igl ce ide
- *Myxoedema Coma!:
o Most Severe Complication
o Aetiology:
Longstanding Undiagnosed Hypothyroidism + Precipitant (Infection/Surgery/MI/CHF)
o Clinical Features:
Hypothermia
Hypoventilation
Bradycardia
Hypertension
Hypoglycaemia
Stupor
o Lab Findings:
T T
TSH
Hypoglycaemia
Check ACTH & Cortisol for ?Concomitant Adrenal Insufficiency?.
o Treatment:
Emergency management (ABCs)
Keep Pt Warm
Loading Dose Thyroxine
Treat Precipitant

Treatment:
- Thyroid Hormone Replacement:
o L-Thyroxine (Thyroid Hormone Replacement)
o NB: Thyroxine is the preferred agent as it is the least biologically active (Longer Half-life), and can
be Deiodinated by the body to T3 (Thyronine) when needed.

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 Non-Toxic Goitres (Diffuse & Multinodular Goitres):

Terminology:
- Goitre = Enla gemen of he Th oid
- Non-Toxic Goitre Enla gemen of he Th oid Gland in a EUTHYROID Individual that is NOT DUE TO
Inflamma o o Neo la ic Change

Epidemiology:
- Adolescents
- Pregnancy
- Lactation
- 3rd World Countries

(Simple) Diffuse Goitre (Early):

- Aetiologies:
o Normal Physiological Conditions (Adolescence, Pregnancy, Lactation):
o Iodine Deficiency Most Common:
- Pathogenesis:
o NB: Hyperplasia; NOT Neoplastic D e o TSH S im la ion
- Morphology:
o Goitre is Mild, Diffuse & Symmetrical
- Clinical Features:
o Most Pts are Euthyroid
- Ix:
o TSH
o Normal T3/T4 (Unless Severe - T T
- Complications:
o Mechanical (Dysphagia, Airway Obstruction)
o Endocrine (Toxic Nodule Hyperthyroidism)

(A = Normal; B = Diffuse Goitre)

Non-Toxic Multinodular Goitre (Late):
- Aetiology:
o Prolonged Hyperplasia of a Diffuse Goitre due to Iodine Deficiency
- Pathogenesis:
o 1. Simple Diffuse Goitre due to Iodine Deficiency
o 2. Prolonged Hyperplasia of a Diffuse Goitre Multinodular Goitre.
- Morphology:
o Asymmetrical, Multinodular, Multilobulated, Goitres
o Can be MASSIVE
o Nodules are Un-Encapsulated, & Contain Variable amounts of Colloid (Brown, Gelatinous)
- Clinical Features:
o Massive Goitre
o Most Pts are Euthyroid
- Complications:
o Toxic Adenoma/Toxic Nodule.

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 Thyroid Neoplasms (Adenomas & Carcinomas):

Terminology:
- Hot Nodules - Those secreting Thyroid Hormones regardless of TSH Levels.
- Cold Nodules Those that are Hypofunctioning regardless of TSH Levels

Clinical Features:
- Mostly Asymptomatic
- Palpable (sometimes visible) lump in throat
- Red Flags:
o Rapid Growth
o Firm/Hard
o Immobile
o Voice Hoarseness
o Dyspnoea
o Dysphagia
o Lymphadenopathy
- Green Flags:
o Mobile, Painful & Inflammation Non Neoplastic.

Universal Investigations of Thyroid Neoplasms (Despite Patterns):

- 1. Imaging
- 2. TFTs
- 3. FNA + Biopsy
- 4. Surgical Resection & Histology.

Th roid Adenoma Follicular Adenoma Benign Neoplasms 90%:

- Cold or Hot Adenomas
- Morphology:
o Solitary, Spherical Mass
o Well-Defined, Intact Fibrous Capsule
o cm Diame e
o Colour:
Cold Adenoma = Grey-Whi e colo D e o Colloid
Hot (Toxic) Adenoma = Red-B o n colo D e o Colloid Con en
o Areas of Haemorrhage, Fibrosis & Calcification (Similar to MNG)
- Clinical Features:
o Unilateral Painless Mass
o Cold Adenomas = Euthyroid
o Hot (Toxic) Adenomas = Hyperthyroid
- Investigations:
o As above
- Complications:
o Excellent Prognosis (post surgery) No Recurrence or Metastasis.

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Thyroid Carcinomas (Malignant Neoplasms) 10%:
- 4x Types (NB: ALL begin as Follicular Cells Except Medullary Carcinomas, which are Parafolicular Cells):
- Papillary Carcinoma of the Thyroid MOST COMMON:
o Clinical Features:
Asymptomatic, Mobile Thyroid Nodule (Indistinguishable from Benign Nodule)
NB: Presenting Symptom is often Cervical Lymphadenopathy.
Symptoms of Severe Disease: Dysphagia, Hoarseness, Cough.
o Investigations:
As above
o Treatment:
Surgical Excision
o Prognosis:
Malignant, but Clinically Benign Ie. High survival rate (98% @ 10yrs).
Rarely extends outside the thyroid capsule or to other structures.

- Follicular Carcinoma of the Thyroid:

o Morphology:
Single Nodules
May be Well-Demarcated (Similar to Follicular Adenoma) or Infiltrative
Grey-Tan Colour
Central Fibrosis & Calcification
o Clinical Features:
Slow-Growing, Painless Nodules
Follicular Carcinoma prefers Haematogenous Metastasis rather than Lymphatic
:. No Lymphadenopathy
Aggressive - Spreads Early to Bone (May present as a pathological fracture)
o Treatment:
Total Thyroidectomy
+ Radioactive Iodine Ablation for ?Metastases.
+ Supportive Thyroid Hormone Replacement

- Anaplastic Carcinoma of the Thyroid:

o Pathogenesis:
Typically arise due to De-Differentiation of a Papillary or Follicular Carcinoma
o Morphology:
Invasion out of the Thyroid Capsule & Into Adjacent Structures (Eg. Trachea & Jugular Vein)
o Clinical Features:
Typically Elderly
Rapid-Growing Nodule.
Compressive Symptoms: Dysphagia, Dyspnoea, Hoarseness, Cough.
o Treatment/Prognosis:
Highly Aggressive Local Invasion & Metastasis @ Presentation.
No Treatments
100% Mortality @ 1yr.

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- Medullary Carcinoma of the Thyroid:
o Aetiology:
70% Sporadic Proto-oncogene Mutation.
30% Occur in Multiple Endocrine Neoplasia Syndrome Type 2 (MEN-2a & 2b)
o Morphology:
Solitary if Sporadic; Multiple/Bilateral if MEN-2a/b.
Firm, Pale Grey-Tan, Areas of Haemorrhage & Necrosis
Invasion outside the Thyroid Capsule
o Clinical Features:
Sporadic:
Thyroid Nodule + Dysphagia or Hoarseness
NB NO H ocalcaemia de i e Calci onin
MEN-2 Also Involves:
(Thyroid Gland Medullary Carcinoma of the Thyroid )
Adrenal Medulla Phaeochromocytoma
Parathyroid Gland Parathyroid Hyperplasia

Summary:

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