Endocrine Notes - All in One File

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.
www.MedStudentNotes.com
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]
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.
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.
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.
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
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.
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.)
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.
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’)

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.

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.
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:
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)
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
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:
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
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

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)

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.

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

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))
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:
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:
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
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)

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

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
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
High Blood Pressure (Atrial Stretch)
o Works by:
Dilating Afferent Glomerular Arteriole
Constricting Efferent Glomerular Arteriole
Filtration Pressure Filtration H2O & Na Excretion.
- Atrial Natriuretic Peptide (ANP):
o Acts to:
§ ↓blood volume
§ ↓Blood [Na]
§
o Secreted by Atrial Myocytes of the Heart
§ 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)
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
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.
*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
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.

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.

- 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.

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 )
- -
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
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)

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

- 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)

- 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:
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

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

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

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

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.

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.
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.
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)

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.
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

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

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)

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):
PITUITARY GLAND . . . CONT.
Pathology
❏ secondary hypersecretion in gonadal failure
❏ decreased gonadotropins (see Gynecology Chapter)
• hypogonadism
• amenorrhea
• impotence
• loss of body hair
• fine skin
• testicular atrophy
• failure of pubertal development
• treated with Pergonal and hCG, or LHRH analogue if fertility desired;
otherwise treat with estrogen/testosterone
ANTIDIURETIC HORMONE (ADH)
❏ octapeptide synthesized in supraoptic nuclei of hypothalamus and
secreted down pituitary stalk to posterior lobe of pituitary
❏ also known as “vasopressin”
Physiology
❏ major action is via cAMP in renal collecting ducts; alters permeability of membrane to water
❏ allows reabsorption of water thereby increasing urine concentration
Regulation
❏ major secretory stimulus is serum osmotic pressure detected by osmoreceptors in hypothalamus
❏ hypovolemia, stress, fever, pain may also stimulate ADH
❏ contracted plasma volume is a more potent stimulator of water retention than osmolality change
(mediated through renin-angiotensin system)
Pathology
1. Diabetes Insipidus (DI) (see Nephrology Chapter)
❏ definition: passage of large volumes of dilute urine
❏ central vs. nephrogenic
• central DI: insufficient ADH due to dysfunction of hypothalamic nuclei
(e.g. tumours, hydrocephalus, histiocytosis, trauma)
• nephrogenic DI: collecting tubules in kidneys resistant to ADH
(e.g. drugs including lithium, hypercalcemia, hypokalemia)
• psychogenic polydipsia must be ruled out
❏ diagnosis
• fluid deprivation will differentiate true DI (high urine output persists,
urine osmolality < plasma osmolality) from psychogenic DI
• response to exogenous ADH will distinguish central from nephrogenic DI
❏ treatment
• DDAVP (vasopressin) for total DI
• DDAVP or chlorpropamide, clofibrate, carbamazepine for partial DI
• nephrogenic DI treated with solute restriction and thiazides
2. Syndrome of Inappropriate ADH secretion (SIADH)
❏ ADH excess associated with hyponatremia without edema; must rule out
other causes of excess ADH e.g. hypovolemic (adrenocortical insufficiency),
edematous (hypothyroidism), and hypertensive (renovascular stenosis) states
❏ causes
• malignancy (lung, pancreas, lymphoma)
• CNS disease (inflammatory, hemorrhage, tumour, Guillain-Barré syndrome)
• chest disease (TB, pneumonia, empyema)
• drugs (vincristine, chlorpropamide, cyclophosphamide, carbamazepine, nicotine, morphine)
• stress (post-surgical)
❏ diagnosis
• euvolemic hyponatremia with inappropriately concentrated urine
• normal thyroid, adrenal and renal functions
❏ treatment
• treat underlying cause, fluid restriction, demeclocycline (antibiotic with anti-ADH effects)
OXYTOCIN (see Obstetrics and Gynecology Chapters)
❏ a nonapeptide synthesized in paraventricular nuclei and supraoptic nuclei of hypothalamus
and stored in posterior pituitary
Physiology
❏ causes uterine contractions but physiologic role in initiating labour unclear
as impairment of oxytocin production does not interfere with normal labour
❏ causes breast milk secretion
Regulation
❏ secretion stimulated by suckling and distention of the female genital tract
❏ secretion inhibited by ethanol
MCCQE 2002 Review Notes Endocrinology – E15
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)
- 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
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
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.
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
**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
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.
ADRENAL CORTEX
ADRENOCORTICOTROPIN HORMONE (ACTH)
❏ polypeptide
❏ part of long prohormone (pro-opiomelanocorticotropin, POMC) which contains
α, ß and γ MSH, ß-endorphin, and lipotropin as well as ACTH
Physiology
❏ secretion from pituitary is both pulsatile and diurnally varied, peaking at 0200-0400 hours,
lowest at 1800-2400 hours
❏ stimulates growth of adrenal cortex and secretion of its hormones via cAMP
• stimulates glucocorticoids, androgens and, to a limited extent, mineralocorticoids
❏ may have some melanocyte stimulating activity
Regulation
❏ primary control by CRH from hypothalamus
❏ feedback inhibition by cortisol on pituitary, hypothalamus and CNS; also regulated
by sleep-wake cycle and stress (pyrogens, surgery, hypoglycemia, exercise, severe
emotional trauma)
ADRENOCORTICAL HORMONES
❏ all derived from cholesterol (see Figure 4)
• mineralocorticoids (aldosterone) from zona glomerulosa (outermost layer = “salt”)
• glucocorticoids (cortisol) from zona fasciculata (middle layer = “sugar”)
• androgens from zona reticularis (innermost layer = “sex”)
cholesterol
pregnenolone
2 1
progesterone 17-OH-pregnenolone DHEA-S
3* 1 2 2
11-deoxycorticosterone 17-OH-progesterone androstenedione
4 3* 5
corticosterone 11-deoxycortisol testosterone
8 4 6 7
aldosterone cortisol estradiol dihydrotestosterone
Mineralocorticoids Glucocorticoids Sex Steroids

(zona glomerulosa) (zona fasciculata) (zona reticularis)
1 17-hydroxylase 2 3-ß-dehydrogenase 3 21-hydroxylase

4 11-hydroxylase 5 17-ß-dehydrogenase 6 aromatase
7 5-α-reductase 8 18-hydroxylase *most common enzyme defect
Figure 4. Pathways of Major Steroid Synthesis in the

Adrenal Gland and Their Enzymes
Aldosterone
❏ regulates extracellular fluid (ECF) volume through Na+ retention and K+ excretion
(by stimulation of distal tubule Na+/K+ ATPase)
❏ aldosterone regulated principally by the renin-angiotensin-aldosterone system (see Figure 5)
❏ negative feedback to juxtaglomerular apparatus by long loop
(aldosterone via volume expansion) and short loop (angiotensin II
via peripheral vasoconstriction)
ADRENAL CORTEX . . . CONT.
volume depletion volume expansion

decreased arterial pressure increased arterial pressure
decreased Na+ delivery to macula densa dopamine
PGs, ADH renal Na+ retention
sympathetic stimulation
stimulation of JGA inhibition of JGA
Renin ACE
Angiotensinogen Angiotensin I Angiotensin II*

(with negative feedback to inhibit JGA)
Aldosterone release renal Na+ retention, K+ excretion

Arteriolar vascoconstriction
Promotion of ADH release
JGA - juxtaglomerular apparatus ACE - angiotensin converting enzyme
Figure 5. Renin-Angiotensin-Aldosterone Axis
Glucocorticoids
❏ secretion regulated by
• diurnal variation of ACTH (higher in a.m. than p.m., with peak around 0200 hours)
• inhibition of both ACTH and CRH release (negative feedback)
• stress (e.g. fever, pain, hypoglycemia), in addition to stimulating ACTH release,
directly stimulates CRH release, over-riding diurnal variation and negative feedback
❏ 10% free in plasma, 90% bound to transcortin (inactive)
❏ physiologic effects
• stimulate hepatic glucose production (gluconeogenesis)
• increase insulin resistance in peripheral tissues
• increase protein catabolism
• stimulate leukocytosis and lymphopenia
• inhibit bone formation; stimulate bone resorption
• inhibit fibroblasts, causing collagen and connective tissue loss
• suppress inflammation; impair cell-mediated immunity
• regulate extracellular fluid volume; promote renal solute-free water clearance
Androgens
❏ principal adrenal androgens are dihydroepiandrosterone (DHEA),
androstenedione and 11-hydroxyandrostenedione
❏ peak concentrations in puberty
❏ proportion of total androgens (adrenal to gonadal) increases in old age
❏ primarily responsible for adrenarche (pubic and axillary hair)
❏ adrenal androgen formation is regulated by ACTH (not LH)
TESTS OF ADRENOCORTICAL FUNCTION
Plasma Cortisol
❏ has diurnal variation; therefore, random measurements are of little value
❏ response to stimulation or suppression is more informative
24 Hour Urinary Free Cortisol
❏ correlates well with secretory rates
❏ good screening test for adrenal hyperfunction
Serum ACTH
❏ high in primary adrenal insufficiency
❏ low in secondary adrenal insufficiency
Serum DHEA-S
❏ the main adrenal androgen
Cosyntropin Stimulation Test
❏ cosyntropin is an ACTH analogue
❏ for diagnosing adrenal insufficiency
E26 – Endocrinology MCCQE 2002 Review Notes
Short Cosyntropin Stimulation Test

❏ 25 U of cosyntropin IM, measure serum cortisol at baseline and at 60 minutes
❏ POSITIVE response: increase in plasma cortisol level by > 200 nmol/L and
an absolute level of > 500 nmol/L (rules out primary adrenal insufficiency)
❏ NEGATIVE response: may be due to lack of stimulation —> proceed to long cosyntropin test
Long Cosyntropin Stimulation Test
❏ to determine primary vs. secondary adrenal insufficiency
❏ 25 U of synthetic ACTH infused for 8 hours on 3 consecutive days, cortisol measured qa.m.
❏ POSITIVE response rules out primary but not necessarily secondary adrenal insufficiency
❏ NEGATIVE response rules in primary adrenal insufficiency
Metyrapone Test
❏ one of best tests of integrity of pituitary-adrenal axis, but rarely used
❏ useful in diagnosing suspected secondary adrenal insufficiency
❏ 750 mg PO q4h x 24 h; measure serum cortisol, 11-deoxycortisol, and ACTH
❏ blocks 11-hydroxylase, the final step of cortisol synthesis, causing elevated
level of the cortisol precursor, 11-deoxycortisol and decreased serum cortisol levels
❏ normal response is reduced cortisol, elevated 11-deoxycortisol
and elevated ACTH (response of pituitary to decreased cortisol)
Dexamethasone (DXM) Suppression Tests
❏ gold standard to determine presence and etiology of hypercortisolism
❏ principle: DXM suppresses pituitary ACTH, so plasma cortisol should be lowered by
negative feedback if HPA axis is normal
❏ if 24 hour urinary free cortisol (screening test) is positive, begin with low-dose DST to confirm diagnosis
❏ low dose DST: 0.5 mg DXM q6h for 48 hours, then 24 hour urinary free cortisol twice
❏ following this, measure ACTH; if undetectable, proceed to high-dose DST (8X higher dose than above)
to confirm diagnosis of adrenal Cushing’s
❏ if ACTH normal or increased, proceed to a CRF stimulation test via inferior petrosal sinus sampling to
distinguish Cushing’s disease from ectopic Cushing’s syndrome
HYPERALDOSTERONISM
❏ state of hypersecretion of the mineralocorticoid aldosterone
1. Primary Hyperaldosteronism
❏ diagnostic criteria:
• diastolic hypertension without edema
• decreased renin and increased aldosterone secretion both
unresponsive to increases in volume
❏ aldosterone-producing adrenal adenoma (Conn’s syndrome)
❏ idiopathic bilateral adrenal hyperplasia
❏ adrenal carcinoma (rare)
Clinical Features
❏ hypertension uncontrolled by standard therapy
❏ hypokalemia OFF diuretics
❏ other symptoms may include
• polyuria, polydipsia, nocturia
• fatigue, weakness, paresthesias
• headaches
Laboratory Findings
❏ hypokalemia
❏ high normal Na+
❏ metabolic alkalosis
❏ high 24 hour urinary or plasma aldosterone
❏ low random plasma renin
Treatment
❏ medical: spironolactone (aldosterone antagonist) or amiloride
❏ surgical: removal of adenoma is curative
2. Secondary Hyperaldosteronism
❏ increase in aldosterone in response to activation of renin-angiotensin system
❏ overproduction of renin (e.g. primary reninism from renin-producing tumour - rare)
❏ secondary hyperreninism - due to hypoperfusion of kidneys (e.g. renal artery stenosis), or edematous states
(CHF, liver cirrhosis), where arterial hypovolemia and/or hypotension is stimulus for aldosterone secretion
• Bartter’s syndrome - severe secondary hyperaldosteronism
without edema or hypertension (due to JGA hyperplasia)
CUSHING’S SYNDROME
❏ results from chronic glucocorticoid excess (endogenous or exogenous sources)
❏ endogenous Cushing’s syndrome is due to increased cortisol production by the adrenal gland
Etiology
❏ ACTH-dependent: bilateral adrenal hyperplasia and hypersecretion due to
• ACTH-secreting pituitary adenoma (Cushing’s disease)
• ectopic ACTH-secreting tumour (e.g. small cell lung carcinoma, bronchial carcinoid)
❏ ACTH-independent
• long-term use of exogenous glucocorticoids (most common cause of Cushing’s syndrome)
• primary adrenocortical tumours: adenoma and carcinoma (uncommon)
• bilateral adrenal nodular hyperplasia
Clinical Features (see Figure 6, see Colour Atlas E1)
❏ general
• truncal (centripetal) obesity, thin extremities, supraclavicular fat pads,
posterior cervical fat (“buffalo hump”), “moon facies”
• hypertension
❏ skin
• thin skin, facial plethora, hirsutism in women, wide purple striae,
acne, easy bruising, poor wound healing, mucocutaneous candidiasis
❏ musculoskeletal
• osteoporosis, pathologic fractures, avascular necrosis (AVN)
• proximal muscle weakness (more prominent in lower limbs)
❏ neuropsychiatric
• emotional lability, depression, euphoria, frank psychosis
❏ gonadal dysfunction
• oligomenorrhea / amenorrhea in women, decreased libido / impotence in men
❏ metabolic
• glucose intolerance (frank diabetes less common), hyperlipidemia, polyuria, nephrocalcinosis
❏ ectopic ACTH production
• hyperpigmentation, hypertension, hypokalemic metabolic alkalosis,
weight loss, weakness (typical features of Cushing’s syndrome usually absent)
CONT. buffalo hump red cheeks, acne, moon face
purple striae
osteoporosis
large abdomen
avascular necrosis
thin arms and legs

easy bruising
poor wound healing
Figure 6. Cushing’s Syndrome

Illustration by Marisa Bonofiglio
clinical features suspicious for hypercortisolism
24 hour urinary free cortisol
normal < 4X increase > 4X increase
no low dose DST diagnosis of Cushing’s

Cushing’s to confirm diagnosis syndrome established
syndrome
measure ACTH
ACTH increased ACTH decreased
MRI pituitary, CT adrenal, confirmatory high-dose DST

inferior petrosal sinus sampling with
CRF stimulation test
• DST = DXM suppression test
Figure 7. Hypercortisolism: Algorithm for Diagnosis
Treatment
❏ pituitary
• transsphenoidal resection, with glucocorticoid supplement peri- and post-operatively
• irradiation: only 50% effective, with significant risk of hypopituitarism
❏ adrenal
• adenoma: unilateral adrenalectomy (curative)
• carcinoma: palliative (frequent metastases, very poor prognosis)
adjunctive chemotherapy often not useful
❏ ectopic ACTH tumour - usually bronchogenic cancer (a paraneoplastic syndrome)
• chemotherapy/radiation for primary tumour
• agents blocking adrenal steroid synthesis: metyrapone or ketoconazole
• poor prognosis
CONGENITAL ADRENAL HYPERPLASIA (CAH) (see Pediatrics Chapter)
Pathophysiology
❏ autosomal recessive pattern of transmission, leading to enzyme defects, which can range from partial to total
❏ 21-hydroxylase (21-OH) deficiency is the most common form (95%) (see Figure 4)
❏ results in decreased cortisol and aldosterone with shunting toward adrenal androgen pathway
❏ deficiency of cortisol leads to elevated ACTH, which increases levels of unaffected steroids and
causes bilateral adrenal hyperplasia
Late-Onset 21-Hydroxylase Deficiency
❏ allelic variant of classic 21-hydroxylase deficiency
❏ mild enzymatic defect
❏ manifests during or after puberty: signs of androgenization
(hirsutism and acne) and amenorrhea or oligomenorrhea
❏ consider in women with unexplained hirsutism and menstrual abnormalities
❏ diagnosis
• increased plasma 17-OH-progesterone after ACTH stimulation test
❏ treatment
• dexamethasone, spironolactone (anti-androgen)
• mineralocorticoid replacement is not needed
HIRSUTISM AND VIRILIZATION
❏ both terms refer to states of androgen excess
❏ hirsutism
• male pattern of hair growth in women: back, chest, upper abdomen
❏ virilization
• hirsutism, frontal balding
• clitoral enlargement
• deepening of voice
• acne
• increase in musculature
❏ defeminization
• amenorrhea
• decreased breast size
Etiology
❏ constitutional
• most common
• family history, ethnic background
❏ medications
• androgen-mediated: ACTH, anabolic steroids, androgens, progestational agents
• non-androgen mediated (hypertrichosis): phenytoin, diazoxide, cyclosporine, minoxidil
❏ ovarian
• polycystic ovarian disease (PCOD) (see Gynecology Chapter)
• tumours
❏ adrenal
• congenital hyperplasia (CAH, late-onset CAH)
• tumours
❏ Cushing’s disease - high ACTH
Investigations
❏ increased testosterone
❏ DHEA-S as measure of adrenal androgen production
❏ increased LH/FSH, seen commonly in PCOD as ratio > 2.5
Treatment
❏ cosmetic therapy
❏ discontinue causative medications
❏ oral contraceptives
❏ low dose glucocorticoid
❏ spironolactone - acts as peripheral androgen antagonist
❏ cyproterone acetate - blocks androgen receptor binding;
being increasingly used in combination with estradiol (Diane-35)
ADRENOCORTICAL INSUFFICIENCY
Primary (Addison’s Disease)
❏ rare form of adrenal pathology
❏ most cases are idiopathic
• likely autoimmune destruction of adrenals (50% of patients
have circulating adrenal antibodies)
• high association with other autoimmune diseases (e.g. chronic lymphocytic thyroiditis,
type 1 DM, vitiligo, pernicious anemia)
❏ metastatic tumour - second commonest cause
❏ hemorrhagic infarction - coagulopathy in adults or Waterhouse-Friderichsen syndrome
in children (meningococcal or Pseudomonas septicemia)
❏ adrenalectomy
❏ granulomatous disease (e.g. TB, sarcoidosis)
❏ infection - particularly AIDS
Secondary
❏ inadequate pituitary ACTH secretion
❏ multiple etiologies (see Hypopituitarism section), including withdrawal of
exogenous steroids that have suppressed pituitary ACTH production
Clinical Features
❏ both primary and secondary
• weakness and fatigue
• postural hypotension
• weight loss, anorexia, nausea/vomiting, diarrhea
• abdominal, muscle, and joint pain
❏ primary
• hyperpigmentation of skin and mucous membranes
(e.g. palmar creases and buccal mucosa)
• dehydration, salt craving
❏ secondary
• usually more chronic than primary
• pallor, normal K+ and hydration
❏ acute adrenal crisis
• unable to secrete increased cortisol, ACTH in response to stress
(e.g. infection, dehydration, surgery)
• hypovolemic shock, fever, extreme weakness, decreased LOC,
nausea / vomiting, hypoglycemia
Laboratory Findings
❏ hyponatremia, hyperkalemia, elevated BUN/creatinine
❏ chronic anemia (normochromic, normocytic)
❏ primary
• low cortisol unresponsive to exogenous ACTH
• high ACTH
• adrenal antibodies if autoimmune etiology
❏ secondary
• low cortisol, low ACTH
• usually normal K+, BUN/creatinine
Treatment
❏ acute condition - can be life-threatening
• IV NS or D5W/NS in large volumes
• hydrocortisone 100 mg IV q6-8h for 24h, then gradual tapering
• identify and correct precipitating factor
❏ maintenance
• cortisone acetate 25 mg PO qa.m. and 12.5 mg qp.m.
• Florinef (synthetic mineralocorticoid) 0.05-0.2 mg PO daily if
mineralocorticoid deficient
• increase dose of steroid in times of illness or for surgery
ADRENAL MEDULLA
Catecholamine Metabolism
❏ catecholamines synthesized from tyrosine in postganglionic sympathetic nerves
and chromaffin cells of adrenal medulla
❏ predominant adrenal catecholamine = epinephrine (adrenaline)
❏ predominant peripheral catecholamine = norepinephrine (noradrenaline)
PHEOCHROMOCYTOMA
Pathophysiology
❏ rare tumour arising from chromaffin cells of the sympathetic system
❏ most commonly a single tumour of adrenal medulla
❏ 10% extra-adrenal, 10% multiple tumours, 10% malignant, 10% familial
❏ tumour not innervated but via unknown mechanism, able to
synthesize and release catecholamines
❏ cases sporadic or part of MEN (see Multiple Endocrine Neoplasia section)
❏ rare cause of hypertension (< 0.1% of all hypertensives)
❏ curable if recognized and properly treated, but fatal if not
Clinical Features
❏ symptoms often paroxysmal, may be triggered by stress, exertion, certain foods
❏ hallmark is paroxysmal or sustained HTN (sustained HTN more common,
present between attacks in 60% of patients)
❏ classic triad: “pounding” headache, palpitations, diaphoresis
❏ others: tremor, anxiety, chest or abdominal pain, nausea / vomiting
Lab Findings
❏ increased urinary catecholamines usually sufficient to confirmdiagnosis
❏ elevated plasma epinephrine unsuppressed by clonidine (central α-adrenergic)
❏ positive adrenal CT scan
❏ meta-iodo-benzoguanidine (MIBG) uptake by tumour site during scan;
useful to locate tumour for surgery
Treatment
❏ adequate pre-operative preparation
• α-blockade - PO phenoxybenzamine (pre-op), IV phentolamine (peri-operative)
• ß-blockade - propranolol
• volume restoration with vigorous salt-loading
❏ surgical removal of tumour with careful pre-operative and post-operative ICU monitoring
❏ rescreen urine one month post-operatively
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
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
Laboratory Findings
❏ primary
• high ACTH
❏ secondary
Treatment
❏ maintenance
ADRENAL MEDULLA
PHEOCHROMOCYTOMA
Pathophysiology
Clinical Features
Lab Findings
Treatment
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.
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
MULTIPLE ENDOCRINE NEOPLASM (MEN)
❏ neoplastic syndromes involving multiple endocrine glands
❏ tumours of neuroectodermal origin APUD (amine precursor uptake and
decarboxylation) cells
❏ autosomal dominant inheritance with considerable variability in
penetrance and in specific tumour incidences among kindred
❏ genetic screening methods becoming more available
Table 12. MEN Classification
Type Chromosome Tissues Involved Clinical Features
Implicated
I 11 syndrome can evolve over 30-40 years
Wermer’s 1. Pituitary • ant. pituitary adenomas, often non-secreting
syndrome but may secrete GH and PRL
2. Parathyroid • primary hyperparathyroidism from hyperplasia
3. Pancreas • pancreatic islet cell tumours
• gastrinoma (peptic ulcers)
• insulinomas (hypoglycemia)
• VIPomas (secretory diarrhea)
IIa 10 1. Thyroid • medullary thyroid cancer
Sipple’s 2. Parathyroid • primary hyperparathyroidism from hyperplasia
syndrome 3. Adrenal medulla • pheochromocytoma
IIb 10 1. Thyroid • medullary thyroid cancer
2. Adrenal medulla • pheochromocytoma
• other: mucosal neuromas, Marfanoid features
CALCIUM DISORDERS
CALCIUM2+HOMEOSTASIS
❏ serum Ca is about 50% protein bound (mostly albumin) and not exchangeable
❏ alterations in protein content of the blood for any number of reasons
may affect the total serum Ca2+ without altering the ionized form
❏ normal total serum Ca2+ range is 2.25-2.62 mmol/L (9.0-10.5 mg/dL)
❏ to correct for changes in albumin:
corrected Ca2+ (mmol/L) = measured Ca2+ + 0.25(40-albumin)
10
❏ ionic Ca2+ levels are maintained within narrow limits (1.15-1.31 mmol/L; 4.6-5.25 mg/dL)
❏ sources of ECF Ca2+: diet, resorption from bone
❏ loss of Ca2+ from ECF space via: GI losses, renal excretion, deposition in bone matrix
❏ regulated mainly by two factors: parathyroid hormone (PTH) and Vitamin D
❏ actions mainly on three organs: GI tract, bone, and kidney
Parathyroid Hormone (PTH)
❏ secretion increased by low serum Ca2+ and inhibited by low serum Mg
• not influenced directly by PO4 (except by PO4 effect on the ionic calcium levels)
❏ major actions
• increased osteoclast activity ––> increased Ca2+ and increased PO4
• increased renal tubular Ca2+ (and Mg) reabsorption
• inhibits renal tubular reabsorption of PO4 (and HCO3)
• increased 1-α-hydroxylase activity ––> vitamin D ––> increased Ca2+ and PO4 absorption from gut
• NET EFFECT: increased serum Ca2+ ––> increased vit D, decreased PO4
Vitamin D
❏ necessary for Ca2+ and PO4 absorption from GI tract
❏ cholecalciferol formed in the skin by the action of UV light
❏ converted to 25(OH)-vit D by the liver
❏ converted to 1,25(OH)2-vit D in the kidney
❏ production of 1,25(OH)2-vit D is enhanced by PTH and low PO4 levels
❏ if a PTH deficiency exists, metabolism is shunted into the production of 24,25- or 25,26(OH)2-vit D
(relatively inert)
❏ major actions
• increased Ca2+ and PO4 absorption from gut
• increased bone resorption
• increased osteoclasts
• increased renal Ca2+ reabsorption
• NET EFFECT: increased serum Ca2+ and PO4
CALCIUM DISORDERS . . . CONT.
Calcitonin
❏ polypeptide secreted by thyroid C cells
❏ secretion enhanced by Ca2+, GI hormones, pentagastrin
❏ major actions
• decreased osteoclastic bone resorption
• increased renal PO4 and Na+ clearance
• ACUTE NET EFFECT: decreased serum Ca2+ when given in pharmacologic doses
Magnesium
❏ major intracellular divalent cation
❏ Ca2+ is resorbed from the kidney with Mg, and thus Ca2+ balance is difficult to maintain in Mg deficiency
Phosphorus
❏ found in all tissues and necessary for most biochemical processes as well as bone formation
Table 13. Summary of Effects
Hormone Net Effect
Parathyroid Hormone (PTH) increased Ca2+
increased vit D
decreased PO4
Vitamin D increased Ca2+
increased PO4
Calcitonin decreased Ca2+
(in pharmacologic doses)
HYPERCALCEMIA
Definition
❏ total corrected serum Ca2+ > 2.62 mmol/L (10.5 mg/dL) OR ionized Ca2+ > 1.35 mmol/L (5.4 mg/dL)
❏ a medical emergency
• volume depletion
• arrhythmias
Pathophysiology
❏ increased bone resorption
❏ increased gastrointestinal absorption
❏ decreased renal excretion
Clinical Features
❏ symptoms dependent on the absolute Ca2+ value and the rate of its rise (may be asymptomatic)
Table 14. Symptoms of Hypercalcemia

Cardiovascular Gastrointestinal Renal Neurologic MSK Psychiatric
hypertension anorexia polyuria hypotonia bone pain cognitive changes
8digoxin toxicity nausea polydipsia hyporeflexia (bones) increased alertness
arrhythmia (groans) nephrogenic DI myopathy psychosis (moans)
9QT interval vomiting nephrolithiasis paresis
PUD (stones)
pancreatitis renal failure
Clinical Pearl
❏ The symptoms and signs of hypercalcemia include:
“Bones, Stones, psychosis-based Moans, and abdominal Groans”
Differential Diagnosis
Clinical Pearl
❏ > 90% of hypercalcemia is caused by either parathyroid disease or malignancy.
1. Parathyroid Disease
❏ primary hyperparathyroidism
• major cause of hypercalcemia
• PTH hypersecretion causes increase in Ca2+ and bone metabolism/turnover while decreasing PO4
• includes solitary adenoma (most common, 81%), hyperplasia (15%), carcinoma (4%), MEN I and IIa
• presentation: 50% asymptomatic, renal calculi, neuromuscular disease, decreased bone
density and associated consequences
• investigations: serum Ca2+, PO4, PTH, diagnostic imaging for renal calculi and osteopenia
• treatment: continued surveillance vs. surgery
❏ secondary hyperparathyroidism
• associated with renal failure - due to reduced Vit D synthesis, associated with malabsorption
2. Malignancy
❏ solid tumours
• bone metastases (e.g. breast): mediated by osteoclast activating factor (OAF)
and various cytokines
• humoral mediation of hypercalcemia (e.g lung and renal cell carcinoma):
secondary to production of PTH-related peptides (PTHrp)
❏ hematological malignancy (e.g. multiple myeloma, lymphoma, leukemia)
3. Vitamin D-Related
❏ vitamin D intoxication
❏ granulomatous diseases (e.g. sarcoidosis)
4. High Bone Turnover
❏ hyperthyroidism
❏ Paget's disease
❏ vitamin A excess
5. Renal Failure
❏ milk-alkali syndrome (hypercalcemia with alkalosis and renal failure)
❏ aluminum intoxication
❏ tertiary hyperparathyroidism
• persistent increase in PTH after correction of secondary hyperparathyroidism
(seen in renal transplant patients)
6. Drugs
❏ thiazides
❏ lithium
❏ calcium carbonate
❏ theophylline
7. Familial Hypocalciuric Hypercalcemia
❏ autosomal dominant
❏ mutation in Ca2+ sensing receptor gene leads to abnormal sensing of Ca2+ by parathyroid glands and
renal tubules (inappropriate secretion of PTH and excessive tubal reabsorption of Ca2+)
Treatment of Hypercalcemia
❏ treatment depends on the Ca2+ level and the symptoms
❏ treat acute, symptomatic hypercalcemia aggressively
❏ rehydration and calciuresis
• IV NS infusion (usually requires 4-5 L of fluid)
• only after adequately rehydrated, promote calciuresis with a loop diuretic, i.e. furosemide
❏ bisphosphonates
• treatment of choice
• inhibit osteoclast activity
• indicated in malignancy-related hypercalcemia
• pamidronate is most commonly used
• IV route since poorly absorbed from the GI tract
• several days until full effect but effect is long-lasting
❏ mithramycin
• effective when patient can not tolerate large fluid load (dangerous - hematotoxic and hepatotoxic)
❏ calcitonin
• inhibits osteoclastic bone resorption and promotes renal excretion of calcium
• acts rapidly but often transient response
• combination of calcitonin and steroids may prolong reduction in calcium
• tachyphylaxis may occur
❏ steroids
• anti-tumour effects
• useful in vitamin D-related hypercalcemia (including sarcoidosis)
and hematogenous malignancies (myeloma, lymphoma)
• slow to act (5-10 days); need high dose
❏ prostaglandin inhibitors
❏ surgical treatment if indicated
❏ avoid immobilization
HYPOCALCEMIA
Definition
❏ total corrected serum Ca2+ < 2.25 mmol/L (9.0 mg/dL)
Clinical Features
❏ most characteristic symptom is tetany
❏ differential diagnosis of tetany
• metabolic alkalosis (with hyperventilation)
• hypokalemia
• hypomagnesemia
Table 15. Signs and Symptoms of Hypocalcemia

Acute Hypocalcemia Chronic Hypocalcemia
• paresthesias • CNS: lethargy, seizures, psychosis, basal ganglia calcification
• hyperreflexia extrapyramidal effects, papilledema, pseudotumour cerebri
• tetany • CVS: prolonged QT interval
• laryngospasm (with stridor) • GI: malabsorption, diarrhea
• confusion • Skin: dry, scaling, alopecia, brittle and fissured nails,
• Chvostek’s sign (tap CN VII) moniliasis, abnormal dentition
• Trousseau’s sign (carpal spasm) • Ocular: cataracts, papilledema
1. Deficient PTH Action
❏ results in
• decreased bone resorption
• decreased intestinal Ca2+ absorption
• increased renal Ca2+ excretion
❏ iatrogenic hypoparathyroidism
• post-thyroidectomy/131I ablation
❏ idiopathic/autoimmune hypoparathyroidism
• congenital (DiGeorge syndrome) - dysgenesis of thymus and parathyroid glands
• acquired (polyglandular autoimmune disease - hypoparathyroidism
± adrenal insufficiency ± gonadal failure ± hypothyroidism and rarely
hypopituitarism, diabetes insipidis, type 1 DM)
❏ hemochromatosis
❏ pseudohypoparathyroidism
• PTH resistance secondary to Gs protein deficiency
❏ severe hypomagnesemia
• normally low Mg level stimulates PTH secretion, but chronic hypomagnesemia
is paradoxically associated with impaired PTH secretion
• low Mg levels also impair peripheral responsiveness to PTH
2. Deficient Vitamin D Action
❏ decreased intestinal absorption
❏ vitamin D deficiency
❏ receptor defect (vitamin D-dependent rickets type II)
❏ hydroxylation defects
• congenital: type I rickets
• acquired: chronic renal failure (CRF), hepatic failure
3. Renal Disease
❏ most common cause of hypocalcemia; increased loss of Ca2+
❏ chronic renal failure, nephrotic syndrome, acute renal failure
4. Drugs
❏ phosphate
❏ calcitonin
❏ aminoglycosides
❏ antineoplastic drugs (cisplatin, mithramycin)
❏ loop diuretics
5. Alcoholism
6. Acute Pancreatitis
❏ saponification of Ca2+ by lipids
7. Pregnancy
❏ low total Ca2+ (due to hypoalbuminemia) but normal ionized level
Treatment of Hypocalcemia
❏ correct underlying disorder
❏ acute/severe hypocalcemia
• calcium gluconate (generally requires continuous infusion)
• goal is to raise Ca2+ to low normal range (2.0-2.1 mmol/L) to prevent
symptoms but allow maximum stimulation of PTH
❏ if PTH recovery not expected, requires long-term therapy with vitamin D and calcium
❏ do not correct hypocalcemia if it is suspected to be a transient response
METABOLIC BONE DISEASE

OSTEOPOROSIS
Definition
❏ an age-related condition characterized by decreased bone mass and microarchitectural deterioration
of bone tissue with a consequent increase in bone fragility and susceptibility to bone fracture
Pathophysiology
❏ bone resorption > bone formation/remodelling
Risk Factors
❏ low peak bone mass
• small Caucasian or Asian female
• family history
❏ estrogen-related bone mass
• early menopause
• oophorectomy
• amenorrhea
❏ advanced age
❏ secondary to medical disease
❏ other
• diet, smoking, alcohol, caffeine
• minimal weight-bearing physical activity
Classification
1. Primary Osteoporosis
❏ usually in women, within 20 years after menopause
❏ affects mainly trabecular bone
2. Secondary Osteoporosis
❏ endocrinopathies
• hyperparathyroidism
• hyperthyroidism
• premature menopause
• diabetes
• acromegaly
❏ malignancy
• multiple myeloma
❏ gastrointestinal disease
• malabsorption
• liver disease
❏ drugs
• steroids
• phenytoin
• chronic heparin
❏ other
• rheumatoid arthritis
• renal disease
• poor nutrition
• immobilization
Clinical Features
❏ commonly asymptomatic
❏ pain, especially backache
❏ collapsed vertebrae ––> height loss
❏ fractures
• hip, vertebrae, humerus, and wrists most common
• Dowager’s hump = collapse fracture of vertebral bodies in mid-dorsal region
\
METABOLIC BONE DISEASE . . . CONT.
Investigations
❏ laboratory
• usually normal serum Ca2+, PO4, alkaline phosphatase
❏ densitometry
• single-energy x-ray absorptiometry, dual-energy x-ray absorptiometry (most useful),
quantitative CT, ultrasonography
• lumbar spine and views of femur
• compared to controls
❏ 1-2.5 SD = osteopenia
❏ > 2.5 SD = osteoporosis
Treatment
❏ not very satisfactory
❏ prevention and lifestyle modification
• safety measures to prevent falls
• weight-bearing exercises
• vitamin D with Ca2+ supplementation
• limits to smoking and alcohol use
❏ measures to decrease further bone loss/bone resorption
• postmenopausal estrogen replacement
• Ca2+ supplementation (1,000-1,500 mg/day for postmenopausal women)
• bisphosphonates - inhibitors of osteoclast binding
• calcitonin - osteoclast receptor binding
• thiazide diuretics (for hypercalcuria)
• combination therapy (synergistic): estrogen + bisphosphonate
❏ measures to increase bone mass
• fluoride - stimulates osteoblasts for bone formation
• parathyroid hormone
OSTEOMALACIA AND RICKETS
Definitions
❏ abnormal concentration of ions leads to higher proportion of osteoid (unmineralized) tissue
❏ disease prior to epiphyseal closure (in childhood) = rickets
❏ disease after epiphyseal closure (in adulthood) = osteomalacia
Etiology
❏ vitamin disorders
• decreased availability of vitamin D
• insufficient sunlight exposure
• nutritional deficiency
• malabsorption
• hydroxylation defects
• nephrotic syndrome
• liver disease
• chronic renal failure
• anticonvulsant therapy
❏ mineral deficiencies
• Ca2+ deficiency
• PO4 deficiency
• decreased GI absorption
• increased renal loss
❏ disorders of bone matrix
❏ inhibitors of mineralization
• aluminum
• bisphosphonates
Table 16. Clinical Presentations of Rickets and Osteomalacia

Rickets Osteomalacia
• skeletal deformities, bowlegs • not as dramatic
• fracture susceptibililty • diffuse skeletal pain
• weakness and hypotonia • bone tenderness
• disturbed growth • fractures
• rachitic rosary • gait disturbances
(prominent costochondral junctions) • proximal muscle weakness
• Harrison’s groove
(indentation of lower ribs)
• hypocalcemia
Investigations
❏ laboratory
• decreased serum Ca2+
• decreased serum phosphorus
• increased serum alkaline phosphatase (ALKP)
• decreased urinary Ca2+
❏ radiologic findings
• pseudofractures – thought to be healed microfractures
• radiolucent banding of spine
❏ bone biopsy
• usually not necessary but considered the gold standard for diagnosis
Treatment
❏ depends on the underlying cause
❏ vitamin D supplementation
❏ PO4 supplements if low serum PO4 is present
❏ Ca2+ supplements for isolated calcium deficiency
❏ HCO3 if chronic acidosis
RENAL OSTEODYSTROPHY
Pathophysiology
❏ metabolic bone disease secondary to chronic renal failure
❏ combination of hyperphosphatemia (inhibits 1,25(OH)2-vit D synthesis)
and loss of renal mass (reduced 1-α-hydroxylase)
Types
❏ produces a mixture of four types of bone disease
• osteomalacia - from acidosis and retention of toxic metabolites
• osteoporosis - metabolic acidosis dissolution of bone buffers
• osteitis fibrosa cystica - from increased PTH
• osteosclerosis - from increased PTH
❏ metastatic calcification secondary to hyperphosphatemia may occur
Clinical Features
❏ soft tissue calcifications ––> necrotic skin lesions if vessels involved
❏ osteodystrophy ––> bone pain and fractures
❏ pruritus
❏ neuromuscular irritability and tetany may occur
❏ radiologic features of osteitis fibrosa cystica, osteomalacia,
osteosclerosis, osteoporosis
Treatment
❏ prevention
• maintenance of normal serum Ca2+ and PO4 by restricting PO4 intake to 1 g/day
• Ca2+ supplements
• PO4 binding agents
• prophylactic use of vitamin D with close monitoring to avoid
hypercalcemia and metastatic calcification
PAGET’S DISEASE OF BONE
Definition
❏ a metabolic disease characterized by excessive bone destruction and repair
Epidemiology
❏ a common disease: 5% of the population, 10% of population > 80 years old
Etiology
❏ postulated to be related to a slow viral infection of osteoclasts, possibly paramyxovirus
❏ strong familial incidence
Pathophysiology
❏ initiated by increased osteoclastic activity leading to increased bone resorption;
osteoblastic activity increases in response to produce new bone that
is structurally abnormal and fragile
Clinical Features
❏ usually asymptomatic (routine x-ray finding or elevated alkaline phosphatase)
❏ severe bone pain (e.g. pelvis, femur, tibia) is often the presenting complaint
❏ skeletal deformities – bowed tibias, kyphosis, frequent fractures
❏ skull involvement – headaches, increased hat size, deafness
❏ increased warmth over involved bones due to increased vascularity
Investigations
❏ laboratory
• serum alkaline phosphatase is usually very high
• normal or increased serum Ca2+
• normal serum PO4
• increased urinary hydroxyproline (indicates resorption)
❏ imaging
• evaluate the extent of disease with bone scan
• initial lesion may be destructive and radiolucent
• involved bones are expanded and denser than normal
• multiple fissure fractures in long bones
❏ primary bone lesions
• osteogenic sarcoma
• fibrous dysplasia
❏ secondary bone lesions
• osteitis fibrosa cystica
• metastases
Complications
❏ fractures
❏ hypercalcemia and nephrolithiasis
❏ cranial nerve compression and palsies, e.g. deafness
❏ spinal cord compression
❏ osteosarcoma/sarcomatous change
• 1-3%
• indicated by marked bone pain, new lytic lesions and
sudden increased alkaline phosphatase
❏ high output congestive heart failure due to increased vascularity
❏ osteoarthritis
Treatment
❏ symptomatic therapy
❏ calcitonin
❏ bisphosphonates, e.g. alendronate
MALE REPRODUCTIVE ENDOCRINOLOGY

Androgen Regulation
❏ both positive and negative feedback may occur by androgens
directly or after conversion to estrogen
❏ testosterone (from the Leydig cell) primarily involved in negative feedback
on LH, whereas inhibin (from the Sertoli cell) suppresses FSH secretion
TESTS OF TESTICULAR FUNCTION
❏ testicular size (lower limit = 4 x 2.5 cm)
❏ serum LH, FSH, testosterone
❏ hCG stimulation test
• assesses ability of Leydig cell to respond to gonadotropin
❏ semen analysis
• semen volume
• sperm count, morphology and motility
❏ testicular biopsy
• indicated in the context of normal FSH and azoospermia/oligospermia
HYPOGONADISM
❏ deficiencies in gametogenesis or the secretion of gonadal hormones
Etiology
1. Hypergonadotropic Hypogonadism
(Primary Testicular Failure)
❏ characterized by increased LH/FSH
❏ congenital
• chromosomal defects, i.e. Klinefelter syndrome, Noonan syndrome
• cryptorchidism
• male pseudohermaphroditism
• bilateral anorchia
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))
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.

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.

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

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

- 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.


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

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
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.

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
Diabetes Qs
Lecture Keypad Questions:
DISORDERS OF GLUCOSE METABOLISM
DIABETES MELLITUS (DM)
❏ diagnosis (confirm with the same test on another day)
• symptoms of diabetes (polyuria, polydipsia, weight loss,
nocturia, polyphagia, blurry vision) PLUS random plasma
glucose ≥ 11.1 mmol/L (200 mg/dL) OR
• FBS ≥ 7.0 mmol/L (126 mg/dL) OR
• plasma glucose value ≥ 11.1 mmol/L (200 mg/dL)
during two hour OGTT
❏ diagnostic testing
• fasting blood glucose (FBG): best drawn the morning after overnight fast
• oral glucose tolerance test (OGTT): 75 g glucose ingested, then plasma glucose levels
measured following 0 and 120 minutes
Classification of Diabetes Mellitus (DM)
Table 1. Comparison of Type 1 and Type 2 Diabetes

Type 1 Diabetes Type 2 Diabetes
Etiology • idiopathic • genetically-linked
• auto-immune
Onset • usually before age 30 • usually after age 40
Genetics • associated with HLA DR3, • greater heritability than Type 1
DR4 and DQ alleles • non-HLA-associated
• 40% concordance in monozygotic • 80-100% concordance in monozygotic twins
twins
Pathophysiology • completely insulin-deficient • abnormal insulin secretion
• increased insulin resistance in target tissues,
likely due to receptor and post-receptor
abnormalities
• increased hepatic gluconeogenesis
Risk Factors • personal history of autoimmune • obesity
diseases increases likelihood of • family history
developing DM • prior abnormal glucose tolerance
• e.g. Graves’ disease, myasthenia • hypertension
gravis, Addison’s disease, pernicious • hyperlipidemia
anemia • gestational diabetes mellitus (GDM)
Population Prevalence • highest in Finland • higher in black, Aboriginal and Hispanic people
• rare in Asian, black, Aboriginal and
Hispanic people
Body Habitus • typically normal to wasted • typically overweight
Pharmacological • insulin required • combination of oral hypoglycemic agents
Therapy ± insulin therapy
Circulating Islet • 50-85% • < 10%

Cell Antibodies
Other Aspects • prone to ketoacidosis • not prone to ketoacidosis but prone to
hyperosmolar coma
Diabetes Secondary to Specific Etiologies

❏ genetic
• Down syndrome, Turner’s syndrome, Huntington’s disease,
genetic defects in ß-cell function and insulin action
❏ diseases of the endocrine/exocrine pancreas
• pancreatitis, neoplasia, cystic fibrosis (CF), hemochromatosis (bronzed diabetes)
• acromegaly, Cushing’s syndrome, glucagonoma, hyperthyroidism
❏ drug-induced
• ß-agonists, glucocorticoids, thiazides, phenytoin
❏ infections
• cytomegalovirus (CMV), congenital rubella
DISORDERS OF GLUCOSE METABOLISM . . . CONT.
Gestational Diabetes (GDM) (see Obstetrics Chapter)

❏ glucose intolerance that develops during pregnancy
❏ incidence
• 2-4% of all pregnancies
❏ risk factors
• age > 25 • member of high-risk ethnic group
• obesity • previous GDM
• 1º relative with DM • previous macrosomic baby (> 4 kg)
❏ screening and diagnosis
• any pregnant woman should be screened between 24 and 28 weeks
• 50 g glucose challenge test, measuring glucose one hour later
• if abnormal (7.8 mmol/L; 140 mg/dL), then 75 g oral glucose tolerance test (OGTT) should be done
• if any two of the following three values are met or exceeded, a diagnosis of GDM is established
• fasting glucose ≥ 5.3 mmol/L (95 mg/dL)
• 1 hr value ≥ 10.6 mmol/L (190 mg/dL)
• 2 hr ≥ 8.9 mmol/L (160 mg/dL)
Fetus
❏ maternal hyperglycemia induces hyperinsulinemia in fetus
❏ results in macrosomia (insulin acts as a growth factor)
❏ GDM: prone to respiratory distress, neonatal hypoglycemia,
hypocalcemia, hyperbilirubinemia, polycythemia, and prematurity
❏ preexisting DM: all of the above plus intrauterine growth restriction (IUGR), sacral agenesis,
cardiac structural defects
Mother
❏ increased risk of developing subsequent type 2 DM
❏ progression of diabetic retinopathy and nephropathy
❏ management
• preconception care to normalize HbA1c (if preexisting DM)
• tight glucose control (shown to decrease both fetal and maternal complications)
• oral hypoglycemics contraindicated
• insulin to maintain tight glycemic control if diet inadequate
• fetus must be monitored carefully
Impaired Glucose Tolerance (IGT)
❏ diagnosis based on
• fasting glucose 6.1-6.9 mmol/L (110-125 mg/dL)
• 2-hour OGTT 7.8-11.1 mmol/L (140-199 mg/dL)
❏ 1-5% per year develop DM
❏ 50-80% revert to normal glucose tolerance
❏ weight loss may improve glucose tolerance
❏ associated with progressively greater risk of developing macrovascular complications
COMPLICATIONS OF DIABETES
❏ the majority of complications involve the vascular system
❏ aggravating factors: poor glycemic control, inadequate control of hypertension and cholesterol,
smoking, high fat diet
Macroangiopathy
❏ accelerated atherosclerosis leading to coronary artery disease (CAD), stroke,
pulmonary vascular disease (PVD)
❏ most common cause of death in type 2 DM
Microangiopathy
❏ major chronic complication of type 1 and type 2 DM
❏ pathognomonic lesion is basement membrane thickening
❏ classically causes retinopathy, nephropathy and neuropathy
❏ can involve many other organs, including heart and skin
1. Retinopathy (see Ophthalmology Chapter)
❏ epidemiology
• present in 50% of patients after 10 years with DM
• one of the leading causes of blindness in North America
❏ types
• non-proliferative (background)
• generally no symptoms but may affect macula and impair vision
• microaneurysms, hard exudates, dot and blot hemorrhages
• pre-proliferative
• 10-40% progress to proliferative within one year
• macular edema, venous shunts and beading, nerve fibre layer microinfarcts (cotton wool spots)
• proliferative (see Color Atlas OP13)

• great risk for loss of vision
• neovascularization, fibrous scarring, vitreal detachment, retinal detachment
❏ presentation
• asymptomatic to complete loss of vision
❏ prevention and management
• tight glycemic control
• photocoagulation (eliminates neovascularization)
• vitrectomy
• frequent follow-up visits with an ophthalmologist (immediate
referral after diagnosis of type 2 DM; in type 1, only after 5 years of DM
2. Nephropathy (see Nephrology Chapter)
❏ epidemiology
• diabetes-induced renal failure is the most common cause of
renal failure in North America
• 20-40% of persons with type 1 DM (after 5-10 years) and 4-20% with
type 2 DM have progressive nephropathy
❏ presentation
• initial changes include microalbuminuria, increased glomerular filtration rate (GFR)
(up to 140%), enlarged kidneys
• over 15 years, progresses to cause hypertension, persistent proteinuria (macroalbuminuria),
nephrotic syndrome, renal failure
• tight glucose control
• tight blood pressure control – ACE inhibitors
(shown to reduce nephropathic complications) and calcium channel blockers (CCB)
• limit use of nephrotoxic drugs and dyes
• protein restriction (controversial)
3. Neuropathy (see Neurology Chapter)
❏ epidemiology
• common in both type 1 and type 2 DM
❏ pathophysiology
• metabolic defect thought to be due to increased sorbitol
and/or decreased myoinositol (exact mechanisms not understood)
❏ types
• distal symmetric “glove and stocking” polyneuropathy
• autonomic dysfunction (e.g. gastroparesis)
• mononeuropathy (e.g. carpal tunnel syndrome)
❏ presentation
• paresthesias or neuropathic pain
• motor or sensory deficits (including cranial nerves)
• orthostatic hypotension
• impotence
• voiding difficulties
• foot ulcers
• anti-depressants (e.g. amitriptyline), capsaicin, and anti-epileptics
(e.g. Tegretol, Neurontin) for painful neuropathic syndromes
• erythromycin and domperidone for gastroparesis
• foot care education
4. Other Complications
❏ skin disease (see Colour Atlas E5)
❏ bone and joint disease
❏ cataracts
TREATMENT OF DIABETES
❏ Diabetes Control and Complications Trial (DCCT) (1993) demonstrated a 50-70% decrease
in microvascular complications in type 1 DM in an intensively treated group
as compared to a conventionally treated group
❏ United Kingdom Prospective Diabetes Study (1998) demonstrated a
• decrease in diabetes complications in intensively treated
group compared to conventionally treated group
• marked decrease in vascular complications in those with
well-controlled blood pressure
Diet
❏ energy intake to achieve and maintain desirable weight
❏ other recommendations as per Canada's Food Guide
Lifestyle
❏ regular physical exercise can improve insulin sensitivity and lower lipid concentrations and blood pressure
❏ stop smoking and decrease alcohol consumption
Oral Hypoglycemic Agents (see Table 2)
❏ mainly for type 2 DM
Table 2. Oral Hypoglycemics

Medication Mechanism of Action Side Effects Contraindications
Sulfonylureas stimulate release of endogenous insulin hypoglycemia hepatic or renal
glyburide (Diabeta) nausea impairment
chlorpropamide (Diabinase) GI discomfort
Meglitimides stimulate release of endogenous insulin hypoglycemia hypersensitivity,
repaglinide (Gluconorm) (rapid-acting, better post-prandial glucose (less frequent than diabetic ketoacidosis (DKA)
control) with sulfonylureas)
Biguanides reduce gluconeogenesis, increase glucose lactic acidosis, hepatic or renal

metformin (Glucophage) utilization anorexia, nausea, impairment,
diarrhea, GI alcoholism,
discomfort advanced age
Thiazolidinediones increase peripheral insulin sensitivity, increased TG, liver disease,
rosiglitazone (Avandia) reduce gluconeogenesis weight gain, congestive heart failure (CHF)
pyoglitazone (Actos) hepatotoxicity,
anemia
α-Glucosidase decrease the absorption of flatulence, hypersensitivity, DKA,
Inhibitors carbohydrates (thus decreasing abdominal inflammatory bowel
acarbose (Prandase) postprandial rise of glucose) cramping, diarrhea disease (IBD)
Clinical Pearl
❏ Sulfonyureas and Meglitimides “squeeze” endogenous insulin from the pancreas.
❏ Biguanides and Thiazolidinediones act primarily in peripheral tissues remote from
the pancreas.
Insulin (see Table 3 and Figure 1)
❏ doses adjusted for individual patient needs to meet target glycemic control
❏ administration
• subcutaneous injections
• continuous subcutaneous insulin infusion pump
• IV infusion (regular insulin only)
❏ preparations
• ultra-rapid (Humalog)
• rapid or regular (R or Toronto)
• intermediate (N or NPH, L or Lente)
• long-acting (U or Ultralente)
❏ multiple daily injections of different types of insulin usually necessary for optimal glucose control
❏ estimate of total daily insulin requirement when starting an adult type 1 diabetes patient
on insulin = 0.5 - 0.6 units/kg
Table 3. Kinetics of Different Insulins
Insulin Duration Onset Peak Usual Effective Duration of
(hours) (hours) Action (hours)
Humalog (H) very short 5-10 min 30-40 min 2-3
Regular (R) short 1/2-1 1-3 5-7 (dose-dependent; may be longer)
NPH/lente (N) intermediate 2-4 6-10 14-18
Ultralente long 4-5 — 18-28
Humalog
activity regular
lente and NPH
ultralente
breakfast lunch dinner bed

Figure 1. Duration of Activity of Different Insulins
Glucose Monitoring
❏ frequent self-monitoring and recording of blood glucose is now standard management
❏ hemoglobin A1c (HbA1c or glycosylated hemoglobin)
• percentage indicates level of plasma glucose over past 3 months
• extremely useful for monitoring patient’s long-term diabetes control
• goal is to maintain HbA1c within 5-8% range (i.e. average blood glucose 5.0-11.0 mmol/L)
• HbA1c ≥ 10% indicates poor control
Variable Insulin Dose Schedule (“Sliding Scale”)
❏ patient takes fixed doses of intermediate-acting insulin (N) but varies doses of fast-acting
insulin (R or H) based on blood glucose reading at time of dose
❏ use baseline R or H dose when in blood glucose target range; add or subtract units when
above or below target
❏ allows patient to make corrections to avoid long periods of hyper- or hypoglycemia
Table 4. Sample Insulin Sliding Scale for Regimen of 3 Daily Injections

Blood Glucose Insulin (number of units)
(mmol/L)
Breakfast Supper Bed
R or H N R or H N
< 3.0 -2 -2
25 18
3.1-3.9 -1 -1
target range: 4.0-8.0 12 9
8.1-12.0 +1 +1
12.1-17.0 +2 +2
> 17.0 +3 +3
Insulin Pump Therapy

❏ external, battery-operated pump continuously delivers basal dose of
fast-acting insulin through small subcutaneous catheter
❏ at meals, patient programs pump to deliver extra insulin bolus
❏ basal dose may be increased or decreased based on activity, sleep, etc.
❏ advantages: more flexible lifestyle (sleep in, eat / skip meals when desired), better glucose control
❏ disadvantages: very expensive, increased risk of DKA if pump inadvertently disconnected,
frequent blood glucose testing required
DIABETIC KETOACIDOSIS (DKA)
Pathophysiology
❏ insulin deficiency combined with increased counter-regulatory hormones
i.e. glucagon, cortisol, growth hormone (GH), catecholamines
❏ clinically involves two factors: lack of insulin (non-compliance, inadequate dose,
initial presentation of DM) and/or precipitant (surgery, infection, emotional stress)
❏ unrestricted hepatic glucose production ––> extreme hyperglycemia
❏ lipolysis ––> free fatty acids (FFA) ––> ketoacids ––> acidosis
❏ osmotic diuresis causes dehydration and electrolyte abnormalities
Clinical Features
❏ typical patient: young type 1 DM
❏ presentation preceded by polyuria and polydipsia
❏ level of consciousness (LOC) may be decreased with high serum osmolality (> 330 mOsm/kg)
❏ dehydration and ketoacidosis
• anorexia, nausea, vomiting, fatigue
• abdominal pain (especially in children)
• fruity-smelling breath (due to acetone)
• Kussmaul’s respirations (rapid deep breathing)
Investigations and Laboratory Findings
❏ increased blood glucose (BG) (11 mmol/L to > 55 mmol/L), decreased Na, decreased HCO3, increased BUN
❏ also measure K+, urine glucose and ketones
❏ hyperglycemia and ketonemia
• ketones in range of 15 mmol/L
❏ wide anion gap metabolic acidosis (pH ≤ 7.3 and/or HCO3 ≤ 15) plus possible secondary respiratory
alkalosis due to Kussmaul’s respirations; can also have metabolic alkalosis from vomiting and dehydration
Treatment
❏ rapid diagnosis and close medical supervision are essential
❏ in general, monitor degree of ketoacidosis with anion gap, not blood glucose or ketone level
❏ rehydration
• critical in order to maintain adequate cardiac output and renal function
• bolus of NS initially followed by high rate NS infusion
• ~ 400 mEq Na+ is lost in the urine (osmotic diuresis, buffering of
ketone acid anions, hyperglucagonemia and hypoinsulinemia
leading to direct renal excretion)
❏ insulin
• initial bolus of 5-10 U (or 0.1 U/kg) IV in adults followed by
continuous infusion at 5-10 U (or 0.1 U/kg) per hour
• when blood glucose ≤ 15 mmol/L (270 mg/dL) add D5W
❏ potassium
• avoid hypokalemia
• K+ lost from cells due to insulin deficiency and general catabolic state
• blood levels do not reflect total body losses which may be 400-500 mEq
• K+ falls during treatment due to rehydration and insulin action (drives K+ into cells)
• normal or low K+ level initially indicates severe deficiency and requires cardiac monitoring
• replace as KCl
❏ bicarbonate
• avoid giving unless life-threatening situation and/or shock
❏ treatment of precipitating cause with patient education to prevent further episodes of DKA
❏ treat cerebral edema with mannitol
Prognosis
❏ 2-5% mortality in developed countries
❏ serious morbidity and mortality often result from
• sepsis
• pulmonary and cardiovascular complications
• thromboembolic complications
• cerebral edema
HYPEROSMOLAR NONKETOTIC HYPERGLYCEMIC SYNDROME
Pathophysiology
❏ usually complication of type 2 DM
❏ profound dehydration resulting from hyperglycemia
❏ precipitating events: infection, stroke, myocardial infarction, trauma, drugs
(glucocorticoids, immunosuppressives, diuretics), medical procedures (dialysis), burns
❏ reduced fluid intake, especially in elderly, bedridden patients
Clinical Features
❏ extreme hyperglycemia, hyperosmolality, volume depletion and CNS signs
Investigations and Lab Findings
❏ high urine glucose, negative or low ketones
❏ BG often > 55 mmol/L (1,000 mg/dL), but not a good indicator of severity
❏ urine negative for ketones; blood ketones reflect only starvation ketosis
❏ high serum osmolality
❏ electrolytes may show spurious hyponatremia (decrease in
3 mEq/L Na+ for every 10 mmol/L (180 mg/dL) increase in glucose)
❏ nonketotic mixed metabolic acidosis may be present due to other
acute underlying conditions (sepsis, renal failure, lactic acidosis)
Treatment
❏ rehydration with NS to restore intravascular volume, then 1/2 NS
❏ identify and treat precipitating cause(s)
❏ insulin (0.1 U/kg/hour) may or may not be necessary
❏ cerebral edema may result if osmolality is treated too aggressively
❏ overall mortality high (> 50%)
HYPOGLYCEMIA
Definition (Whipple’s Triad)
❏ serum glucose below a certain level (see below) PLUS
• neuroglycopenic symptoms OR
• adrenergic symptoms (autonomic response) PLUS
• relief provided by administration of glucose
❏ serum glucose at onset of symptoms
• < 2.5 mmol/L (45 mg/dL) in male patients
• < 2.2 mmol/L (40 mg/dL) in female patients
❏ occurs most often in insulin-treated diabetics, usually due to problems
with matching insulin dose to estimated blood glucose levels
Clinical Features of Hypoglycemia
❏ adrenergic symptoms (typically occur first)
• palpitations, sweating, anxiety, tremor, tachycardia, hunger
❏ neuroglycopenic symptoms
• dizziness, headache, clouding of vision, mental dullness,
fatigue, confusion, seizures, coma
Types of Hypoglycemia
1. Postprandial (Reactive) Hypoglycemia
❏ occurs 1.5-6 hours after a meal and recovers spontaneously
❏ manifested primarily as adrenergic symptoms due to autonomic discharge
❏ thought to be over-diagnosed and over-treated
❏ etiology
• alimentary hyperinsulinism
• post-GI surgery (gastrectomy, pyloroplasty, vagotomy)
• may also be induced by galactosemia and fructose intolerance
❏ treatment
• frequent, small feeds
• weight loss
2. Fasting Hypoglycemia
❏ imbalance between production of glucose by liver and utilization
in peripheral tissues
❏ etiology
• defective gluconeogenesis with inability to maintain
glucose concentration if food is withheld
• hormone deficiencies (hypopituitarism, adrenal
insufficiency, inadequate catecholamines or glucagon)
• enzyme defects
• substrate deficiency
• liver disease (cirrhosis, uremia)
• drugs (ethanol, propranolol, salicylates)
• excessive utilization of glucose
• hyperinsulinism (insulinoma, sulfonylurea,
exogenous insulin, sepsis)
• appropriate insulin levels (extrapancreatic tumours)
❏ treat underlying cause
SYNDROME X - INSULIN RESISTANCE SYNDROME
❏ postulated syndrome related to insulin resistance
• association between hyperglycemia, hyperinsulinemia,
hypertension, central obesity, and dyslipidemia
(elevated LDL, VLDL and TG and reduced HDL)
❏ obesity aggravates extent of insulin resistance
❏ complications include atherosclerosis, coronary artery disease (CAD), stroke and MI
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
- 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)
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)
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
Investigations
❏ laboratory
❏ imaging
• metastases
Complications
❏ fractures
• 1-3%
❏ osteoarthritis
Treatment
❏ calcitonin

Androgen Regulation
❏ semen analysis
• semen volume
HYPOGONADISM
Etiology
❏ congenital
• cryptorchidism
MALE REPRODUCTIVE ENDOCRINOLOGY . . . CONT.
❏ germ cell defects

• Sertoli cell only syndrome (arrest of sperm development)
• Leydig cell aplasia/failure
❏ inflammation
• orchitis – mumps, tuberculosis, lymphoma, leprosy
• genital tract infection
❏ physical factors
• trauma, heat, irradiation
❏ drugs
• marijuana, alcohol, chemotherapeutic agents
❏ myotonic dystrophy
❏ defects in androgen biosynthesis
❏ idiopathic
2. Hypogonadotropic Hypogonadism (Hypothalamic Pituitary Failure)
❏ characterized by decreased or normal LH
❏ congenital
• Kallman’s syndrome, Prader-Willi syndrome
❏ constitutional delay
❏ endocrine
• Cushing’s syndrome
• hypothyroidism
• hypopituitarism (pituitary tumours, hypothalamic lesions, hemochromatosis)
• estrogen-secreting tumours (testicular, adrenal)
❏ drugs
• alcohol
• marijuana
• spironolactone
• ketoconazole
• GnRH agonists
• prior androgen use
❏ chronic illness
❏ malnutrition
❏ idiopathic
3. Defects in Androgen Action
❏ complete androgen insensitivity (testicular femininization)
❏ incomplete androgen insensitivity
• 5-α-reductase deficiency
Clinical Presentation
❏ depends on age of onset
❏ fetal life
• ambiguous genitalia and male pseudohermaphroditism
❏ prepubertal
• poor secondary sexual development, poor muscle development
• eunuchoid skeletal proportions (upper/lower segment ratio < 1; arm span/height ratio > 1)
❏ postpubertal
• decreased libido, erectile dysfunction, infertility
• decreased facial and body hair if very significant androgen
deficiency (very low levels required to maintain sexual hair)
• fine wrinkles in the corners of mouth and eyes
• osteoporosis with longstanding hypogonadism
Treatment
❏ consider testosterone replacement
INFERTILITY (see Urology Chapter)
ERECTILE DYSFUNCTION (see Urology Chapter)
GYNECOMASTIA
❏ proliferation of the glandular component of the male breast
❏ estrogen/androgen imbalance - increased estrogen/androgen ratio
Etiology
❏ physiologic
• neonatal (maternal hormone)
• puberty
• aging
❏ pathologic
• endocrinopathies - primary hypogonadism, hyperthyroidism
extreme hyperprolactinemia, adrenal disease
• tumours - pituitary, adrenal, testicular, breast
• chronic diseases - liver, renal, malnutrition, etc.
• drugs - spironolactone, cimetidine, digoxin, chemotherapy, marijuana
• congenital/genetic - Klinefelter’s syndrome
• other - idiopathic, familial
Investigations
❏ history
• age, onset, duration, pain, family history, chronic diseases, drugs
❏ physical examination
• general health, feminization
• breast, thyroid, adrenal, liver, testicular exams
❏ investigations
• laboratory - serum TSH, PRL, LH, FSH, free testosterone, estradiol, LFTs
• CXR to rule out tumour
• testicular U/S to rule out testicular mass
Treatment
❏ medical
• correct the underlying disorder, discontinue responsible drug
• androgens for hypogonadism
• anti-estrogens - tamoxifen, clomiphene
❏ surgical
• usually required if gynecomastia present for > 1 year
• reduction mammoplasty
REFERENCES
Dayan CM. (2001). Interpretation of thyroid function tests. Lancet 357: 619-24.
DCCT Research Group. (1993). The Diabetes Control and Complications Trial (DCCT). The Effect of Intensive Treatment of
Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N Engl J
Med 329: 977-986.
Defronzo R. (1999). Pharmacologic Therapy for Type 2 Diabetes Mellitus. An Int Med 131(4): 281-303.
Fodor JG et al. (2000). Recommendations for the Management and Treatment of Dyslipidemia. CMAJ 162(10): 1441-1447.
Meltzer S et al. (1998). Clinical Practice Guidelines for the Management of Diabetes in Canada. CMAJ 159 (8 Suppl).
NIH Consensus Conference. (2001). Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785-795.
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)
PITUITARY GLAND
Hypothalamic Control of Pituitary
❏ trophic and inhibitory factors control the release of pituitary hormones
❏ most hormones are primarily under trophic stimulation except
prolactin which is primarily under inhibitory control
❏ transection of the pituitary stalk (i.e. dissociation of hypothalamus and pituitary) leads to
pituitary hypersecretion of prolactin and hyposecretion of all remaining hormones
Anterior Pituitary Hormones
❏ growth hormone (GH), leutenizing hormone (LH), follicle stimulating hormone (FSH),
thyroid stimulating hormone (TSH), adrenocorticopin hormone (ACTH), prolactin (PRL)
Posterior Pituitary (Hypothalamic) Hormones
❏ antidiuretic hormone (ADH) and oxytocin
❏ peptides synthesized in the supraoptic and paraventricular nuclei of the hypothalamus
❏ stored in and released from the posterior pituitary
Table 10. The Pituitary Hormones

Hormone Inhibitory Stimulus Secretory Stimulus
PRL • dopamine • dopamine antagonists
• D2-receptor agonists • thyroid releasing hormone (TRH)
(bromocriptine)
ACTH • dexamethasone • cortisol releasing hormone (CRH)

• cortisol • metyrapone
(11-ß-hydroxylase inhibitor)
• insulin-induced hypoglycemia
• fever, pain
TSH • circulating thyroid hormones • TRH
GH • glucose challenge • insulin-induced hypoglycemia
• somatostatin • exercise, REM sleep
• dopamine agonists • arginine, clonidine,
• insulin like growth factor propranolol, L-dopa
(IGF)-1 • growth hormone releasing hormone (GHRH)
LH/FSH • estrogen • GnRH in boluses
• testosterone
• continuous GnRH infusion
ADH • decreased serum osmolality • increased serum osmolality
• hypovolemia
• stress, fever, pain
Oxytocin • EtOH • suckling

• distention of female genital tract
GROWTH HORMONE (GH)

❏ polypeptide, secreted in bursts
Physiology
❏ serum GH undetectable much of the day, suppressed after meals
that are high in glucose content, sustained rise during sleep
❏ necessary for normal linear growth
❏ acts indirectly through serum factors synthesized in liver
• insulin-like growth factors (IGF)
• previously known as “somatomedins”
❏ IGF shares some insulin-like actions and thus stimulates growth of bone and cartilage
Regulation
❏ stimulated by GHRH, sleep, exercise, insulin, hypoglycemia, arginine, L-dopa, propranolol, clonidine
❏ inhibited by somatostatin, glucocorticoids, hyperglycemia, hypothyroidism
❏ “long loop” negative feedback by IGF-1 (somatomedin C)
Pathology
❏ decreased GH
• not very significant in adults but important in children (see Pediatrics Chapter)
• treatment: recombinant human growth hormone
❏ increased GH
• hypersecretion causes gigantism in children, acromegaly in adults
• clinically seen as thickened soft tissues (palms, heels), sweating,
large bones, coarse features, diabetes, carpal tunnel syndrome,
osteoarthritis, hypertension, and increased risk of colon cancer
• definitive diagnosis: increase in GH with oral glucose tolerance test (OGTT)
• causes
• pituitary adenomas most common
• occasionally pituitary adenoma produces both prolactin and GH
• rarely carcinoid tumours and pancreatic islet tumours make GHRH
• treatment: surgery, radiation, bromocriptine (dopamine agonist),
octreotide (somatostatin analogue)
PROLACTIN (PRL)
❏ polypeptide
Physiology
❏ promotes milk production
❏ antagonizes sex steroids peripherally
Regulation
❏ stimulation
• physiologic: sleep, stress, pregnancy, hypoglycemia,
mid-menstrual cycle, breast feeding, TRH, sexual activity
• pharmacologic: psychotropics (e.g. haloperidol, risperidone),
antihypertensives (e.g. reserpine, verapamil), α-methyldopa, opiates,
high-dose estrogens, metoclopramide, domperidone, cimetidine
• pathologic
• various hypothalamic-pituitary causes (e.g. pituitary microadenoma,
pituitary stalk transection)
• primary hypothyroidism (increased TRH)
• chronic renal failure (secondary to reduced clearance)
• liver cirrhosis
❏ inhibition
• physiologic: tonic inhibition by dopamine
• pharmacologic: dopamine agonists (e.g. bromocriptine)
Pathology
❏ hypoprolactinemia
• inability to lactate
• may be the first sign of Sheehan’s syndrome (postpartum pituitary hemorrhage)
(see Obstetrics Chapter)
❏ hyperprolactinemia
• galactorrhea, infertility, hypogonadism (women and men)
• serum prolactin levels > 300 µg/L (300 ng/mL) virtually diagnostic of prolactinoma
• prolactin-secreting tumours may be induced by estrogens and may grow during pregnancy
• treatment includes bromocriptine or carbegoline (long-acting dopamine agonist),
surgery +/– radiation
• these tumours are very slow-growing and sometimes require no treatment
LEUTINIZING HORMONE (LH) AND FOLLICLE STIMULATING HORMONE (FSH)
❏ glycoproteins with same α subunit as TSH and hCG
❏ possibly secreted by the same cells (gonadotrophs)
Physiology
❏ both released in pulsatile fashion, but FSH has a longer half-life (3-4 hours vs. 50 minutes for LH)
and thus fluctuates less throughout the day
❏ gonadotropins: stimulate gonads (ovaries and testicles) via cAMP
❏ in the ovary
• LH stimulates ovarian theca cells to produce androgens (which are subsequently converted
to estrogens in granulosa cells) and induces luteinization in ovarian follicles
• FSH stimulates growth of granulosa cells in ovarian follicle and controls estrogen formation
❏ in the testis
• LH controls testicular production of testosterone in Leydig cells
• FSH, together with intra-testicular testosterone, stimulates Sertoli cells tubules to produce sperm
Regulation
❏ GnRH stimulates both FSH and LH
❏ inhibition
• female: estrogen and progesterone
• male: testosterone and inhibin
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
Implicated
CALCIUM DISORDERS
10
❏ major actions
Vitamin D
(relatively inert)
❏ major actions
PITUITARY DYSFUNCTION
Hyperpituitarism:
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
o SIADH (Syndrome of Inappropriate ADH Secretion):
Hypopituitarism:
o Sheehan Di ea e AKA Postpartum Hypopituitarism (Pituitary Infarction):
o Diabetes Insipidus:
PITUITARY GLAND

(bromocriptine)

• fever, pain
• testosterone
• hypovolemia

GROWTH HORMONE (GH)

Physiology
Regulation
Pathology
❏ decreased GH
❏ increased GH
• causes
PROLACTIN (PRL)
❏ polypeptide
Physiology
Regulation
❏ stimulation
• pathologic
• liver cirrhosis
❏ inhibition
Pathology
Physiology
❏ in the ovary
❏ in the testis
Regulation
❏ inhibition
Pathology
• hypogonadism
• amenorrhea
• impotence
• fine skin
Physiology
Regulation
Pathology
❏ diagnosis
❏ treatment
❏ causes
❏ diagnosis
❏ treatment
Physiology
Regulation
PITUITARY PATHOLOGY
Pituitary Adenoma (see Colour Atlas NS18)
❏ related to size and location
• visual field defects (usually bitemporal hemianopsia),
oculomotor palsies, increased ICP (may have headaches)
• skull radiograph: “double floor” (large sella or erosion), calcification
• CT and MRI far more sensitive for diagnosis
❏ related to destruction of gland
• hypopituitarism
❏ related to increased hormone secretion
• PRL
• prolactinoma is most common pituitary tumour
• galactorrhea
• GH
• acromegaly in adults (see Colour Atlas E4), gigantism in children
• ACTH
• Cushing’s disease = Cushing’s syndrome caused by a pituitary tumour
• tumours secreting LH, FSH and TSH are rare
Craniopharyngioma (see Pediatrics Chapter)
Empty Sella Syndrome
❏ sella turcica appears enlarged on x-ray because pituitary gland is distorted
❏ generally eupituitary - no treatment necessary
Pituitary Apoplexy
❏ acute hemorrhage/infarction of pituitary tumour
❏ sudden severe headache
❏ altered LOC
❏ ocular symptoms
❏ note: ophthalmoplegia with pituitary tumour likely indicates apoplexy
since tumour rarely gets big enough to encroach on cranial nerves
❏ neurosurgical emergency: acute decompression of pituitary via
trans-sphenoidal route
Clinical Pearl
GH, LH, FSH, TSH, ACTH, PRL
❏ A compressive adenoma in the pituitary will impair hormone production in this order
(i.e. GH-secreting cells are most sensitive to compression)
❏ Mnemonic: “Go Look For The Adenoma Please”
HYPOPITUITARISM
Etiology
❏ Mnemonic: eight “I”s
• Invasive: generally primary tumours
• Infarction: e.g. Sheehan’s syndrome
• Infiltrative disease e.g. sarcoidosis, hemochromatosis, histiocytosis
• Iatrogenic: following surgery or radiation
• Infectious: e.g. syphilis, TB
• Injury: severe head trauma
• Immunologic: autoimmune destruction
• Idiopathic: familial forms, congenital midline defects
Clinical Features
❏ typical clinical progression in panhypopituitarism
• fall in GH, clinically not apparent
• fall in PRL is variable, but may present as decreased lactation
• gonadotropin insufficiency then causes erectile dysfunction in men,
and amenorrhea or infertility in women
• TSH deficiency produces clinical hypothyroidism
• ACTH deficiency leads to adrenal insufficiency
Diagnosis by Triple Bolus Test
❏ stimulates release of all anterior pituitary hormones in normal individuals
❏ rapid sequence IV infusion of insulin, LHRH and TRH
❏ insulin ––> hypoglycemia ––> increased GH and ACTH
❏ LHRH ––> increased LH and FSH
❏ TRH ––> increased TSH and PRL
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.
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
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
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
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
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)
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)
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.
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
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)
o Massive Goitre
o Most Pts are Euthyroid
- Complications:
o Toxic Adenoma/Toxic Nodule.
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)
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.
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:
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
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)
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.
- 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
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:
THYROID
THYROID STIMULATING HORMONE (TSH)
❏ glycoprotein
❏ α subunit similar to those in FSH, LH, hCG, but all have unique ß subunits
❏ stimulates growth of thyroid and secretion of T4 and T3 via cAMP
❏ regulation
• stimulated by hypothalamic TRH
• inhibited by circulating T4, intrapituitary T3, opiates, dopamine
THYROID HORMONES
Biochemistry
❏ free T4 (0.03%) and free T3 (0.3%) represent the hormonally active fraction
• the remainder is hormonally inactive, mainly bound to thyroxine binding globulin (TBG) and albumin
❏ T3 is more biologically active than T4
❏ some T4 is converted to T3 in peripheral tissues by 5’-deiodinase
❏ metabolized by most tissues; metabolites reach liver and are excreted in bile
Regulation of Thyroid Function
❏ extrathyroid
• stimulation of thyroid by TSH, epinephrine, prostaglandins (cAMP stimulators)
❏ intrathyroid (autoregulation)
• response to iodide - with increasing iodide supply, inhibition of iodide organification occurs,
thus decreasing T3 and T4 synthesis (Wolff-Chaikoff effect)
• varying thyroid sensitivity to TSH in response to iodide availability
• increased ratio of T3 to T4 in iodide deficiency
TESTS OF THYROID FUNCTION AND STRUCTURE
Circulating Thyroid Hormones
❏ total T3 and T4 levels depend on amount of thyroid binding globulin (TBG)
❏ TBG increases with: pregnancy, oral contraceptive (OCP) use, acute infectious hepatitis, biliary cirrhosis
❏ TBG decreases with: androgens, glucocorticoids, cirrhosis, hyponatremia,
phenytoin, ASA, NSAIDS, nephrotic syndrome, severe systemic illness
❏ standard assessment of thyroid function includes TSH and if necessary, free T4 and free T3
TSH
❏ sensitive TSH (sTSH) is the single best test for assessing thyroid function
❏ hyperthyroidism
• primary: TSH is low and does not rise in response to TRH because
of negative feedback from increased levels of circulating T3 and T4
• secondary: increased TSH
❏ hypothyroidism
• primary: increased TSH (most sensitive test) because of less
negative feedback from T3 and T4
• secondary: TSH is low with variable response to TRH
depending on the site of the lesion (pituitary or hypothalamic)
Iodine Kinetics
❏ an index of thyroid function
❏ radioactive iodine uptake (RAIU) is high in Graves’ disease and low in subacute thyroiditis
Effects of Thyroid Hormones on Peripheral Tissues
❏ sex hormone binding globulin (non-specific)
• liver increases production in hyperthyroidism; decreases production in hypothyroidism
❏ pre-ejection period/ left ventricular ejection time is a measure of the effect of thyroid hormones
on the heart
❏ basal metabolic rate (BMR)
Thyroid Assessment (see Otolaryngology Chapter)
❏ normal gland size 15-20 g (estimated by palpation)
❏ thyroid U/S to detect size of gland, solid vs. cystic nodule
❏ fine needle aspiration for cytology
❏ thyroid scan (Technetium99)
• for hot vs. cold nodules
• to distinguish between three major types of high-uptake hyperthyroidism
• Graves’ disease (diffuse uptake)
• toxic multinodular goiter (multiple discrete areas)
• solid toxic adenoma (single intense area of uptake)
Miscellaneous Tests
❏ thyroid antibodies
• antithyroglobulin antibodies, microsomal antibodies
• increased in Hashimoto’s disease
❏ TSH receptor antibodies
• thyroid stimulating immunoglobulin (TSI) or TSAb
• increased in Graves’ disease
THYROID . . . CONT.
❏ plasma thyroglobulin level

• used to monitor thyroid carcinoma activity
• undetectable levels = remission
• normal or elevated levels = probable, persistent, recurrent, or metastatic disease
❏ serum calcitonin
• not routinely done to investigate most thyroid nodules
• ordered if suspicious of medullary thyroid carcinoma
HYPERTHYROIDISM
❏ hyperthyroidism: excess production of thyroid hormone
❏ thyrotoxicosis: denotes clinical, physiological and biochemical
findings in response to elevated thyroid hormone
Table 11. Differential Diagnosis of Hyperthyroidism

Disorder/Disease Investigations
TSH T4/T3 Thyroid antibodies RAIU Other
1. Graves’ Disease decreased increased TSI Abs increased
2. Toxic Nodular Goitre decreased increased none increased
3. Toxic Nodule decreased increased none increased
4. Thyroiditis ESR increased

a) classical subacute thyroiditis decreased increased up to 50% of time decreased in
b) silent thyroiditis classical
c) post-partum thyroiditis SAT
5. McCune-Albright decreased increased none

Syndrome
6. Jod Basedow decreased increased none decreased

(iodine-induced)
7. Extra-thyroidal Sources
of Thyroid Hormone
a) endogenous
(struma ovariae, ovarian decreased increased none decreased
teratoma metastases from
follicular carcinoma)
b) exogenous (drugs)
8. Excessive Thyroid
Stimulation
a) pituitary thyrotrophoma increased increased none increased
b) pituitary thyroid hormone increased increased none increased
receptor resistance
c)8hCG (e.g. molar pregnancy) decreased increased none increased
Clinical Features
❏ GENERAL: fatigue, heat intolerance, irritability, fine tremor
❏ CVS: tachycardia, atrial fibrillation, palpitations
• elderly patients may have only CVS symptoms, commonly new onset atrial fibrillation
❏ GI: weight loss with increased appetite, thirst, increased frequency of bowel movements (hyperdefecation)
❏ NEUROLOGY: proximal muscle weakness, hypokalemic periodic paralysis (patients of Oriental origin)
❏ GU: scant menses, decreased fertility
❏ DERMATOLOGY: fine hair, skin moist and warm, vitiligo, soft nails with onycholysis (“Plummer’s nails”)
❏ MUSCULOSKELETAL (rare): decreased bone mass, hypercalcemia
❏ HEMATOLOGY: leukopenia, lymphocytosis, splenomegaly, lymphadenopathy
(occasionally in Graves’ disease)
A. GRAVES’ DISEASE (see Colour Atlas E2)

❏ triad of hyperthyroidism with diffuse goiter, ophthalmopathy, dermopathy (need not appear together)
THYROID . . . CONT.
Epidemiology
❏ relatively common, occurs at any age with peak in 3rd and 4th decade
❏ runs in families
❏ F>M
❏ association with HLA B8 and DR3
❏ may be associated with other autoimmune disorders in family
(e.g. pernicious anemia, Hashimoto’s disease)
Etiology and Pathogenesis
❏ autoimmune disorder due to a defect in T-suppressor cells
❏ B-lymphocytes produce thyroid stimulating immunoglobulins (TSI)
directed against TSH receptor that mediate thyroid stimulation
❏ cause of ophthalmopathy uncertain
• antibodies against extraocular muscle antigens (fibroblasts implicated) with lymphocytic infiltration
• glycosaminoglycan deposition
❏ dermopathy may be related to cutaneous glycosaminoglycan deposition
• pretibial myxedema (see Colour Atlas E3)
Additional Clinical Features
❏ diffuse goiter +/– bruit
❏ ophthalmopathy: proptosis, lid lag, lid retraction, diplopia, characteristic stare, conjunctival injection
❏ dermopathy (rare): pretibial myxedema (thickening of dermis)
❏ acropachy: clubbing and thickening of distal phalanges
Diagnosis
❏ increased free T4 (and/or increased T3)
❏ positive for TSI
❏ TRH stimulation test (flat TSH response) is diagnostic if sTSH and free T4 are inconclusive
Treatment
❏ propylthiouracil (PTU) or methimazole (MMI)
• inhibit thyroid hormone synthesis
• major side effects: rash, hepatitis and agranulocytosis
❏ symptomatic treatment with ß-adrenergic antagonists
❏ thyroid ablation with radioactive 131I if PTU or MMI trial does not produce disease remission
❏ subtotal thyroidectomy (indicated rarely for large goitres)
• risks include hypoparathyroidism and vocal cord palsy
❏ both MMI and 131I are contraindicated in pregnancy
❏ 1/3 of cases achieve long-term remission on drug therapy alone
❏ small goitre and recent onset are good indicators for long-term remission with medical therapy
❏ high incidence of hypothyroidism after 131I, requiring lifelong thyroid hormone replacement
❏ ophthalmopathy: prevent drying
• high dose prednisone in severe cases
• orbital radiation, surgical decompression
• note that PTU or MMI may worsen ophthalmopathy
B. SUBACUTE THYROIDITIS (Thyrotoxic Phase)
❏ acute inflammation of the thyroid, probably viral in origin, characterized by giant cells and lymphocytes
❏ often preceded by upper respiratory tract infection (URTI)
❏ disruption of thyroid follicles by inflammatory process results in the release of stored hormone
Clinical Features
❏ begins with fever, malaise, soreness in neck
❏ gland becomes enlarged
❏ two forms
• painful (“DeQuervain’s”) thyroid, ears, jaw and occiput
• painless (“Silent”)
❏ usually transient thyrotoxicosis with a subsequent hypothyroidism phase due to depletion of stored
hormone, finally resolving in a euthyroid state over a period of months
Laboratory
❏ elevated T4, T3
❏ radioactive iodine uptake (RAIU) markedly reduced
❏ marked elevation of ESR in painful variety only
❏ as disease progresses, values consistent with hypothyroidism may appear;
rise in RAIU reflects gland recovery
Treatment
❏ ASA can be used for painful form (increases peripheral conversion)
❏ prednisone may be required for severe pain, fever, or malaise
❏ ß-adrenergic blockade is usually effective in reversing most of the hypermetabolic and cardiac symptoms
❏ if symptomatically hypothyroid may treat short-term with thyroxine
THYROID . . . CONT.
Prognosis
❏ full recovery in most cases, but permanent hypothyroidism in 10% of painless thyroiditis
C. TOXIC MULTINODULAR GOITRE
❏ autonomous thyroid hormone production, may arise from a nodule in a nontoxic multinodular goitre
❏ may be singular or multiple
❏ multinodular goitre also known as Plummer’s Disease
Clinical Features
❏ goitre with adenomatous changes
❏ occurs more frequently in elderly people
❏ atrial fibrillation is a common presentation in the elderly
Diagnosis
❏ thyroid scan with increased uptake in nodule(s), and suppression of the
remainder of the gland
Treatment
❏ initiate therapy with antithyroid medications to attain euthyroid state in
order to avoid radiation thyroiditis
❏ then use high dose radioactive iodine to ablate tissue over weeks
❏ propranolol often necessary for symptomatic treatment prior to definitive therapy
(works by blocking the peripheral action of T3 and T4)
D. POSTPARTUM THYROIDITIS
❏ a type of painless thyroiditis
❏ autoimmune-mediated
❏ occurs in 5-10% of postpartum mothers, one-third of whom develops symptoms
❏ typical presentation includes thyrotoxicosis 2-3 months postpartum with a hypothyroid phase
at 4-8 months; usually resolves spontaneously without need for supplementation
❏ may be mistakenly diagnosed as postpartum depression
❏ may recur with subsequent pregnancies
❏ treat as per painless subacute thyroiditis
E. THYROTOXIC STORM
❏ a severe state of uncontrolled hyperthyroidism, extreme fever,
tachycardia, vomiting, diarrhea, vascular collapse and confusion
❏ often precipitated by infection, trauma, or surgery in hyperthyroid patient
❏ sepsis
❏ pheochromocytoma
❏ malignant hyperthermia
Clinical Features
❏ hyperthyroidism
❏ hyperthermia, often with dry skin
❏ arrhythmia ––> congestive heart failure , pulmonary edema
❏ mental status changes ranging from delirium to coma
Laboratory Findings
❏ increased T3, T4, undetectable TSH
❏ +/– anemia, leukocytosis, hypercalcemia, elevated LFTs
Treatment
❏ initiate prompt therapy; don’t wait for confirmation from lab
❏ fluid and electrolyte maintenance, vasopressors as indicated
❏ cooling blanket, acetaminophen for pyrexia
❏ inderal (decreases peripheral conversion of T4 to T3) but watch for CHF
❏ high dose PTU
❏ iodide (NaI, KI, Lugol’s solution) to inhibit release of thyroid hormone
❏ dexamethasone to block peripheral conversion and to lower body temperature
❏ treat precipitant
Prognosis
❏ 50% mortality rate
HYPOTHYROIDISM
Epidemiology
❏ 2-3% of general population
❏ F:M = 10:1
❏ 10-20% of women over age 50 have subclinical hypothyroidism (normal T4, TSH mildly elevated)
THYROID . . . CONT.
❏ primary thyroid disease (90%)
• iatrogenic: post-ablative (131I or surgical thyroidectomy)
• autoimmune: Hashimoto’s thyroiditis
• hypothyroid phase of subacute thyroiditis
• drugs: goitrogens (iodine), PTU, MMI, lithium
• infiltrative disease (progressive systemic sclerosis, amyloid)
• iodine deficiency
• congenital (1/4,000 births)
❏ pituitary hypothyroidism
• insufficiency of pituitary TSH
❏ hypothalamic hypothyroidism
• decreased TRH from hypothalamus (rare)
❏ peripheral tissue resistance to thyroid hormone
• rare
Clinical Features
❏ GENERAL: fatigue, cold intolerance, slowing of mental and physical performance, hoarseness,
enlarged tongue
❏ CVS: slow pulse, generalized atherosclerosis (increased serum cholesterol and triglycerides),
pericardial effusion
❏ GI: anorexia, weight gain, constipation, poor appetite
❏ NEUROLOGY: paresthesia, slow speech, muscle cramps, delay in relaxation phase of
deep tendon reflexes (“hung reflexes”)
❏ GU: menorrhagia, amenorrhea, anovulatory cycles
❏ DERMATOLOGY: puffiness of face, periorbital edema, cool, dry and rough skin, hair dry and coarse,
eyebrows thinned (lateral 1/3)
❏ HEMATOLOGY: anemia
Laboratory
❏ sensitive TSH (sTSH) is the most sensitive test for primary hypothyroidism
❏ must measure TSH to rule out secondary or tertiary causes
Treatment
❏ L-thyroxine (dose range usually 0.05 to 0.2 mg/day)
❏ elderly patients and those with CAD: start at 0.025 mg daily and increase gradually
❏ monitor sTSH
❏ at the optimal replacement dosage, TSH is in the middle of its normal range;
can also monitor free T4, particularly in pituitary hypothyroidism
A. CONGENITAL HYPOTHYROIDISM (see Pediatrics Chapter)
B. HASHIMOTO’S THYROIDITIS
❏ two variants
• goitrous: presents with a euthyroid or hypothyroid goitre
• atrophic: presents initially with hypothyroid state and atrophic gland
Etiology and Epidemiology
❏ defect in clone of T-suppressors leads to cell-mediated destruction of thyroid follicles
❏ B-lymphocytes produce antithyroglobulin antibody and antithyroid peroxidase
(anti-TPO or antimicrosomal antibody)
❏ associated with HLA B8 and DR3, and other autoimmune diseases
(e.g. Sjögren’s syndrome, SLE, RA, pernicious anemia, adrenal insufficiency)
❏ more common in females of middle age and is the most common cause of sporadic goiter in children
Clinical Features
❏ goitrous variant usually presents with a rubbery goitre and euthyroidism,
then hypothyroidism becomes evident
❏ atrophic variant patients are hypothyroid from the start
❏ association with thyroid lymphoma
Laboratory Findings
❏ thyroid function test reveals hypothyroidism, or a euthyroid state with a compensatory increase
in TSH; followed by decreased free T4 and eventually decreased free T3
❏ antimicrosomal and anti-thyroglobulin antibodies
Treatment
❏ if hypothyroid, replace with L-thyroxine
❏ if euthyroid, also treat with L-thyroxine if significant anti-thyroid antibody present
C. RIEDEL’S STRUMA
❏ rare type of chronic thyroiditis
❏ fibrotic inflammatory process that extends from the thyroid into surrounding tissues
THYROID . . . CONT.
Clinical Features
❏ ill-defined, firm mass with possible compressive symptoms of dysphagia, stridor, hoarseness, pain
❏ chief importance is differentiation from malignancy
Treatment
❏ surgical wedge resection of the isthmus (to prevent tracheal compression)
D. MYXEDEMA COMA
❏ most severe complication of hypothyroidism
❏ generally seen in patients with longstanding unrecognized hypothyroidism
and associated with a precipitating event (infection, surgery, MI, CHF)
Clinical Features
❏ hypothyroidism, stupor, hypoventilation, hypothermia, bradycardia, hypertension
Laboratory Findings
❏ decreased T3 and T4, increased TSH, decreased glucose
❏ check ACTH and cortisol for evidence of adrenal insufficiency
Treatment
❏ ABCs
❏ no active re-warming, but avoid cooling
❏ NG tube (since ileus often present)
❏ corticosteroids (due to the possibility of concomitant adrenal insufficiency)
❏ L-thyroxine 0.2-0.5 mg IV loading dose, then 0.1 mg IV OD until oral therapy tolerated
❏ monitor in ICU setting
E. SICK EUTHYROID SYNDROME (SES)
❏ serious illness, trauma, or stress can induce changes in circulating levels
of thyroid hormones
❏ not due to intrinsic thyroid or pituitary disease
❏ the abnormalities in SES include alterations in
• peripheral transport and metabolism of thyroid hormone
• regulation of TSH secretion
• thyroid function itself
❏ several variants exist
❏ normal-T4 variant
• characterized by low T3, normal T4
• proposed mechanism involves inhibition of peripheral 5’ monodeiodination of T4 to T3
• differentiated from primary hypothyroidism by a normal TSH
❏ low-T4 variant
• characterized by low T3, low T4
• low T4 likely due to inhibited T4 binding to serum proteins and accelerated
metabolic clearance
• differentiated from primary hypothyroidism with normal or low TSH
• poorer prognosis
❏ treat the underlying disease
❏ thyroid hormone replacement worsens the outcome
NON-TOXIC GOITRE
❏ generalized enlargement of the thyroid gland in a euthyroid individual
that does not result from inflammatory or neoplastic processes
❏ appearance of a goitre is more likely during adolescence, pregnancy,
and lactation because of increased thyroid hormone requirements
• early stages: goitre is usually diffuse
• later stages: multinodular nontoxic goitre with nodule, cyst formation
and areas of ischemia, hemorrhage, and fibrosis
Etiology
❏ iodine deficiency or excess
❏ goitrogens: brassica vegetables (turnip, cassava)
❏ drugs: iodine, lithium, para-aminosalicylic acid
❏ any disorder of hormone synthesis with compensatory growth
❏ peripheral resistance to thyroid hormone
Complications
❏ compression of neck structures, causing stridor, dysphagia, pain, and hoarseness
❏ multinodular goitre may become autonomous leading to toxic multinodular goitre and hyperthyroidism
THYROID . . . CONT.
Treatment
❏ remove goitrogens
❏ suppression with L-thyroxine may be effective in any TSH-dependent goitre
❏ surgery may be necessary for severe compressive symptoms
THYROID NODULES (see Otolaryngology Chapter)
❏ clearly defined discrete mass, separated from the thyroid parenchyma
Etiology
❏ benign tumours (e.g. follicular adenoma)
❏ thyroid malignancy
❏ hyperplastic area in a multinodular goitre
❏ cyst: true thyroid cyst, area of cystic degeneration in a multinodular goitre
Investigations
❏ fine needle aspiration (FNA)
• useful only if positive for malignancy (specific, not sensitive)
❏ thyroid function tests
❏ thyroid scan
• 15-20% of cold nodules (minimal 131I uptake into nodule) are malignant, very low
malignant potential if warm or hot (significant 131I uptake into nodule)
TSH
Detectable Undetectable
- observe if euthyroid
- RAI or surgery if hyperthyroid
Fine Needle Aspiration Biopsy
(FNA)
Benign Inconclusive Malignant
trial of L-thyroxine repeat FNA surgery ± adjuvant

suppression x 6mos therapy
smaller larger still inconclusive:

trial of L-thyroxine
suppression
observe surgery
smaller unchanged larger
observe repeat FNA surgery

Figure 3. Workup of Thyroid Nodule
THYROID MALIGNANCIES
Risk Factors
❏ history
• head or neck irradiation especially during childhood (e.g. acne therapy)
• family history (especially of medullary carcinoma)
• rapid growth (and failure to shrink on L-thyroxine)
• onset < 30 years of age
• male gender (thyroid nodules more common in females, malignancy more common in males)
• compressive symptoms (e.g. pain, dysphagia, stridor, hoarseness)
• cervical lymphadenopathy
• nodule in patient with Hashimoto’s (must rule out lymphoma)
• solitary nodule
• hardness and irregularity of nodule
• surrounding tissue involvement
• regional lymphadenopathy
❏ investigations
• fine needle aspiration (see Figure 3)
THYROID . . . CONT.
Classification
1. Papillary Carcinoma (50-70%)
❏ well-differentiated
❏ seen more commonly in younger patients
❏ may be induced by radiation
❏ multicentric, some follicular components histologically
❏ usually metastasizes to regional lymph nodes first
❏ lifespan not affected if confined to one lobe and < 2 cm
❏ remember the “P’s”: Papillary, Popular, Psammoma, Palpable nodes,
Positive Prognosis, Positive 131I uptake
2. Follicular Carcinoma (10-15%)
❏ well-differentiated but more aggressive than papillary
❏ not associated with radiation exposure
❏ tends to be angioinvasive, spreading to lung, bones and distant
sites without lymph node involvement
❏ most important prognostic factor is invasion, not primary tumour size
❏ Hurtle cell cancer: aggressive variant of follicular cancer, frequent
pulmonary metastases
❏ remember the “F’s”: Follicular, Far away mets (blood), Female,
FNA biopsy not diagnostic, Favourable prognosis
3. Anaplastic Carcinoma (10%)
❏ occurs most commonly in elderly patients
❏ rapidly progressive
❏ poor prognosis
4. Medullary Carcinoma (1-2%)
❏ high familial aggregation, associated with multiple endocrine neoplasia (MEN) IIa or IIb
❏ may produce calcitonin, prostaglandins, ACTH, serotonin, kallikrein, bradykinin
• these substances can be used as tumour markers
❏ worse prognosis than papillary or follicular cancer
❏ need to screen asymptomatic relatives
• inappropriate rise in calcitonin with the administration of
calcium and pentagastrin
❏ remember the “M’s”: Medullary, MEN IIa, or IIb, aMyloid, Median node dissection
5. Lymphoma (< 1%)
❏ seen in the context of a nodule or an enlarging goitre in a patient
with Hashimoto’s thyroiditis
Treatment
❏ lobectomy for small, well-differentiated papillary carcinoma with no
evidence of aggressive behaviour or metastases
❏ near-total thyroidectomy for large tumours with marked angioinvasion or
capsular invasion
❏ nodal dissection required only if nodes present
❏ generally follow with large dose of ablative radioactive iodine for
large, well-differentiated tumours
❏ thyroid malignancies may be dependent on TSH and may regress
with L-thyroxine suppression
❏ follow thyroglobulin (papillary, follicular), calcitonin (medullary)
❏ inappropriate serum thyroglobulin level post surgery/ablation may indicate metastases
• total body 131I scan will identify metastases
• treatment by high dose radioactive iodine
ENDOCRINOLOGY
Dr. R. Silver
Orlee Guttman and Jennifer Shin, chapter editors
Christopher Tam, associate editor
DISORDERS OF GLUCOSE METABOLISM . . . 2 ADRENAL CORTEX . . . . . . . . . . . . . . . . . . . . . . . .25

Diabetes Mellitus (DM) Adrenocorticotropin Hormone (ACTH)
Complications of Diabetes Adrenocortical Hormones
Treatment of Diabetes Tests of Adrenocortical Function
Diabetic Ketoacidosis (DKA) Hyperaldosteronism
Hyperosmolar Nonketotic Hyperglycemic Syndrome Cushing’s Syndrome
Hypoglycemia Congenital Adrenal Hyperplasia (CAH)
Syndrome X - Insulin Resistance Syndrome Hirsutism and Virilization
Adrenocortical Insufficiency
DYSLIPIDEMIAS . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Lipoproteins ADRENAL MEDULLA . . . . . . . . . . . . . . . . . . . . . .31
Secondary Causes of Hyperlipidemias Pheochromocytoma
Approach to Dyslipidemias
Treatment of Dyslipidemias MULTIPLE ENDOCRINE NEOPLASIA (MEN) 32
OBESITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 CALCIUM DISORDERS . . . . . . . . . . . . . . . . . . . .32

Calcium Homeostasis
PITUITARY GLAND . . . . . . . . . . . . . . . . . . . . . . . .13 Hypercalcemia
Growth Hormone Hypocalcemia
Prolactin
Leutinizing Hormone (LH) and METABOLIC BONE DISEASE . . . . . . . . . . . . . .36
Follicle Stimulating Hormone (FSH) Osteoporosis
Antidiuretic Hormone Osteomalacia and Rickets
Oxytocin Renal Osteodystrophy
Pituitary Pathology Paget’s Disease of Bone
Hypopituitarism
MALE REPRODUCTIVE . . . . . . . . . . . . . . . . . . . .39
THYROID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17 ENDOCRINOLOGY
Thyroid Stimulating Hormone (TSH) Tests of Testicular Function
Thyroid Hormones Hypogonadism
Tests of Thyroid Function and Structure Infertility
Hyperthyroidism Erectile Dysfunction
A. Graves’ Disease Gynecomastia
B. Subacute Thyroiditis (Thyrotoxic Phase)
C. Toxic Multinodular Goitre COMMON MEDICATIONS . . . . . . . . . . . . . . . . . .42
D. Postpartum Thyroiditis
E. Thyrotoxic Storm REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41
Hypothyroidism
A. Congenital Hypothyroidism
B. Hashimoto’s Thyroiditis
C. Riedel’s Struma
D. Myxedema Coma
E. Sick Euthyroid Syndrome (SES)
Non-toxic Goitre
Thyroid Nodules
Thyroid Malignancies

DISORDERS OF GLUCOSE METABOLISM
DIABETES MELLITUS (DM)
❏ diagnosis (confirm with the same test on another day)
• symptoms of diabetes (polyuria, polydipsia, weight loss,
nocturia, polyphagia, blurry vision) PLUS random plasma
glucose ≥ 11.1 mmol/L (200 mg/dL) OR
• FBS ≥ 7.0 mmol/L (126 mg/dL) OR
• plasma glucose value ≥ 11.1 mmol/L (200 mg/dL)
during two hour OGTT
❏ diagnostic testing
• fasting blood glucose (FBG): best drawn the morning after overnight fast
• oral glucose tolerance test (OGTT): 75 g glucose ingested, then plasma glucose levels
measured following 0 and 120 minutes
Classification of Diabetes Mellitus (DM)
Table 1. Comparison of Type 1 and Type 2 Diabetes

Type 1 Diabetes Type 2 Diabetes
Etiology • idiopathic • genetically-linked
• auto-immune
Onset • usually before age 30 • usually after age 40
Genetics • associated with HLA DR3, • greater heritability than Type 1
DR4 and DQ alleles • non-HLA-associated
• 40% concordance in monozygotic • 80-100% concordance in monozygotic twins
twins
Pathophysiology • completely insulin-deficient • abnormal insulin secretion

• increased insulin resistance in target tissues,
likely due to receptor and post-receptor
abnormalities
• increased hepatic gluconeogenesis
Risk Factors • personal history of autoimmune • obesity
diseases increases likelihood of • family history
developing DM • prior abnormal glucose tolerance
• e.g. Graves’ disease, myasthenia • hypertension
gravis, Addison’s disease, pernicious • hyperlipidemia
anemia • gestational diabetes mellitus (GDM)
Population Prevalence • highest in Finland • higher in black, Aboriginal and Hispanic people
• rare in Asian, black, Aboriginal and
Hispanic people
Body Habitus • typically normal to wasted • typically overweight
Pharmacological • insulin required • combination of oral hypoglycemic agents
Therapy ± insulin therapy
Circulating Islet • 50-85% • < 10%

Cell Antibodies
Other Aspects • prone to ketoacidosis • not prone to ketoacidosis but prone to
hyperosmolar coma
Diabetes Secondary to Specific Etiologies

❏ genetic
• Down syndrome, Turner’s syndrome, Huntington’s disease,
genetic defects in ß-cell function and insulin action
❏ diseases of the endocrine/exocrine pancreas
• pancreatitis, neoplasia, cystic fibrosis (CF), hemochromatosis (bronzed diabetes)
• acromegaly, Cushing’s syndrome, glucagonoma, hyperthyroidism
❏ drug-induced
• ß-agonists, glucocorticoids, thiazides, phenytoin
❏ infections
• cytomegalovirus (CMV), congenital rubella

Gestational Diabetes (GDM) (see Obstetrics Chapter)

❏ glucose intolerance that develops during pregnancy
❏ incidence
• 2-4% of all pregnancies
❏ risk factors
• age > 25 • member of high-risk ethnic group
• obesity • previous GDM
• 1º relative with DM • previous macrosomic baby (> 4 kg)
❏ screening and diagnosis
• any pregnant woman should be screened between 24 and 28 weeks
• 50 g glucose challenge test, measuring glucose one hour later
• if abnormal (7.8 mmol/L; 140 mg/dL), then 75 g oral glucose tolerance test (OGTT) should be done
• if any two of the following three values are met or exceeded, a diagnosis of GDM is established
• fasting glucose ≥ 5.3 mmol/L (95 mg/dL)
• 1 hr value ≥ 10.6 mmol/L (190 mg/dL)
• 2 hr ≥ 8.9 mmol/L (160 mg/dL)
Fetus
❏ maternal hyperglycemia induces hyperinsulinemia in fetus
❏ results in macrosomia (insulin acts as a growth factor)
❏ GDM: prone to respiratory distress, neonatal hypoglycemia,
hypocalcemia, hyperbilirubinemia, polycythemia, and prematurity
❏ preexisting DM: all of the above plus intrauterine growth restriction (IUGR), sacral agenesis,
cardiac structural defects
Mother
❏ increased risk of developing subsequent type 2 DM
❏ progression of diabetic retinopathy and nephropathy
❏ management
• preconception care to normalize HbA1c (if preexisting DM)
• tight glucose control (shown to decrease both fetal and maternal complications)
• oral hypoglycemics contraindicated
• insulin to maintain tight glycemic control if diet inadequate
• fetus must be monitored carefully
Impaired Glucose Tolerance (IGT)
❏ diagnosis based on
• fasting glucose 6.1-6.9 mmol/L (110-125 mg/dL)
• 2-hour OGTT 7.8-11.1 mmol/L (140-199 mg/dL)
❏ 1-5% per year develop DM
❏ 50-80% revert to normal glucose tolerance
❏ weight loss may improve glucose tolerance
❏ associated with progressively greater risk of developing macrovascular complications
COMPLICATIONS OF DIABETES
❏ the majority of complications involve the vascular system
❏ aggravating factors: poor glycemic control, inadequate control of hypertension and cholesterol,
smoking, high fat diet
Macroangiopathy
❏ accelerated atherosclerosis leading to coronary artery disease (CAD), stroke,
pulmonary vascular disease (PVD)
❏ most common cause of death in type 2 DM
Microangiopathy
❏ major chronic complication of type 1 and type 2 DM
❏ pathognomonic lesion is basement membrane thickening
❏ classically causes retinopathy, nephropathy and neuropathy
❏ can involve many other organs, including heart and skin
1. Retinopathy (see Ophthalmology Chapter)
❏ epidemiology
• present in 50% of patients after 10 years with DM
• one of the leading causes of blindness in North America
❏ types
• non-proliferative (background)
• generally no symptoms but may affect macula and impair vision
• microaneurysms, hard exudates, dot and blot hemorrhages
• pre-proliferative
• 10-40% progress to proliferative within one year
• macular edema, venous shunts and beading, nerve fibre layer microinfarcts (cotton wool spots)

• proliferative (see Color Atlas OP13)

• great risk for loss of vision
• neovascularization, fibrous scarring, vitreal detachment, retinal detachment
❏ presentation
• asymptomatic to complete loss of vision
• tight glycemic control
• photocoagulation (eliminates neovascularization)
• vitrectomy
• frequent follow-up visits with an ophthalmologist (immediate
referral after diagnosis of type 2 DM; in type 1, only after 5 years of DM
2. Nephropathy (see Nephrology Chapter)
❏ epidemiology
• diabetes-induced renal failure is the most common cause of
renal failure in North America
• 20-40% of persons with type 1 DM (after 5-10 years) and 4-20% with
type 2 DM have progressive nephropathy
❏ presentation
• initial changes include microalbuminuria, increased glomerular filtration rate (GFR)
(up to 140%), enlarged kidneys
• over 15 years, progresses to cause hypertension, persistent proteinuria (macroalbuminuria),
nephrotic syndrome, renal failure
• tight blood pressure control – ACE inhibitors
(shown to reduce nephropathic complications) and calcium channel blockers (CCB)
• limit use of nephrotoxic drugs and dyes
• protein restriction (controversial)
3. Neuropathy (see Neurology Chapter)
❏ epidemiology
• common in both type 1 and type 2 DM
❏ pathophysiology
• metabolic defect thought to be due to increased sorbitol
and/or decreased myoinositol (exact mechanisms not understood)
❏ types
• distal symmetric “glove and stocking” polyneuropathy
• autonomic dysfunction (e.g. gastroparesis)
• mononeuropathy (e.g. carpal tunnel syndrome)
❏ presentation
• paresthesias or neuropathic pain
• motor or sensory deficits (including cranial nerves)
• orthostatic hypotension
• impotence
• voiding difficulties
• foot ulcers
• anti-depressants (e.g. amitriptyline), capsaicin, and anti-epileptics
(e.g. Tegretol, Neurontin) for painful neuropathic syndromes
• erythromycin and domperidone for gastroparesis
• foot care education
4. Other Complications
❏ skin disease (see Colour Atlas E5)
❏ bone and joint disease
❏ cataracts
TREATMENT OF DIABETES
❏ Diabetes Control and Complications Trial (DCCT) (1993) demonstrated a 50-70% decrease
in microvascular complications in type 1 DM in an intensively treated group
as compared to a conventionally treated group
❏ United Kingdom Prospective Diabetes Study (1998) demonstrated a
• decrease in diabetes complications in intensively treated
group compared to conventionally treated group
• marked decrease in vascular complications in those with
well-controlled blood pressure

Diet
❏ energy intake to achieve and maintain desirable weight
❏ other recommendations as per Canada's Food Guide
Lifestyle
❏ regular physical exercise can improve insulin sensitivity and lower lipid concentrations and blood pressure
❏ stop smoking and decrease alcohol consumption
Oral Hypoglycemic Agents (see Table 2)
❏ mainly for type 2 DM
Table 2. Oral Hypoglycemics

Medication Mechanism of Action Side Effects Contraindications
Sulfonylureas stimulate release of endogenous insulin hypoglycemia hepatic or renal

glyburide (Diabeta) nausea impairment
chlorpropamide (Diabinase) GI discomfort
Meglitimides stimulate release of endogenous insulin hypoglycemia hypersensitivity,
repaglinide (Gluconorm) (rapid-acting, better post-prandial glucose (less frequent than diabetic ketoacidosis (DKA)
control) with sulfonylureas)
Biguanides reduce gluconeogenesis, increase glucose lactic acidosis, hepatic or renal

metformin (Glucophage) utilization anorexia, nausea, impairment,
diarrhea, GI alcoholism,
discomfort advanced age
Thiazolidinediones increase peripheral insulin sensitivity, increased TG, liver disease,
rosiglitazone (Avandia) reduce gluconeogenesis weight gain, congestive heart failure (CHF)
pyoglitazone (Actos) hepatotoxicity,
anemia
α-Glucosidase decrease the absorption of flatulence, hypersensitivity, DKA,

Inhibitors carbohydrates (thus decreasing abdominal inflammatory bowel
acarbose (Prandase) postprandial rise of glucose) cramping, diarrhea disease (IBD)
Clinical Pearl
❏ Sulfonyureas and Meglitimides “squeeze” endogenous insulin from the pancreas.
❏ Biguanides and Thiazolidinediones act primarily in peripheral tissues remote from
the pancreas.
Insulin (see Table 3 and Figure 1)
❏ doses adjusted for individual patient needs to meet target glycemic control
❏ administration
• subcutaneous injections
• continuous subcutaneous insulin infusion pump
• IV infusion (regular insulin only)
❏ preparations
• ultra-rapid (Humalog)
• rapid or regular (R or Toronto)
• intermediate (N or NPH, L or Lente)
• long-acting (U or Ultralente)
❏ multiple daily injections of different types of insulin usually necessary for optimal glucose control
❏ estimate of total daily insulin requirement when starting an adult type 1 diabetes patient
on insulin = 0.5 - 0.6 units/kg
Table 3. Kinetics of Different Insulins
Insulin Duration Onset Peak Usual Effective Duration of
(hours) (hours) Action (hours)
Humalog (H) very short 5-10 min 30-40 min 2-3

Regular (R) short 1/2-1 1-3 5-7 (dose-dependent; may be longer)
NPH/lente (N) intermediate 2-4 6-10 14-18
Ultralente long 4-5 — 18-28

Humalog
activity regular
lente and NPH
ultralente
breakfast lunch dinner bed

Figure 1. Duration of Activity of Different Insulins
Glucose Monitoring
❏ frequent self-monitoring and recording of blood glucose is now standard management
❏ hemoglobin A1c (HbA1c or glycosylated hemoglobin)
• percentage indicates level of plasma glucose over past 3 months
• extremely useful for monitoring patient’s long-term diabetes control
• goal is to maintain HbA1c within 5-8% range (i.e. average blood glucose 5.0-11.0 mmol/L)
• HbA1c ≥ 10% indicates poor control
Variable Insulin Dose Schedule (“Sliding Scale”)
❏ patient takes fixed doses of intermediate-acting insulin (N) but varies doses of fast-acting
insulin (R or H) based on blood glucose reading at time of dose
❏ use baseline R or H dose when in blood glucose target range; add or subtract units when
above or below target
❏ allows patient to make corrections to avoid long periods of hyper- or hypoglycemia
Table 4. Sample Insulin Sliding Scale for Regimen of 3 Daily Injections

Blood Glucose Insulin (number of units)
(mmol/L)
Breakfast Supper Bed
R or H N R or H N
< 3.0 -2 -2
25 18
3.1-3.9 -1 -1
target range: 4.0-8.0 12 9
8.1-12.0 +1 +1
12.1-17.0 +2 +2
> 17.0 +3 +3
Insulin Pump Therapy

❏ external, battery-operated pump continuously delivers basal dose of
fast-acting insulin through small subcutaneous catheter
❏ at meals, patient programs pump to deliver extra insulin bolus
❏ basal dose may be increased or decreased based on activity, sleep, etc.
❏ advantages: more flexible lifestyle (sleep in, eat / skip meals when desired), better glucose control
❏ disadvantages: very expensive, increased risk of DKA if pump inadvertently disconnected,
frequent blood glucose testing required
DIABETIC KETOACIDOSIS (DKA)
Pathophysiology
❏ insulin deficiency combined with increased counter-regulatory hormones
i.e. glucagon, cortisol, growth hormone (GH), catecholamines
❏ clinically involves two factors: lack of insulin (non-compliance, inadequate dose,
initial presentation of DM) and/or precipitant (surgery, infection, emotional stress)
❏ unrestricted hepatic glucose production ––> extreme hyperglycemia
❏ lipolysis ––> free fatty acids (FFA) ––> ketoacids ––> acidosis
❏ osmotic diuresis causes dehydration and electrolyte abnormalities
Clinical Features
❏ typical patient: young type 1 DM
❏ presentation preceded by polyuria and polydipsia
❏ level of consciousness (LOC) may be decreased with high serum osmolality (> 330 mOsm/kg)
❏ dehydration and ketoacidosis
• anorexia, nausea, vomiting, fatigue
• abdominal pain (especially in children)
• fruity-smelling breath (due to acetone)
• Kussmaul’s respirations (rapid deep breathing)
Investigations and Laboratory Findings
❏ increased blood glucose (BG) (11 mmol/L to > 55 mmol/L), decreased Na, decreased HCO3, increased BUN
❏ also measure K+, urine glucose and ketones
❏ hyperglycemia and ketonemia
• ketones in range of 15 mmol/L
❏ wide anion gap metabolic acidosis (pH ≤ 7.3 and/or HCO3 ≤ 15) plus possible secondary respiratory
alkalosis due to Kussmaul’s respirations; can also have metabolic alkalosis from vomiting and dehydration
Treatment
❏ rapid diagnosis and close medical supervision are essential
❏ in general, monitor degree of ketoacidosis with anion gap, not blood glucose or ketone level
❏ rehydration
• critical in order to maintain adequate cardiac output and renal function
• bolus of NS initially followed by high rate NS infusion
• ~ 400 mEq Na+ is lost in the urine (osmotic diuresis, buffering of
ketone acid anions, hyperglucagonemia and hypoinsulinemia
leading to direct renal excretion)
❏ insulin
• initial bolus of 5-10 U (or 0.1 U/kg) IV in adults followed by
continuous infusion at 5-10 U (or 0.1 U/kg) per hour
• when blood glucose ≤ 15 mmol/L (270 mg/dL) add D5W
❏ potassium
• avoid hypokalemia
• K+ lost from cells due to insulin deficiency and general catabolic state
• blood levels do not reflect total body losses which may be 400-500 mEq
• K+ falls during treatment due to rehydration and insulin action (drives K+ into cells)
• normal or low K+ level initially indicates severe deficiency and requires cardiac monitoring
• replace as KCl
❏ bicarbonate
• avoid giving unless life-threatening situation and/or shock
❏ treatment of precipitating cause with patient education to prevent further episodes of DKA
❏ treat cerebral edema with mannitol
Prognosis
❏ 2-5% mortality in developed countries
❏ serious morbidity and mortality often result from
• sepsis
• pulmonary and cardiovascular complications
• thromboembolic complications
• cerebral edema
HYPEROSMOLAR NONKETOTIC HYPERGLYCEMIC SYNDROME
Pathophysiology
❏ usually complication of type 2 DM
❏ profound dehydration resulting from hyperglycemia
❏ precipitating events: infection, stroke, myocardial infarction, trauma, drugs
(glucocorticoids, immunosuppressives, diuretics), medical procedures (dialysis), burns
❏ reduced fluid intake, especially in elderly, bedridden patients
Clinical Features
❏ extreme hyperglycemia, hyperosmolality, volume depletion and CNS signs
Investigations and Lab Findings
❏ high urine glucose, negative or low ketones
❏ BG often > 55 mmol/L (1,000 mg/dL), but not a good indicator of severity
❏ urine negative for ketones; blood ketones reflect only starvation ketosis
❏ high serum osmolality
❏ electrolytes may show spurious hyponatremia (decrease in
3 mEq/L Na+ for every 10 mmol/L (180 mg/dL) increase in glucose)
❏ nonketotic mixed metabolic acidosis may be present due to other
acute underlying conditions (sepsis, renal failure, lactic acidosis)
Treatment
❏ rehydration with NS to restore intravascular volume, then 1/2 NS
❏ identify and treat precipitating cause(s)
❏ insulin (0.1 U/kg/hour) may or may not be necessary
❏ cerebral edema may result if osmolality is treated too aggressively
❏ overall mortality high (> 50%)
HYPOGLYCEMIA
Definition (Whipple’s Triad)
❏ serum glucose below a certain level (see below) PLUS
• neuroglycopenic symptoms OR
• adrenergic symptoms (autonomic response) PLUS
• relief provided by administration of glucose
❏ serum glucose at onset of symptoms
• < 2.5 mmol/L (45 mg/dL) in male patients
• < 2.2 mmol/L (40 mg/dL) in female patients
❏ occurs most often in insulin-treated diabetics, usually due to problems
with matching insulin dose to estimated blood glucose levels
Clinical Features of Hypoglycemia
❏ adrenergic symptoms (typically occur first)
• palpitations, sweating, anxiety, tremor, tachycardia, hunger
❏ neuroglycopenic symptoms
• dizziness, headache, clouding of vision, mental dullness,
fatigue, confusion, seizures, coma
Types of Hypoglycemia
1. Postprandial (Reactive) Hypoglycemia
❏ occurs 1.5-6 hours after a meal and recovers spontaneously
❏ manifested primarily as adrenergic symptoms due to autonomic discharge
❏ thought to be over-diagnosed and over-treated
❏ etiology
• alimentary hyperinsulinism
• post-GI surgery (gastrectomy, pyloroplasty, vagotomy)
• may also be induced by galactosemia and fructose intolerance
❏ treatment
• frequent, small feeds
• weight loss
2. Fasting Hypoglycemia
❏ imbalance between production of glucose by liver and utilization
in peripheral tissues
❏ etiology
• defective gluconeogenesis with inability to maintain
glucose concentration if food is withheld
• hormone deficiencies (hypopituitarism, adrenal
insufficiency, inadequate catecholamines or glucagon)
• enzyme defects
• substrate deficiency
• liver disease (cirrhosis, uremia)
• drugs (ethanol, propranolol, salicylates)
• excessive utilization of glucose
• hyperinsulinism (insulinoma, sulfonylurea,
exogenous insulin, sepsis)
• appropriate insulin levels (extrapancreatic tumours)
❏ treat underlying cause
SYNDROME X - INSULIN RESISTANCE SYNDROME
❏ postulated syndrome related to insulin resistance
• association between hyperglycemia, hyperinsulinemia,
hypertension, central obesity, and dyslipidemia
(elevated LDL, VLDL and TG and reduced HDL)
❏ obesity aggravates extent of insulin resistance
❏ complications include atherosclerosis, coronary artery disease (CAD), stroke and MI

DYSLIPIDEMIAS
❏ metabolic disorders characterized by elevations of fasting plasma
cholesterol and/or triglycerides (TG), and/or low HDL
LIPOPROTEINS
❏ consist of a lipid core that is surrounded by a shell of water-soluble
proteins and phospholipids
❏ transport lipids within the body
Table 5. Lipoprotein Physiology

Lipoprotein Function
Exogenous Pathway transports dietary triglycerides from gut to
Chylomicron adipose tissue and muscle
Endogenous Pathway
VLDL transports hepatic-synthesized TG from liver
to adipose tissue and muscle
LDL transports cholesterol from liver to peripheral tissues
HDL transports cholesterol from peripheral tissues to liver;

acts as reservoir for apolipoproteins
Table 6. Abnormal Lipid Values in mmol/L (mg/dL)

LDL TG HDL
Mild 3.4-4.1 (130-160) 2.3-4.0 (90-155) 0.6-0.95 (23-37)
Moderate 4.1-4.9 (160-190) 4.0-10.0 (155-385) –
Marked > 4.9 (190) > 10.0 (385) < 0.6 (23)
DYSLIPIDEMIAS . . . CONT.
Figure 2. Lipid Pathways

Illustration by Glen Oomen

Table 7. Hyperlipidemias
Hyperlipidemia Lipoproteins Lipid Defect Clinical Outcomes
Abnormalities
Chol TG Other
1. Hypercholesterolemias
a) Familial Hypercholesterolemia IIa 888 – 8LDL • defective or absent • homozygotes: manifest CAD
• autosomal dominant LDL receptors and other vascular disease
in childhood and die
young (< 20 yrs.) if untreated
• heterozygotes: develop CAD,
50% chance of MI by age 30
in men
• tendonous xanthomata,
xanthelasmas, corneal arcus
b) Polygenic Hypercholesterolemia IIa 8 – 8LDL • few mild • asymptomatic until vascular
(most common) inherited defects disease develops
in cholesterol metabolism
2. Hypertriglyceridemias
a) Familial Hypertriglyceridemia IV – 888 8VLDL • excessive hepatic • 8risk premature
TG synthesis atherosclerosis
• expressed in early adulthood;
triad of obesity,
hypertriglyceridemia, and
hyperinsulinemia
(also hyperuricemia)
b) Familial Lipoprotein Lipase I, V – 8 8 • defective or absent • associated with
Deficiency chylomicrons lipoprotein lipase hepatosplenomegaly,
lipemia retinalis, eruptive
xanthomata, pancreatitis
• can be asymptomatic
3. Combined Disorders
a) Familial Combined IIb 8 8 8LDL • excessive hepatic • CAD and other vascular
Hyperlipidemia 8VLDL synthesis of problems but otherwise
apolipoprotein B asymptomatic
b) Dysbetalipoproteinemia III 8 8 8IDL • abnormal apoprotein E • palmar or tuberous
xanthomata seen
• can be well until vascular
disease develops
SECONDARY CAUSES OF HYPERLIPIDEMIAS

1. Hypercholesterolemia
❏ diet
❏ hypothyroidism
❏ renal disease (nephrotic syndrome)
❏ liver disease (cholestatic)
❏ drugs (cyclosporine)
❏ diabetes
❏ paraproteinemia
2. Hypertriglyceridemia
❏ obesity
❏ alcohol
❏ diabetes
❏ drugs (ß-blockers without intrinsic sympathetic activity (ISA) birth control pill, hydrochlorothiazide,
retinoic acid, glucocorticoid)
❏ renal disease (uremia)
❏ liver disease (acute hepatitis)
APPROACH TO DYSLIPIDEMIAS
❏ establish presence of coronary artery disease (CAD), peripheral vascular disease (PVD),
cerebrovascular disease (CVD) risk factors outlined below for purpose of risk stratification
History Suggestive of Primary Dyslipidemia
❏ marked hyperlipidemia
❏ personal and/or family history of premature CAD < 40 yrs and resistance to conventional therapy
❏ tendon xanthomas, xanthelasma, eruptive xanthomas, lipemia retinalis, arcus in young person
Screening and Investigation
❏ increased LDL cholesterol is a major risk factor for atherosclerosis, especially CAD
❏ lowering LDL cholesterol associated with decreased CVD risk, and decreased total mortality
❏ increased HDL associated with decreased CVD risk
❏ hypertriglyceridemia is an independent risk factor for CAD in people with diabetes and
postmenopausal women
❏ screening recommended for those with
• CAD
• family history of hyperlipidemia or premature CAD
• other risk factors (e.g. hypertension, renal failure, obesity, smokers, diabetes)
❏ good evidence for both primary and secondary intervention
Risk Factors for CAD (see Cardiology Chapter)
❏ modified from National Cholesterol Education Program (NCEP)
❏ positive risk factors
• age: males > 45; females > 55, or premature menopause without hormone replacement therapy
• family history of CAD: MI or sudden death < age 55 in father or other first-degree male relative,
or < age 65 in mother or other first-degree female relative
• current smoker
• hypertension (BP > 140/90) or on anti-hypertensive medications
• low HDL-cholesterol (< 0.90 mmol/L; 35 mg/dL)
• DM or impaired glucose tolerance (IGT)
• hypertriglyceridemia (> 2.3 mmol/L; 90 mg/dL)
• abdominal obesity (BMI ≥ 27; waist:hip ≥ 0.9 in M, ≥ 0.8 in F)
❏ negative risk factors
• high HDL-cholesterol
Table 8. Risk Stratification for CAD in Individuals with Elevated LDL

CAD Risk Classification % over 10 years Profile
Very High > 40% • clinical macrovascular disease
High > 20% • males > 35
• postmenopausal females
• > 3 risk factors or marked hyperlipidemia with no
clinical macrovascular disease
Intermediate 10-20% • males > 35
• 2-3 risk factors with no clinical macrovascular disease
Low < 10% • males < 35
• < 2 other risk factors
TREATMENT OF DYSLIPIDEMIAS
❏ for clinical guidelines, see Fodor et al., (2000) in the References section
❏ for anti-lipidemic agents, see the Common Medications section
Hypercholesterolemia
❏ conservative for 4-6 months
• Phase I diet
• < 30% calories from fat with < 10% saturated
• < 300 mg cholesterol/day
• smoking cessation
• limit alcohol consumption to ≤ 2 drinks/day (especially if elevated TG)
• aerobic exercise (especially if obese, type 2 DM)
• e.g. 30-60 minute brisk walk for 4-7 days/week
• weight loss (especially if BMI > 25, waist circumference > 90 cm for F or > 100 cm for M)
• change medications where appropriate
• treat secondary causes
• hormone replacement therapy (HRT)
Table 9. Initiation and Target LDL Level in mmol/L (mg/dL)

by Risk Group
Level of Risk Target LDL Target Total/HDL Target TG
Very High < 2.5 (100) < 4.0 (155) < 2.0 (75)
High < 3.0 (115) < 5.0 (195) < 2.0 (75)
Moderate < 4.0 (155) < 6.0 (230) < 2.0 (75)
Low < 5.0 (195) < 7.0 (270) < 3.0 (115)

Hypertriglyceridemia
❏ conservative measures usually effective; treat after 4-6 months if
• TG > 10 mmol/L (385 mg/dL) - to prevent pancreatitis
• mild-moderate elevated TG when
• very high CAD risk
• high risk (> 3 RFs)
• diabetes
• associated low HDL plus other risk factors
• combined hyperlipidemia
Isolated Low HDL
❏ no evidence supporting treatment
❏ can justify treatment if very high-risk patient or family history of premature CAD
Follow-Up
❏ every 4-6 months for lipid profiles and LFTs
❏ check CK baseline and again if patient complains of myalgia
❏ increase dose and add second agent to achieve target goals
OBESITY
Definitions
❏ 20% or greater above ideal body weight (IBW) (Met. Life Ins. tables); 170% of IBW or BMI > 40 is morbid obesity
❏ most practical index is BMI (body mass index) = weight/height2 (kg/m2)
• BMI < 20 or > 27 leads to increased health risk
Epidemiology
❏ 15-25% of North American adults
Possible Risk Factors
❏ increasing age
❏ genetic - variations in energy expenditure
❏ behaviour/lifestyle - diet and exercise
❏ secondary causes
• endocrine: e.g. Cushing’s syndrome, polycystic ovarian disease (PCOD)
• drugs: e.g. antidepressants, antiepileptics and antipsychotics
❏ hypothalamic injury: trauma, surgical, lesions in ventromedial or paraventricular median nucleus
Pathophysiology
❏ positive energy balance: energy input > energy output
Complications
❏ cardiovascular
• hypertension, CAD, CHF, varicose veins, sudden death from arrhythmia
❏ respiratory
• dyspnea, sleep apnea, pulmonary embolus, infections
❏ gastrointestinal
• gallbladder disease, gastroesophageal reflux disease (GERD), fatty liver
❏ musculoskeletal
• osteoarthritis
❏ endocrine/metabolic
• impaired glucose tolerance (IGT) to type 2 DM, hyperuricemia, hyperlipidemia
• PCOD, hirsutism, irregular menses, infertility
❏ increased risk of neoplastic diseases
• endometrial, post-menopausal breast, prostate, colorectal cancers
Treatment
❏ general recommendations
• treatment should be based on medical risk
• safest and best therapy is a comprehensive approach including caloric restriction,
increased physical activity and behaviour modification
❏ diet
• caloric restriction with a balanced diet with reduced fat, sugar and alcohol
❏ exercise
❏ behaviour modification
• individual or group therapy
• self-monitoring, stimulus control, stress management, cognitive change, crisis intervention
❏ drug therapy
• serotonergic-appetite suppressants fenfluramine-phentermine (Fen-Phen) were found to
cause valvular heart disease and primary pulmonary hypertension (withdrawn)
• pancreatic lipase inhibitor: orlistat (Xenical) found to be mildly to moderately effective
❏ surgical therapy
• gastroplasty (“stomach stapling”) is treatment of last resort (controversial)
• liposuction
• weight loss is regained by fat accumulation at the same site or elsewhere
• not advocated if patient has significant medical comorbidities
PITUITARY GLAND

(bromocriptine)

• fever, pain
• testosterone
• hypovolemia
GROWTH HORMONE (GH)

Physiology
Regulation
Pathology
❏ decreased GH

❏ increased GH
• causes
PROLACTIN (PRL)
❏ polypeptide
Physiology
Regulation
❏ stimulation
• pathologic
• liver cirrhosis
❏ inhibition
Pathology
Physiology
❏ in the ovary
❏ in the testis
Regulation
❏ inhibition

Pathology
• hypogonadism
• amenorrhea
• impotence
• fine skin
Physiology
Regulation
Pathology
❏ diagnosis
❏ treatment
❏ causes
❏ diagnosis
❏ treatment
Physiology
Regulation
PITUITARY PATHOLOGY
Pituitary Adenoma (see Colour Atlas NS18)
❏ related to size and location
• visual field defects (usually bitemporal hemianopsia),
oculomotor palsies, increased ICP (may have headaches)
• skull radiograph: “double floor” (large sella or erosion), calcification
• CT and MRI far more sensitive for diagnosis
❏ related to destruction of gland
• hypopituitarism
❏ related to increased hormone secretion
• PRL
• prolactinoma is most common pituitary tumour
• galactorrhea
• GH
• acromegaly in adults (see Colour Atlas E4), gigantism in children
• ACTH
• Cushing’s disease = Cushing’s syndrome caused by a pituitary tumour
• tumours secreting LH, FSH and TSH are rare
Craniopharyngioma (see Pediatrics Chapter)
Empty Sella Syndrome
❏ sella turcica appears enlarged on x-ray because pituitary gland is distorted
❏ generally eupituitary - no treatment necessary
Pituitary Apoplexy
❏ acute hemorrhage/infarction of pituitary tumour
❏ sudden severe headache
❏ altered LOC
❏ ocular symptoms
❏ note: ophthalmoplegia with pituitary tumour likely indicates apoplexy
since tumour rarely gets big enough to encroach on cranial nerves
❏ neurosurgical emergency: acute decompression of pituitary via
trans-sphenoidal route
Clinical Pearl
GH, LH, FSH, TSH, ACTH, PRL
❏ A compressive adenoma in the pituitary will impair hormone production in this order
(i.e. GH-secreting cells are most sensitive to compression)
❏ Mnemonic: “Go Look For The Adenoma Please”
HYPOPITUITARISM
Etiology
❏ Mnemonic: eight “I”s
• Invasive: generally primary tumours
• Infarction: e.g. Sheehan’s syndrome
• Infiltrative disease e.g. sarcoidosis, hemochromatosis, histiocytosis
• Iatrogenic: following surgery or radiation
• Infectious: e.g. syphilis, TB
• Injury: severe head trauma
• Immunologic: autoimmune destruction
• Idiopathic: familial forms, congenital midline defects
Clinical Features
❏ typical clinical progression in panhypopituitarism
• fall in GH, clinically not apparent
• fall in PRL is variable, but may present as decreased lactation
• gonadotropin insufficiency then causes erectile dysfunction in men,
and amenorrhea or infertility in women
• TSH deficiency produces clinical hypothyroidism
• ACTH deficiency leads to adrenal insufficiency
Diagnosis by Triple Bolus Test
❏ stimulates release of all anterior pituitary hormones in normal individuals
❏ rapid sequence IV infusion of insulin, LHRH and TRH
❏ insulin ––> hypoglycemia ––> increased GH and ACTH
❏ LHRH ––> increased LH and FSH
❏ TRH ––> increased TSH and PRL

THYROID
THYROID STIMULATING HORMONE (TSH)
❏ glycoprotein
❏ α subunit similar to those in FSH, LH, hCG, but all have unique ß subunits
❏ stimulates growth of thyroid and secretion of T4 and T3 via cAMP
❏ regulation
• stimulated by hypothalamic TRH
• inhibited by circulating T4, intrapituitary T3, opiates, dopamine
THYROID HORMONES
Biochemistry
❏ free T4 (0.03%) and free T3 (0.3%) represent the hormonally active fraction
• the remainder is hormonally inactive, mainly bound to thyroxine binding globulin (TBG) and albumin
❏ T3 is more biologically active than T4
❏ some T4 is converted to T3 in peripheral tissues by 5’-deiodinase
❏ metabolized by most tissues; metabolites reach liver and are excreted in bile
Regulation of Thyroid Function
❏ extrathyroid
• stimulation of thyroid by TSH, epinephrine, prostaglandins (cAMP stimulators)
❏ intrathyroid (autoregulation)
• response to iodide - with increasing iodide supply, inhibition of iodide organification occurs,
thus decreasing T3 and T4 synthesis (Wolff-Chaikoff effect)
• varying thyroid sensitivity to TSH in response to iodide availability
• increased ratio of T3 to T4 in iodide deficiency
TESTS OF THYROID FUNCTION AND STRUCTURE
Circulating Thyroid Hormones
❏ total T3 and T4 levels depend on amount of thyroid binding globulin (TBG)
❏ TBG increases with: pregnancy, oral contraceptive (OCP) use, acute infectious hepatitis, biliary cirrhosis
❏ TBG decreases with: androgens, glucocorticoids, cirrhosis, hyponatremia,
phenytoin, ASA, NSAIDS, nephrotic syndrome, severe systemic illness
❏ standard assessment of thyroid function includes TSH and if necessary, free T4 and free T3
TSH
❏ sensitive TSH (sTSH) is the single best test for assessing thyroid function
❏ hyperthyroidism
• primary: TSH is low and does not rise in response to TRH because
of negative feedback from increased levels of circulating T3 and T4
• secondary: increased TSH
❏ hypothyroidism
• primary: increased TSH (most sensitive test) because of less
negative feedback from T3 and T4
• secondary: TSH is low with variable response to TRH
depending on the site of the lesion (pituitary or hypothalamic)
Iodine Kinetics
❏ an index of thyroid function
❏ radioactive iodine uptake (RAIU) is high in Graves’ disease and low in subacute thyroiditis
Effects of Thyroid Hormones on Peripheral Tissues
❏ sex hormone binding globulin (non-specific)
• liver increases production in hyperthyroidism; decreases production in hypothyroidism
❏ pre-ejection period/ left ventricular ejection time is a measure of the effect of thyroid hormones
on the heart
❏ basal metabolic rate (BMR)
Thyroid Assessment (see Otolaryngology Chapter)
❏ normal gland size 15-20 g (estimated by palpation)
❏ thyroid U/S to detect size of gland, solid vs. cystic nodule
❏ fine needle aspiration for cytology
❏ thyroid scan (Technetium99)
• for hot vs. cold nodules
• to distinguish between three major types of high-uptake hyperthyroidism
• Graves’ disease (diffuse uptake)
• toxic multinodular goiter (multiple discrete areas)
• solid toxic adenoma (single intense area of uptake)
Miscellaneous Tests
❏ thyroid antibodies
• antithyroglobulin antibodies, microsomal antibodies
• increased in Hashimoto’s disease
❏ TSH receptor antibodies
• thyroid stimulating immunoglobulin (TSI) or TSAb
• increased in Graves’ disease
THYROID . . . CONT.
❏ plasma thyroglobulin level

• used to monitor thyroid carcinoma activity
• undetectable levels = remission
• normal or elevated levels = probable, persistent, recurrent, or metastatic disease
❏ serum calcitonin
• not routinely done to investigate most thyroid nodules
• ordered if suspicious of medullary thyroid carcinoma
HYPERTHYROIDISM
❏ hyperthyroidism: excess production of thyroid hormone
❏ thyrotoxicosis: denotes clinical, physiological and biochemical
findings in response to elevated thyroid hormone
Table 11. Differential Diagnosis of Hyperthyroidism

Disorder/Disease Investigations
TSH T4/T3 Thyroid antibodies RAIU Other
1. Graves’ Disease decreased increased TSI Abs increased
2. Toxic Nodular Goitre decreased increased none increased
3. Toxic Nodule decreased increased none increased
4. Thyroiditis ESR increased

a) classical subacute thyroiditis decreased increased up to 50% of time decreased in
b) silent thyroiditis classical
c) post-partum thyroiditis SAT
5. McCune-Albright decreased increased none

Syndrome
6. Jod Basedow decreased increased none decreased

(iodine-induced)
7. Extra-thyroidal Sources
of Thyroid Hormone
a) endogenous
(struma ovariae, ovarian decreased increased none decreased
teratoma metastases from
follicular carcinoma)
b) exogenous (drugs)
8. Excessive Thyroid
Stimulation
a) pituitary thyrotrophoma increased increased none increased
b) pituitary thyroid hormone increased increased none increased
receptor resistance
c)8hCG (e.g. molar pregnancy) decreased increased none increased
Clinical Features
❏ GENERAL: fatigue, heat intolerance, irritability, fine tremor
❏ CVS: tachycardia, atrial fibrillation, palpitations
• elderly patients may have only CVS symptoms, commonly new onset atrial fibrillation
❏ GI: weight loss with increased appetite, thirst, increased frequency of bowel movements (hyperdefecation)
❏ NEUROLOGY: proximal muscle weakness, hypokalemic periodic paralysis (patients of Oriental origin)
❏ GU: scant menses, decreased fertility
❏ DERMATOLOGY: fine hair, skin moist and warm, vitiligo, soft nails with onycholysis (“Plummer’s nails”)
❏ MUSCULOSKELETAL (rare): decreased bone mass, hypercalcemia
❏ HEMATOLOGY: leukopenia, lymphocytosis, splenomegaly, lymphadenopathy
(occasionally in Graves’ disease)
A. GRAVES’ DISEASE (see Colour Atlas E2)

❏ triad of hyperthyroidism with diffuse goiter, ophthalmopathy, dermopathy (need not appear together)

THYROID . . . CONT.
Epidemiology
❏ relatively common, occurs at any age with peak in 3rd and 4th decade
❏ runs in families
❏ F>M
❏ association with HLA B8 and DR3
❏ may be associated with other autoimmune disorders in family
(e.g. pernicious anemia, Hashimoto’s disease)
❏ autoimmune disorder due to a defect in T-suppressor cells
❏ B-lymphocytes produce thyroid stimulating immunoglobulins (TSI)
directed against TSH receptor that mediate thyroid stimulation
❏ cause of ophthalmopathy uncertain
• antibodies against extraocular muscle antigens (fibroblasts implicated) with lymphocytic infiltration
• glycosaminoglycan deposition
❏ dermopathy may be related to cutaneous glycosaminoglycan deposition
• pretibial myxedema (see Colour Atlas E3)
Additional Clinical Features
❏ diffuse goiter +/– bruit
❏ ophthalmopathy: proptosis, lid lag, lid retraction, diplopia, characteristic stare, conjunctival injection
❏ dermopathy (rare): pretibial myxedema (thickening of dermis)
❏ acropachy: clubbing and thickening of distal phalanges
Diagnosis
❏ increased free T4 (and/or increased T3)
❏ positive for TSI
❏ TRH stimulation test (flat TSH response) is diagnostic if sTSH and free T4 are inconclusive
Treatment
❏ propylthiouracil (PTU) or methimazole (MMI)
• inhibit thyroid hormone synthesis
• major side effects: rash, hepatitis and agranulocytosis
❏ symptomatic treatment with ß-adrenergic antagonists
❏ thyroid ablation with radioactive 131I if PTU or MMI trial does not produce disease remission
❏ subtotal thyroidectomy (indicated rarely for large goitres)
• risks include hypoparathyroidism and vocal cord palsy
❏ both MMI and 131I are contraindicated in pregnancy
❏ 1/3 of cases achieve long-term remission on drug therapy alone
❏ small goitre and recent onset are good indicators for long-term remission with medical therapy
❏ high incidence of hypothyroidism after 131I, requiring lifelong thyroid hormone replacement
❏ ophthalmopathy: prevent drying
• high dose prednisone in severe cases
• orbital radiation, surgical decompression
• note that PTU or MMI may worsen ophthalmopathy
B. SUBACUTE THYROIDITIS (Thyrotoxic Phase)
❏ acute inflammation of the thyroid, probably viral in origin, characterized by giant cells and lymphocytes
❏ often preceded by upper respiratory tract infection (URTI)
❏ disruption of thyroid follicles by inflammatory process results in the release of stored hormone
Clinical Features
❏ begins with fever, malaise, soreness in neck
❏ gland becomes enlarged
❏ two forms
• painful (“DeQuervain’s”) thyroid, ears, jaw and occiput
• painless (“Silent”)
❏ usually transient thyrotoxicosis with a subsequent hypothyroidism phase due to depletion of stored
hormone, finally resolving in a euthyroid state over a period of months
Laboratory
❏ elevated T4, T3
❏ radioactive iodine uptake (RAIU) markedly reduced
❏ marked elevation of ESR in painful variety only
❏ as disease progresses, values consistent with hypothyroidism may appear;
rise in RAIU reflects gland recovery
Treatment
❏ ASA can be used for painful form (increases peripheral conversion)
❏ prednisone may be required for severe pain, fever, or malaise
❏ ß-adrenergic blockade is usually effective in reversing most of the hypermetabolic and cardiac symptoms
❏ if symptomatically hypothyroid may treat short-term with thyroxine
THYROID . . . CONT.
Prognosis
❏ full recovery in most cases, but permanent hypothyroidism in 10% of painless thyroiditis
C. TOXIC MULTINODULAR GOITRE
❏ autonomous thyroid hormone production, may arise from a nodule in a nontoxic multinodular goitre
❏ may be singular or multiple
❏ multinodular goitre also known as Plummer’s Disease
Clinical Features
❏ goitre with adenomatous changes
❏ occurs more frequently in elderly people
❏ atrial fibrillation is a common presentation in the elderly
Diagnosis
❏ thyroid scan with increased uptake in nodule(s), and suppression of the
remainder of the gland
Treatment
❏ initiate therapy with antithyroid medications to attain euthyroid state in
order to avoid radiation thyroiditis
❏ then use high dose radioactive iodine to ablate tissue over weeks
❏ propranolol often necessary for symptomatic treatment prior to definitive therapy
(works by blocking the peripheral action of T3 and T4)
D. POSTPARTUM THYROIDITIS
❏ a type of painless thyroiditis
❏ autoimmune-mediated
❏ occurs in 5-10% of postpartum mothers, one-third of whom develops symptoms
❏ typical presentation includes thyrotoxicosis 2-3 months postpartum with a hypothyroid phase
at 4-8 months; usually resolves spontaneously without need for supplementation
❏ may be mistakenly diagnosed as postpartum depression
❏ may recur with subsequent pregnancies
❏ treat as per painless subacute thyroiditis
E. THYROTOXIC STORM
❏ a severe state of uncontrolled hyperthyroidism, extreme fever,
tachycardia, vomiting, diarrhea, vascular collapse and confusion
❏ often precipitated by infection, trauma, or surgery in hyperthyroid patient
❏ sepsis
❏ pheochromocytoma
❏ malignant hyperthermia
Clinical Features
❏ hyperthyroidism
❏ hyperthermia, often with dry skin
❏ arrhythmia ––> congestive heart failure , pulmonary edema
❏ mental status changes ranging from delirium to coma
Laboratory Findings
❏ increased T3, T4, undetectable TSH
❏ +/– anemia, leukocytosis, hypercalcemia, elevated LFTs
Treatment
❏ initiate prompt therapy; don’t wait for confirmation from lab
❏ fluid and electrolyte maintenance, vasopressors as indicated
❏ cooling blanket, acetaminophen for pyrexia
❏ inderal (decreases peripheral conversion of T4 to T3) but watch for CHF
❏ high dose PTU
❏ iodide (NaI, KI, Lugol’s solution) to inhibit release of thyroid hormone
❏ dexamethasone to block peripheral conversion and to lower body temperature
Prognosis
❏ 50% mortality rate
HYPOTHYROIDISM
Epidemiology
❏ 2-3% of general population
❏ F:M = 10:1
❏ 10-20% of women over age 50 have subclinical hypothyroidism (normal T4, TSH mildly elevated)
THYROID . . . CONT.
❏ primary thyroid disease (90%)
• iatrogenic: post-ablative (131I or surgical thyroidectomy)
• autoimmune: Hashimoto’s thyroiditis
• hypothyroid phase of subacute thyroiditis
• drugs: goitrogens (iodine), PTU, MMI, lithium
• infiltrative disease (progressive systemic sclerosis, amyloid)
• iodine deficiency
• congenital (1/4,000 births)
❏ pituitary hypothyroidism
• insufficiency of pituitary TSH
❏ hypothalamic hypothyroidism
• decreased TRH from hypothalamus (rare)
❏ peripheral tissue resistance to thyroid hormone
• rare
Clinical Features
❏ GENERAL: fatigue, cold intolerance, slowing of mental and physical performance, hoarseness,
enlarged tongue
❏ CVS: slow pulse, generalized atherosclerosis (increased serum cholesterol and triglycerides),
pericardial effusion
❏ GI: anorexia, weight gain, constipation, poor appetite
❏ NEUROLOGY: paresthesia, slow speech, muscle cramps, delay in relaxation phase of
deep tendon reflexes (“hung reflexes”)
❏ GU: menorrhagia, amenorrhea, anovulatory cycles
❏ DERMATOLOGY: puffiness of face, periorbital edema, cool, dry and rough skin, hair dry and coarse,
eyebrows thinned (lateral 1/3)
❏ HEMATOLOGY: anemia
Laboratory
❏ sensitive TSH (sTSH) is the most sensitive test for primary hypothyroidism
❏ must measure TSH to rule out secondary or tertiary causes
Treatment
❏ L-thyroxine (dose range usually 0.05 to 0.2 mg/day)
❏ elderly patients and those with CAD: start at 0.025 mg daily and increase gradually
❏ monitor sTSH
❏ at the optimal replacement dosage, TSH is in the middle of its normal range;
can also monitor free T4, particularly in pituitary hypothyroidism
A. CONGENITAL HYPOTHYROIDISM (see Pediatrics Chapter)
B. HASHIMOTO’S THYROIDITIS
❏ two variants
• goitrous: presents with a euthyroid or hypothyroid goitre
• atrophic: presents initially with hypothyroid state and atrophic gland
Etiology and Epidemiology
❏ defect in clone of T-suppressors leads to cell-mediated destruction of thyroid follicles
❏ B-lymphocytes produce antithyroglobulin antibody and antithyroid peroxidase
(anti-TPO or antimicrosomal antibody)
❏ associated with HLA B8 and DR3, and other autoimmune diseases
(e.g. Sjögren’s syndrome, SLE, RA, pernicious anemia, adrenal insufficiency)
❏ more common in females of middle age and is the most common cause of sporadic goiter in children
Clinical Features
❏ goitrous variant usually presents with a rubbery goitre and euthyroidism,
then hypothyroidism becomes evident
❏ atrophic variant patients are hypothyroid from the start
❏ association with thyroid lymphoma
Laboratory Findings
❏ thyroid function test reveals hypothyroidism, or a euthyroid state with a compensatory increase
in TSH; followed by decreased free T4 and eventually decreased free T3
❏ antimicrosomal and anti-thyroglobulin antibodies
Treatment
❏ if hypothyroid, replace with L-thyroxine
❏ if euthyroid, also treat with L-thyroxine if significant anti-thyroid antibody present
C. RIEDEL’S STRUMA
❏ rare type of chronic thyroiditis
❏ fibrotic inflammatory process that extends from the thyroid into surrounding tissues
THYROID . . . CONT.
Clinical Features
❏ ill-defined, firm mass with possible compressive symptoms of dysphagia, stridor, hoarseness, pain
❏ chief importance is differentiation from malignancy
Treatment
❏ surgical wedge resection of the isthmus (to prevent tracheal compression)
D. MYXEDEMA COMA
❏ most severe complication of hypothyroidism
❏ generally seen in patients with longstanding unrecognized hypothyroidism
and associated with a precipitating event (infection, surgery, MI, CHF)
Clinical Features
❏ hypothyroidism, stupor, hypoventilation, hypothermia, bradycardia, hypertension
Laboratory Findings
❏ decreased T3 and T4, increased TSH, decreased glucose
❏ check ACTH and cortisol for evidence of adrenal insufficiency
Treatment
❏ ABCs
❏ no active re-warming, but avoid cooling
❏ NG tube (since ileus often present)
❏ corticosteroids (due to the possibility of concomitant adrenal insufficiency)
❏ L-thyroxine 0.2-0.5 mg IV loading dose, then 0.1 mg IV OD until oral therapy tolerated
❏ monitor in ICU setting
E. SICK EUTHYROID SYNDROME (SES)
❏ serious illness, trauma, or stress can induce changes in circulating levels
of thyroid hormones
❏ not due to intrinsic thyroid or pituitary disease
❏ the abnormalities in SES include alterations in
• peripheral transport and metabolism of thyroid hormone
• regulation of TSH secretion
• thyroid function itself
❏ several variants exist
❏ normal-T4 variant
• characterized by low T3, normal T4
• proposed mechanism involves inhibition of peripheral 5’ monodeiodination of T4 to T3
• differentiated from primary hypothyroidism by a normal TSH
❏ low-T4 variant
• characterized by low T3, low T4
• low T4 likely due to inhibited T4 binding to serum proteins and accelerated
metabolic clearance
• differentiated from primary hypothyroidism with normal or low TSH
• poorer prognosis
❏ treat the underlying disease
❏ thyroid hormone replacement worsens the outcome
NON-TOXIC GOITRE
❏ generalized enlargement of the thyroid gland in a euthyroid individual
that does not result from inflammatory or neoplastic processes
❏ appearance of a goitre is more likely during adolescence, pregnancy,
and lactation because of increased thyroid hormone requirements
• early stages: goitre is usually diffuse
• later stages: multinodular nontoxic goitre with nodule, cyst formation
and areas of ischemia, hemorrhage, and fibrosis
Etiology
❏ iodine deficiency or excess
❏ goitrogens: brassica vegetables (turnip, cassava)
❏ drugs: iodine, lithium, para-aminosalicylic acid
❏ any disorder of hormone synthesis with compensatory growth
❏ peripheral resistance to thyroid hormone
Complications
❏ compression of neck structures, causing stridor, dysphagia, pain, and hoarseness
❏ multinodular goitre may become autonomous leading to toxic multinodular goitre and hyperthyroidism

THYROID . . . CONT.
Treatment
❏ remove goitrogens
❏ suppression with L-thyroxine may be effective in any TSH-dependent goitre
❏ surgery may be necessary for severe compressive symptoms
THYROID NODULES (see Otolaryngology Chapter)
❏ clearly defined discrete mass, separated from the thyroid parenchyma
Etiology
❏ benign tumours (e.g. follicular adenoma)
❏ thyroid malignancy
❏ hyperplastic area in a multinodular goitre
❏ cyst: true thyroid cyst, area of cystic degeneration in a multinodular goitre
Investigations
❏ fine needle aspiration (FNA)
• useful only if positive for malignancy (specific, not sensitive)
❏ thyroid function tests
❏ thyroid scan
• 15-20% of cold nodules (minimal 131I uptake into nodule) are malignant, very low
malignant potential if warm or hot (significant 131I uptake into nodule)
TSH
Detectable Undetectable
- observe if euthyroid
- RAI or surgery if hyperthyroid
Fine Needle Aspiration Biopsy
(FNA)
Benign Inconclusive Malignant
trial of L-thyroxine repeat FNA surgery ± adjuvant

suppression x 6mos therapy
smaller larger still inconclusive:

trial of L-thyroxine
suppression
observe surgery
smaller unchanged larger
observe repeat FNA surgery

Figure 3. Workup of Thyroid Nodule
THYROID MALIGNANCIES
Risk Factors
❏ history
• head or neck irradiation especially during childhood (e.g. acne therapy)
• family history (especially of medullary carcinoma)
• rapid growth (and failure to shrink on L-thyroxine)
• onset < 30 years of age
• male gender (thyroid nodules more common in females, malignancy more common in males)
• compressive symptoms (e.g. pain, dysphagia, stridor, hoarseness)
• cervical lymphadenopathy
• nodule in patient with Hashimoto’s (must rule out lymphoma)
• solitary nodule
• hardness and irregularity of nodule
• surrounding tissue involvement
• regional lymphadenopathy
❏ investigations
• fine needle aspiration (see Figure 3)
THYROID . . . CONT.
Classification
1. Papillary Carcinoma (50-70%)
❏ well-differentiated
❏ seen more commonly in younger patients
❏ may be induced by radiation
❏ multicentric, some follicular components histologically
❏ usually metastasizes to regional lymph nodes first
❏ lifespan not affected if confined to one lobe and < 2 cm
❏ remember the “P’s”: Papillary, Popular, Psammoma, Palpable nodes,
Positive Prognosis, Positive 131I uptake
2. Follicular Carcinoma (10-15%)
❏ well-differentiated but more aggressive than papillary
❏ not associated with radiation exposure
❏ tends to be angioinvasive, spreading to lung, bones and distant
sites without lymph node involvement
❏ most important prognostic factor is invasion, not primary tumour size
❏ Hurtle cell cancer: aggressive variant of follicular cancer, frequent
pulmonary metastases
❏ remember the “F’s”: Follicular, Far away mets (blood), Female,
FNA biopsy not diagnostic, Favourable prognosis
3. Anaplastic Carcinoma (10%)
❏ occurs most commonly in elderly patients
❏ rapidly progressive
❏ poor prognosis
4. Medullary Carcinoma (1-2%)
❏ high familial aggregation, associated with multiple endocrine neoplasia (MEN) IIa or IIb
❏ may produce calcitonin, prostaglandins, ACTH, serotonin, kallikrein, bradykinin
• these substances can be used as tumour markers
❏ worse prognosis than papillary or follicular cancer
❏ need to screen asymptomatic relatives
• inappropriate rise in calcitonin with the administration of
calcium and pentagastrin
❏ remember the “M’s”: Medullary, MEN IIa, or IIb, aMyloid, Median node dissection
5. Lymphoma (< 1%)
❏ seen in the context of a nodule or an enlarging goitre in a patient
with Hashimoto’s thyroiditis
Treatment
❏ lobectomy for small, well-differentiated papillary carcinoma with no
evidence of aggressive behaviour or metastases
❏ near-total thyroidectomy for large tumours with marked angioinvasion or
capsular invasion
❏ nodal dissection required only if nodes present
❏ generally follow with large dose of ablative radioactive iodine for
large, well-differentiated tumours
❏ thyroid malignancies may be dependent on TSH and may regress
with L-thyroxine suppression
❏ follow thyroglobulin (papillary, follicular), calcitonin (medullary)
❏ inappropriate serum thyroglobulin level post surgery/ablation may indicate metastases
• total body 131I scan will identify metastases
• treatment by high dose radioactive iodine

ADRENAL CORTEX
ADRENOCORTICOTROPIN HORMONE (ACTH)
❏ polypeptide
❏ part of long prohormone (pro-opiomelanocorticotropin, POMC) which contains
α, ß and γ MSH, ß-endorphin, and lipotropin as well as ACTH
Physiology
❏ secretion from pituitary is both pulsatile and diurnally varied, peaking at 0200-0400 hours,
lowest at 1800-2400 hours
❏ stimulates growth of adrenal cortex and secretion of its hormones via cAMP
• stimulates glucocorticoids, androgens and, to a limited extent, mineralocorticoids
❏ may have some melanocyte stimulating activity
Regulation
❏ primary control by CRH from hypothalamus
❏ feedback inhibition by cortisol on pituitary, hypothalamus and CNS; also regulated
by sleep-wake cycle and stress (pyrogens, surgery, hypoglycemia, exercise, severe
emotional trauma)
ADRENOCORTICAL HORMONES
❏ all derived from cholesterol (see Figure 4)
• mineralocorticoids (aldosterone) from zona glomerulosa (outermost layer = “salt”)
• glucocorticoids (cortisol) from zona fasciculata (middle layer = “sugar”)
• androgens from zona reticularis (innermost layer = “sex”)
cholesterol
pregnenolone
2 1
progesterone 17-OH-pregnenolone DHEA-S
3* 1 2 2
11-deoxycorticosterone 17-OH-progesterone androstenedione
4 3* 5
corticosterone 11-deoxycortisol testosterone
8 4 6 7
aldosterone cortisol estradiol dihydrotestosterone
Mineralocorticoids Glucocorticoids Sex Steroids

(zona glomerulosa) (zona fasciculata) (zona reticularis)
1 17-hydroxylase 2 3-ß-dehydrogenase 3 21-hydroxylase

4 11-hydroxylase 5 17-ß-dehydrogenase 6 aromatase
7 5-α-reductase 8 18-hydroxylase *most common enzyme defect
Figure 4. Pathways of Major Steroid Synthesis in the

Adrenal Gland and Their Enzymes
Aldosterone
❏ regulates extracellular fluid (ECF) volume through Na+ retention and K+ excretion
(by stimulation of distal tubule Na+/K+ ATPase)
❏ aldosterone regulated principally by the renin-angiotensin-aldosterone system (see Figure 5)
❏ negative feedback to juxtaglomerular apparatus by long loop
(aldosterone via volume expansion) and short loop (angiotensin II
via peripheral vasoconstriction)

volume depletion volume expansion

decreased arterial pressure increased arterial pressure
decreased Na+ delivery to macula densa dopamine
PGs, ADH renal Na+ retention
sympathetic stimulation
stimulation of JGA inhibition of JGA
Renin ACE
Angiotensinogen Angiotensin I Angiotensin II*

(with negative feedback to inhibit JGA)
Aldosterone release renal Na+ retention, K+ excretion

Arteriolar vascoconstriction
Promotion of ADH release
JGA - juxtaglomerular apparatus ACE - angiotensin converting enzyme
Figure 5. Renin-Angiotensin-Aldosterone Axis
Glucocorticoids
❏ secretion regulated by
• diurnal variation of ACTH (higher in a.m. than p.m., with peak around 0200 hours)
• inhibition of both ACTH and CRH release (negative feedback)
• stress (e.g. fever, pain, hypoglycemia), in addition to stimulating ACTH release,
directly stimulates CRH release, over-riding diurnal variation and negative feedback
❏ 10% free in plasma, 90% bound to transcortin (inactive)
❏ physiologic effects
• stimulate hepatic glucose production (gluconeogenesis)
• increase insulin resistance in peripheral tissues
• increase protein catabolism
• stimulate leukocytosis and lymphopenia
• inhibit bone formation; stimulate bone resorption
• inhibit fibroblasts, causing collagen and connective tissue loss
• suppress inflammation; impair cell-mediated immunity
• regulate extracellular fluid volume; promote renal solute-free water clearance
Androgens
❏ principal adrenal androgens are dihydroepiandrosterone (DHEA),
androstenedione and 11-hydroxyandrostenedione
❏ peak concentrations in puberty
❏ proportion of total androgens (adrenal to gonadal) increases in old age
❏ primarily responsible for adrenarche (pubic and axillary hair)
❏ adrenal androgen formation is regulated by ACTH (not LH)
TESTS OF ADRENOCORTICAL FUNCTION
Plasma Cortisol
❏ has diurnal variation; therefore, random measurements are of little value
❏ response to stimulation or suppression is more informative
24 Hour Urinary Free Cortisol
❏ correlates well with secretory rates
❏ good screening test for adrenal hyperfunction
Serum ACTH
❏ high in primary adrenal insufficiency
❏ low in secondary adrenal insufficiency
Serum DHEA-S
❏ the main adrenal androgen
Cosyntropin Stimulation Test
❏ cosyntropin is an ACTH analogue
❏ for diagnosing adrenal insufficiency

Short Cosyntropin Stimulation Test

❏ 25 U of cosyntropin IM, measure serum cortisol at baseline and at 60 minutes
❏ POSITIVE response: increase in plasma cortisol level by > 200 nmol/L and
an absolute level of > 500 nmol/L (rules out primary adrenal insufficiency)
❏ NEGATIVE response: may be due to lack of stimulation —> proceed to long cosyntropin test
Long Cosyntropin Stimulation Test
❏ to determine primary vs. secondary adrenal insufficiency
❏ 25 U of synthetic ACTH infused for 8 hours on 3 consecutive days, cortisol measured qa.m.
❏ POSITIVE response rules out primary but not necessarily secondary adrenal insufficiency
❏ NEGATIVE response rules in primary adrenal insufficiency
Metyrapone Test
❏ one of best tests of integrity of pituitary-adrenal axis, but rarely used
❏ useful in diagnosing suspected secondary adrenal insufficiency
❏ 750 mg PO q4h x 24 h; measure serum cortisol, 11-deoxycortisol, and ACTH
❏ blocks 11-hydroxylase, the final step of cortisol synthesis, causing elevated
level of the cortisol precursor, 11-deoxycortisol and decreased serum cortisol levels
❏ normal response is reduced cortisol, elevated 11-deoxycortisol
and elevated ACTH (response of pituitary to decreased cortisol)
Dexamethasone (DXM) Suppression Tests
❏ gold standard to determine presence and etiology of hypercortisolism
❏ principle: DXM suppresses pituitary ACTH, so plasma cortisol should be lowered by
negative feedback if HPA axis is normal
❏ if 24 hour urinary free cortisol (screening test) is positive, begin with low-dose DST to confirm diagnosis
❏ low dose DST: 0.5 mg DXM q6h for 48 hours, then 24 hour urinary free cortisol twice
❏ following this, measure ACTH; if undetectable, proceed to high-dose DST (8X higher dose than above)
to confirm diagnosis of adrenal Cushing’s
❏ if ACTH normal or increased, proceed to a CRF stimulation test via inferior petrosal sinus sampling to
distinguish Cushing’s disease from ectopic Cushing’s syndrome
HYPERALDOSTERONISM
❏ state of hypersecretion of the mineralocorticoid aldosterone
1. Primary Hyperaldosteronism
❏ diagnostic criteria:
• diastolic hypertension without edema
• decreased renin and increased aldosterone secretion both
unresponsive to increases in volume
❏ aldosterone-producing adrenal adenoma (Conn’s syndrome)
❏ idiopathic bilateral adrenal hyperplasia
❏ adrenal carcinoma (rare)
Clinical Features
❏ hypertension uncontrolled by standard therapy
❏ hypokalemia OFF diuretics
❏ other symptoms may include
• polyuria, polydipsia, nocturia
• fatigue, weakness, paresthesias
• headaches
Laboratory Findings
❏ hypokalemia
❏ high normal Na+
❏ metabolic alkalosis
❏ high 24 hour urinary or plasma aldosterone
❏ low random plasma renin
Treatment
❏ medical: spironolactone (aldosterone antagonist) or amiloride
❏ surgical: removal of adenoma is curative
2. Secondary Hyperaldosteronism
❏ increase in aldosterone in response to activation of renin-angiotensin system
❏ overproduction of renin (e.g. primary reninism from renin-producing tumour - rare)
❏ secondary hyperreninism - due to hypoperfusion of kidneys (e.g. renal artery stenosis), or edematous states
(CHF, liver cirrhosis), where arterial hypovolemia and/or hypotension is stimulus for aldosterone secretion
• Bartter’s syndrome - severe secondary hyperaldosteronism
without edema or hypertension (due to JGA hyperplasia)

CUSHING’S SYNDROME
❏ results from chronic glucocorticoid excess (endogenous or exogenous sources)
❏ endogenous Cushing’s syndrome is due to increased cortisol production by the adrenal gland
Etiology
❏ ACTH-dependent: bilateral adrenal hyperplasia and hypersecretion due to
• ACTH-secreting pituitary adenoma (Cushing’s disease)
• ectopic ACTH-secreting tumour (e.g. small cell lung carcinoma, bronchial carcinoid)
❏ ACTH-independent
• long-term use of exogenous glucocorticoids (most common cause of Cushing’s syndrome)
• primary adrenocortical tumours: adenoma and carcinoma (uncommon)
• bilateral adrenal nodular hyperplasia
Clinical Features (see Figure 6, see Colour Atlas E1)
❏ general
• truncal (centripetal) obesity, thin extremities, supraclavicular fat pads,
posterior cervical fat (“buffalo hump”), “moon facies”
• hypertension
❏ skin
• thin skin, facial plethora, hirsutism in women, wide purple striae,
acne, easy bruising, poor wound healing, mucocutaneous candidiasis
❏ musculoskeletal
• osteoporosis, pathologic fractures, avascular necrosis (AVN)
• proximal muscle weakness (more prominent in lower limbs)
❏ neuropsychiatric
• emotional lability, depression, euphoria, frank psychosis
❏ gonadal dysfunction
• oligomenorrhea / amenorrhea in women, decreased libido / impotence in men
❏ metabolic
• glucose intolerance (frank diabetes less common), hyperlipidemia, polyuria, nephrocalcinosis
❏ ectopic ACTH production
• hyperpigmentation, hypertension, hypokalemic metabolic alkalosis,
weight loss, weakness (typical features of Cushing’s syndrome usually absent)
CONT. buffalo hump red cheeks, acne, moon face
purple striae
osteoporosis
large abdomen
avascular necrosis
thin arms and legs

easy bruising
poor wound healing
Figure 6. Cushing’s Syndrome

Illustration by Marisa Bonofiglio

clinical features suspicious for hypercortisolism
24 hour urinary free cortisol
normal < 4X increase > 4X increase
no low dose DST diagnosis of Cushing’s

Cushing’s to confirm diagnosis syndrome established
syndrome
measure ACTH
ACTH increased ACTH decreased
MRI pituitary, CT adrenal, confirmatory high-dose DST

inferior petrosal sinus sampling with
CRF stimulation test
• DST = DXM suppression test
Figure 7. Hypercortisolism: Algorithm for Diagnosis
Treatment
❏ pituitary
• transsphenoidal resection, with glucocorticoid supplement peri- and post-operatively
• irradiation: only 50% effective, with significant risk of hypopituitarism
❏ adrenal
• adenoma: unilateral adrenalectomy (curative)
• carcinoma: palliative (frequent metastases, very poor prognosis)
adjunctive chemotherapy often not useful
❏ ectopic ACTH tumour - usually bronchogenic cancer (a paraneoplastic syndrome)
• chemotherapy/radiation for primary tumour
• agents blocking adrenal steroid synthesis: metyrapone or ketoconazole
• poor prognosis
CONGENITAL ADRENAL HYPERPLASIA (CAH) (see Pediatrics Chapter)
Pathophysiology
❏ autosomal recessive pattern of transmission, leading to enzyme defects, which can range from partial to total
❏ 21-hydroxylase (21-OH) deficiency is the most common form (95%) (see Figure 4)
❏ results in decreased cortisol and aldosterone with shunting toward adrenal androgen pathway
❏ deficiency of cortisol leads to elevated ACTH, which increases levels of unaffected steroids and
causes bilateral adrenal hyperplasia
Late-Onset 21-Hydroxylase Deficiency
❏ allelic variant of classic 21-hydroxylase deficiency
❏ mild enzymatic defect
❏ manifests during or after puberty: signs of androgenization
(hirsutism and acne) and amenorrhea or oligomenorrhea
❏ consider in women with unexplained hirsutism and menstrual abnormalities
❏ diagnosis
• increased plasma 17-OH-progesterone after ACTH stimulation test
❏ treatment
• dexamethasone, spironolactone (anti-androgen)
• mineralocorticoid replacement is not needed
HIRSUTISM AND VIRILIZATION
❏ both terms refer to states of androgen excess
❏ hirsutism
• male pattern of hair growth in women: back, chest, upper abdomen
❏ virilization
• hirsutism, frontal balding
• clitoral enlargement
• deepening of voice
• acne
• increase in musculature
❏ defeminization
• amenorrhea
• decreased breast size
Etiology
❏ constitutional
• most common
• family history, ethnic background
❏ medications
• androgen-mediated: ACTH, anabolic steroids, androgens, progestational agents
• non-androgen mediated (hypertrichosis): phenytoin, diazoxide, cyclosporine, minoxidil
❏ ovarian
• polycystic ovarian disease (PCOD) (see Gynecology Chapter)
• tumours
❏ adrenal
• congenital hyperplasia (CAH, late-onset CAH)
• tumours
❏ Cushing’s disease - high ACTH
Investigations
❏ increased testosterone
❏ DHEA-S as measure of adrenal androgen production
❏ increased LH/FSH, seen commonly in PCOD as ratio > 2.5
Treatment
❏ cosmetic therapy
❏ discontinue causative medications
❏ oral contraceptives
❏ low dose glucocorticoid
❏ spironolactone - acts as peripheral androgen antagonist
❏ cyproterone acetate - blocks androgen receptor binding;
being increasingly used in combination with estradiol (Diane-35)
ADRENOCORTICAL INSUFFICIENCY
Primary (Addison’s Disease)
❏ rare form of adrenal pathology
❏ most cases are idiopathic
• likely autoimmune destruction of adrenals (50% of patients
have circulating adrenal antibodies)
• high association with other autoimmune diseases (e.g. chronic lymphocytic thyroiditis,
type 1 DM, vitiligo, pernicious anemia)
❏ metastatic tumour - second commonest cause
❏ hemorrhagic infarction - coagulopathy in adults or Waterhouse-Friderichsen syndrome
in children (meningococcal or Pseudomonas septicemia)
❏ adrenalectomy
❏ granulomatous disease (e.g. TB, sarcoidosis)
❏ infection - particularly AIDS
Secondary
❏ inadequate pituitary ACTH secretion
❏ multiple etiologies (see Hypopituitarism section), including withdrawal of
exogenous steroids that have suppressed pituitary ACTH production
Clinical Features
❏ both primary and secondary
• weakness and fatigue
• postural hypotension
• weight loss, anorexia, nausea/vomiting, diarrhea
• abdominal, muscle, and joint pain
❏ primary
• hyperpigmentation of skin and mucous membranes
(e.g. palmar creases and buccal mucosa)
• dehydration, salt craving
❏ secondary
• usually more chronic than primary
• pallor, normal K+ and hydration
❏ acute adrenal crisis
• unable to secrete increased cortisol, ACTH in response to stress
(e.g. infection, dehydration, surgery)
• hypovolemic shock, fever, extreme weakness, decreased LOC,
nausea / vomiting, hypoglycemia

Laboratory Findings
❏ primary
• high ACTH
❏ secondary
Treatment
❏ maintenance
ADRENAL MEDULLA
PHEOCHROMOCYTOMA
Pathophysiology
Clinical Features
Lab Findings
Treatment

Implicated
CALCIUM DISORDERS
10
❏ major actions
Vitamin D
(relatively inert)
❏ major actions

Calcitonin
❏ polypeptide secreted by thyroid C cells
❏ secretion enhanced by Ca2+, GI hormones, pentagastrin
❏ major actions
• decreased osteoclastic bone resorption
• increased renal PO4 and Na+ clearance
• ACUTE NET EFFECT: decreased serum Ca2+ when given in pharmacologic doses
Magnesium
❏ major intracellular divalent cation
❏ Ca2+ is resorbed from the kidney with Mg, and thus Ca2+ balance is difficult to maintain in Mg deficiency
Phosphorus
❏ found in all tissues and necessary for most biochemical processes as well as bone formation
Table 13. Summary of Effects
Hormone Net Effect
Parathyroid Hormone (PTH) increased Ca2+
increased vit D
decreased PO4
Vitamin D increased Ca2+
increased PO4
Calcitonin decreased Ca2+
(in pharmacologic doses)
HYPERCALCEMIA
Definition
❏ total corrected serum Ca2+ > 2.62 mmol/L (10.5 mg/dL) OR ionized Ca2+ > 1.35 mmol/L (5.4 mg/dL)
❏ a medical emergency
• volume depletion
• arrhythmias
Pathophysiology
❏ increased bone resorption
❏ increased gastrointestinal absorption
❏ decreased renal excretion
Clinical Features
❏ symptoms dependent on the absolute Ca2+ value and the rate of its rise (may be asymptomatic)
Table 14. Symptoms of Hypercalcemia

Cardiovascular Gastrointestinal Renal Neurologic MSK Psychiatric
hypertension anorexia polyuria hypotonia bone pain cognitive changes
8digoxin toxicity nausea polydipsia hyporeflexia (bones) increased alertness
arrhythmia (groans) nephrogenic DI myopathy psychosis (moans)
9QT interval vomiting nephrolithiasis paresis
PUD (stones)
pancreatitis renal failure
Clinical Pearl
❏ The symptoms and signs of hypercalcemia include:
“Bones, Stones, psychosis-based Moans, and abdominal Groans”
Clinical Pearl
❏ > 90% of hypercalcemia is caused by either parathyroid disease or malignancy.

1. Parathyroid Disease
❏ primary hyperparathyroidism
• major cause of hypercalcemia
• PTH hypersecretion causes increase in Ca2+ and bone metabolism/turnover while decreasing PO4
• includes solitary adenoma (most common, 81%), hyperplasia (15%), carcinoma (4%), MEN I and IIa
• presentation: 50% asymptomatic, renal calculi, neuromuscular disease, decreased bone
density and associated consequences
• investigations: serum Ca2+, PO4, PTH, diagnostic imaging for renal calculi and osteopenia
• treatment: continued surveillance vs. surgery
❏ secondary hyperparathyroidism
• associated with renal failure - due to reduced Vit D synthesis, associated with malabsorption
2. Malignancy
❏ solid tumours
• bone metastases (e.g. breast): mediated by osteoclast activating factor (OAF)
and various cytokines
• humoral mediation of hypercalcemia (e.g lung and renal cell carcinoma):
secondary to production of PTH-related peptides (PTHrp)
❏ hematological malignancy (e.g. multiple myeloma, lymphoma, leukemia)
3. Vitamin D-Related
❏ vitamin D intoxication
❏ granulomatous diseases (e.g. sarcoidosis)
4. High Bone Turnover
❏ hyperthyroidism
❏ Paget's disease
❏ vitamin A excess
5. Renal Failure
❏ milk-alkali syndrome (hypercalcemia with alkalosis and renal failure)
❏ aluminum intoxication
❏ tertiary hyperparathyroidism
• persistent increase in PTH after correction of secondary hyperparathyroidism
(seen in renal transplant patients)
6. Drugs
❏ thiazides
❏ lithium
❏ calcium carbonate
❏ theophylline
7. Familial Hypocalciuric Hypercalcemia
❏ autosomal dominant
❏ mutation in Ca2+ sensing receptor gene leads to abnormal sensing of Ca2+ by parathyroid glands and
renal tubules (inappropriate secretion of PTH and excessive tubal reabsorption of Ca2+)
Treatment of Hypercalcemia
❏ treatment depends on the Ca2+ level and the symptoms
❏ treat acute, symptomatic hypercalcemia aggressively
❏ rehydration and calciuresis
• IV NS infusion (usually requires 4-5 L of fluid)
• only after adequately rehydrated, promote calciuresis with a loop diuretic, i.e. furosemide
❏ bisphosphonates
• treatment of choice
• inhibit osteoclast activity
• indicated in malignancy-related hypercalcemia
• pamidronate is most commonly used
• IV route since poorly absorbed from the GI tract
• several days until full effect but effect is long-lasting
❏ mithramycin
• effective when patient can not tolerate large fluid load (dangerous - hematotoxic and hepatotoxic)
❏ calcitonin
• inhibits osteoclastic bone resorption and promotes renal excretion of calcium
• acts rapidly but often transient response
• combination of calcitonin and steroids may prolong reduction in calcium
• tachyphylaxis may occur
❏ steroids
• anti-tumour effects
• useful in vitamin D-related hypercalcemia (including sarcoidosis)
and hematogenous malignancies (myeloma, lymphoma)
• slow to act (5-10 days); need high dose
❏ prostaglandin inhibitors
❏ surgical treatment if indicated
❏ avoid immobilization
HYPOCALCEMIA
Definition
❏ total corrected serum Ca2+ < 2.25 mmol/L (9.0 mg/dL)
Clinical Features
❏ most characteristic symptom is tetany
❏ differential diagnosis of tetany
• metabolic alkalosis (with hyperventilation)
• hypokalemia
• hypomagnesemia
Table 15. Signs and Symptoms of Hypocalcemia

Acute Hypocalcemia Chronic Hypocalcemia
• paresthesias • CNS: lethargy, seizures, psychosis, basal ganglia calcification
• hyperreflexia extrapyramidal effects, papilledema, pseudotumour cerebri
• tetany • CVS: prolonged QT interval
• laryngospasm (with stridor) • GI: malabsorption, diarrhea
• confusion • Skin: dry, scaling, alopecia, brittle and fissured nails,
• Chvostek’s sign (tap CN VII) moniliasis, abnormal dentition
• Trousseau’s sign (carpal spasm) • Ocular: cataracts, papilledema
1. Deficient PTH Action
❏ results in
• decreased bone resorption
• decreased intestinal Ca2+ absorption
• increased renal Ca2+ excretion
❏ iatrogenic hypoparathyroidism
• post-thyroidectomy/131I ablation
❏ idiopathic/autoimmune hypoparathyroidism
• congenital (DiGeorge syndrome) - dysgenesis of thymus and parathyroid glands
• acquired (polyglandular autoimmune disease - hypoparathyroidism
± adrenal insufficiency ± gonadal failure ± hypothyroidism and rarely
hypopituitarism, diabetes insipidis, type 1 DM)
❏ hemochromatosis
❏ pseudohypoparathyroidism
• PTH resistance secondary to Gs protein deficiency
❏ severe hypomagnesemia
• normally low Mg level stimulates PTH secretion, but chronic hypomagnesemia
is paradoxically associated with impaired PTH secretion
• low Mg levels also impair peripheral responsiveness to PTH
2. Deficient Vitamin D Action
❏ decreased intestinal absorption
❏ vitamin D deficiency
❏ receptor defect (vitamin D-dependent rickets type II)
❏ hydroxylation defects
• congenital: type I rickets
• acquired: chronic renal failure (CRF), hepatic failure
3. Renal Disease
❏ most common cause of hypocalcemia; increased loss of Ca2+
❏ chronic renal failure, nephrotic syndrome, acute renal failure
4. Drugs
❏ phosphate
❏ calcitonin
❏ aminoglycosides
❏ antineoplastic drugs (cisplatin, mithramycin)
❏ loop diuretics
5. Alcoholism
6. Acute Pancreatitis
❏ saponification of Ca2+ by lipids

7. Pregnancy
❏ low total Ca2+ (due to hypoalbuminemia) but normal ionized level
Treatment of Hypocalcemia
❏ correct underlying disorder
❏ acute/severe hypocalcemia
• calcium gluconate (generally requires continuous infusion)
• goal is to raise Ca2+ to low normal range (2.0-2.1 mmol/L) to prevent
symptoms but allow maximum stimulation of PTH
❏ if PTH recovery not expected, requires long-term therapy with vitamin D and calcium
❏ do not correct hypocalcemia if it is suspected to be a transient response
METABOLIC BONE DISEASE

OSTEOPOROSIS
Definition
❏ an age-related condition characterized by decreased bone mass and microarchitectural deterioration
of bone tissue with a consequent increase in bone fragility and susceptibility to bone fracture
Pathophysiology
❏ bone resorption > bone formation/remodelling
Risk Factors
❏ low peak bone mass
• small Caucasian or Asian female
• family history
❏ estrogen-related bone mass
• early menopause
• oophorectomy
• amenorrhea
❏ advanced age
❏ secondary to medical disease
❏ other
• diet, smoking, alcohol, caffeine
• minimal weight-bearing physical activity
Classification
1. Primary Osteoporosis
❏ usually in women, within 20 years after menopause
❏ affects mainly trabecular bone
2. Secondary Osteoporosis
• hyperparathyroidism
• hyperthyroidism
• premature menopause
• diabetes
• acromegaly
❏ malignancy
❏ gastrointestinal disease
• malabsorption
• liver disease
❏ drugs
• steroids
• phenytoin
• chronic heparin
❏ other
• rheumatoid arthritis
• renal disease
• poor nutrition
• immobilization
Clinical Features
❏ commonly asymptomatic
❏ pain, especially backache
❏ collapsed vertebrae ––> height loss
❏ fractures
• hip, vertebrae, humerus, and wrists most common
• Dowager’s hump = collapse fracture of vertebral bodies in mid-dorsal region
\
Investigations
❏ laboratory
• usually normal serum Ca2+, PO4, alkaline phosphatase
❏ densitometry
• single-energy x-ray absorptiometry, dual-energy x-ray absorptiometry (most useful),
quantitative CT, ultrasonography
• lumbar spine and views of femur
• compared to controls
❏ 1-2.5 SD = osteopenia
❏ > 2.5 SD = osteoporosis
Treatment
❏ not very satisfactory
❏ prevention and lifestyle modification
• safety measures to prevent falls
• weight-bearing exercises
• vitamin D with Ca2+ supplementation
• limits to smoking and alcohol use
❏ measures to decrease further bone loss/bone resorption
• postmenopausal estrogen replacement
• Ca2+ supplementation (1,000-1,500 mg/day for postmenopausal women)
• bisphosphonates - inhibitors of osteoclast binding
• calcitonin - osteoclast receptor binding
• thiazide diuretics (for hypercalcuria)
• combination therapy (synergistic): estrogen + bisphosphonate
❏ measures to increase bone mass
• fluoride - stimulates osteoblasts for bone formation
• parathyroid hormone
OSTEOMALACIA AND RICKETS
Definitions
❏ abnormal concentration of ions leads to higher proportion of osteoid (unmineralized) tissue
❏ disease prior to epiphyseal closure (in childhood) = rickets
❏ disease after epiphyseal closure (in adulthood) = osteomalacia
Etiology
❏ vitamin disorders
• decreased availability of vitamin D
• insufficient sunlight exposure
• nutritional deficiency
• malabsorption
• hydroxylation defects
• nephrotic syndrome
• liver disease
• chronic renal failure
• anticonvulsant therapy
❏ mineral deficiencies
• Ca2+ deficiency
• PO4 deficiency
• decreased GI absorption
• increased renal loss
❏ disorders of bone matrix
❏ inhibitors of mineralization
• aluminum
• bisphosphonates
Table 16. Clinical Presentations of Rickets and Osteomalacia

Rickets Osteomalacia
• skeletal deformities, bowlegs • not as dramatic
• fracture susceptibililty • diffuse skeletal pain
• weakness and hypotonia • bone tenderness
• disturbed growth • fractures
• rachitic rosary • gait disturbances
(prominent costochondral junctions) • proximal muscle weakness
• Harrison’s groove
(indentation of lower ribs)
• hypocalcemia

Investigations
❏ laboratory
• decreased serum Ca2+
• decreased serum phosphorus
• increased serum alkaline phosphatase (ALKP)
• decreased urinary Ca2+
❏ radiologic findings
• pseudofractures – thought to be healed microfractures
• radiolucent banding of spine
❏ bone biopsy
• usually not necessary but considered the gold standard for diagnosis
Treatment
❏ depends on the underlying cause
❏ vitamin D supplementation
❏ PO4 supplements if low serum PO4 is present
❏ Ca2+ supplements for isolated calcium deficiency
❏ HCO3 if chronic acidosis
RENAL OSTEODYSTROPHY
Pathophysiology
❏ metabolic bone disease secondary to chronic renal failure
❏ combination of hyperphosphatemia (inhibits 1,25(OH)2-vit D synthesis)
and loss of renal mass (reduced 1-α-hydroxylase)
Types
❏ produces a mixture of four types of bone disease
• osteomalacia - from acidosis and retention of toxic metabolites
• osteoporosis - metabolic acidosis dissolution of bone buffers
• osteitis fibrosa cystica - from increased PTH
• osteosclerosis - from increased PTH
❏ metastatic calcification secondary to hyperphosphatemia may occur
Clinical Features
❏ soft tissue calcifications ––> necrotic skin lesions if vessels involved
❏ osteodystrophy ––> bone pain and fractures
❏ pruritus
❏ neuromuscular irritability and tetany may occur
❏ radiologic features of osteitis fibrosa cystica, osteomalacia,
osteosclerosis, osteoporosis
Treatment
❏ prevention
• maintenance of normal serum Ca2+ and PO4 by restricting PO4 intake to 1 g/day
• Ca2+ supplements
• PO4 binding agents
• prophylactic use of vitamin D with close monitoring to avoid
hypercalcemia and metastatic calcification
PAGET’S DISEASE OF BONE
Definition
❏ a metabolic disease characterized by excessive bone destruction and repair
Epidemiology
❏ a common disease: 5% of the population, 10% of population > 80 years old
Etiology
❏ postulated to be related to a slow viral infection of osteoclasts, possibly paramyxovirus
❏ strong familial incidence
Pathophysiology
❏ initiated by increased osteoclastic activity leading to increased bone resorption;
osteoblastic activity increases in response to produce new bone that
is structurally abnormal and fragile
Clinical Features
❏ usually asymptomatic (routine x-ray finding or elevated alkaline phosphatase)
❏ severe bone pain (e.g. pelvis, femur, tibia) is often the presenting complaint
❏ skeletal deformities – bowed tibias, kyphosis, frequent fractures
❏ skull involvement – headaches, increased hat size, deafness
❏ increased warmth over involved bones due to increased vascularity

Investigations
❏ laboratory
❏ imaging
• metastases
Complications
❏ fractures
• 1-3%
❏ osteoarthritis
Treatment
❏ calcitonin

Androgen Regulation
❏ semen analysis
• semen volume
HYPOGONADISM
Etiology
❏ congenital
• cryptorchidism

❏ germ cell defects

• Sertoli cell only syndrome (arrest of sperm development)
• Leydig cell aplasia/failure
❏ inflammation
• orchitis – mumps, tuberculosis, lymphoma, leprosy
• genital tract infection
❏ physical factors
• trauma, heat, irradiation
❏ drugs
• marijuana, alcohol, chemotherapeutic agents
❏ myotonic dystrophy
❏ defects in androgen biosynthesis
❏ idiopathic
2. Hypogonadotropic Hypogonadism (Hypothalamic Pituitary Failure)
❏ characterized by decreased or normal LH
❏ congenital
• Kallman’s syndrome, Prader-Willi syndrome
❏ constitutional delay
❏ endocrine
• Cushing’s syndrome
• hypothyroidism
• hypopituitarism (pituitary tumours, hypothalamic lesions, hemochromatosis)
• estrogen-secreting tumours (testicular, adrenal)
❏ drugs
• alcohol
• marijuana
• spironolactone
• ketoconazole
• GnRH agonists
• prior androgen use
❏ chronic illness
❏ malnutrition
❏ idiopathic
3. Defects in Androgen Action
❏ complete androgen insensitivity (testicular femininization)
❏ incomplete androgen insensitivity
• 5-α-reductase deficiency
Clinical Presentation
❏ depends on age of onset
❏ fetal life
• ambiguous genitalia and male pseudohermaphroditism
❏ prepubertal
• poor secondary sexual development, poor muscle development
• eunuchoid skeletal proportions (upper/lower segment ratio < 1; arm span/height ratio > 1)
❏ postpubertal
• decreased libido, erectile dysfunction, infertility
• decreased facial and body hair if very significant androgen
deficiency (very low levels required to maintain sexual hair)
• fine wrinkles in the corners of mouth and eyes
• osteoporosis with longstanding hypogonadism
Treatment
❏ consider testosterone replacement
INFERTILITY (see Urology Chapter)
ERECTILE DYSFUNCTION (see Urology Chapter)
GYNECOMASTIA
❏ proliferation of the glandular component of the male breast
❏ estrogen/androgen imbalance - increased estrogen/androgen ratio
Etiology
❏ physiologic
• neonatal (maternal hormone)
• puberty
• aging
❏ pathologic
• endocrinopathies - primary hypogonadism, hyperthyroidism
extreme hyperprolactinemia, adrenal disease
• tumours - pituitary, adrenal, testicular, breast
• chronic diseases - liver, renal, malnutrition, etc.
• drugs - spironolactone, cimetidine, digoxin, chemotherapy, marijuana
• congenital/genetic - Klinefelter’s syndrome
• other - idiopathic, familial
Investigations
❏ history
• age, onset, duration, pain, family history, chronic diseases, drugs
• general health, feminization
• breast, thyroid, adrenal, liver, testicular exams
❏ investigations
• laboratory - serum TSH, PRL, LH, FSH, free testosterone, estradiol, LFTs
• CXR to rule out tumour
• testicular U/S to rule out testicular mass
Treatment
❏ medical
• correct the underlying disorder, discontinue responsible drug
• androgens for hypogonadism
• anti-estrogens - tamoxifen, clomiphene
❏ surgical
• usually required if gynecomastia present for > 1 year
• reduction mammoplasty
REFERENCES
Dayan CM. (2001). Interpretation of thyroid function tests. Lancet 357: 619-24.
DCCT Research Group. (1993). The Diabetes Control and Complications Trial (DCCT). The Effect of Intensive Treatment of
Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N Engl J
Med 329: 977-986.
Defronzo R. (1999). Pharmacologic Therapy for Type 2 Diabetes Mellitus. An Int Med 131(4): 281-303.
Fodor JG et al. (2000). Recommendations for the Management and Treatment of Dyslipidemia. CMAJ 162(10): 1441-1447.
Meltzer S et al. (1998). Clinical Practice Guidelines for the Management of Diabetes in Canada. CMAJ 159 (8 Suppl).
NIH Consensus Conference. (2001). Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785-795.

Class Generic Name Trade Name Mechanism of action Indications Major Side Effects Contraindications
Sulfonylureas
(see Table 2)
Biguanides
(see Table 2)
E42 – Endocrinology
Thyroid Hormones L-thyroxine Synthroid replace deficient hypothyroidism induced hyperthyroidism caution in heart disease
thyroid hormone thyroid suppression
Thionamides 1. propylthiouracil Propyl-Thyracil inhibits organification hyperthyroidism acute - headache, nausea; breast feeding
(PTU) of iodine and therefore chronic - rash, hepatitis,
synthesis of thyroid agranulocytosis
hormones
2. methimazole Tapazole inhibits organification hyperthyroidism agranulocytosis, leukopenia, nursing mothers

(MMI) of iodine and therefore thrombocytopenia,
synthesis of thyroid aplastic anemia
hormones
HMG Co-A lovastatin Mevacor decrease cholesterol elevated total and GI symptoms, rash, pruritus, active liver disease,
COMMON MEDICATIONS
Reductase simvastatin Zocor synthesis LDL cholesterol, elevated LFTs, myositis persistent elevated
Inhibitors pravastatin Pravachol 20 prevention of MI (uncommon) transaminases
atorvastatin Lipitor
Fibric Acid gemfibrozil Lopid decrease VLDL, hypertriglyceridemia GI upset, enhances hepatic and renal
Derivatives fenofibrate Lipidil increase HDL levels hyperchylo- gallstone formation dysfunction
micronemia
Niacin nicotinic acid decreases synthesis used for a generalized flushing, hypersensitivity, hepatic
Derivatives of VLDL and clearance variety of abnormal LFTs, pruritus, dysfunction, active peptic
of HDL hyperlipidemias worsening glucose tolerance ulcer disease, overt DM,
severe hypertension hyperuricemia
Other Lipid probucol Lorelco decreases LDL, increased LDL, decreased HDL pregnancy
Lowering Drugs anti-oxidant mixed diarrhea, flatulence,
hyperlipidemia abdominal pain,
nausea and vomiting
Resin Binders cholestyramine Questran absorbs and binds bile elevated LDL GI symptoms - constipation, complete biliary
acids which are excreted, nausea, flatulence, bloating obstruction,
decreasing enterohepatic pregnancy, lactation
circulation
Prolactin bromocriptine Parlodel dopamine analogue prolactinoma, nausea and vomiting, uncontrolled hypertension,
Inhibitors cabergoline Dostinex galactorrhea, headaches pre-eclampsia
inhibition of lactation,
acromegaly
MCCQE 2002 Review Notes

Class Generic Name Trade Name Mechanism of action Indications Major Side Effects Contraindications
ADH Analogues desmopressin DDAVP stimulates tubular central DI, headache, tachycardia, hypersensitivity
water reabsorption enuresis hypotension, decreased
urine output,
transient increase hemostasis for hyponatremia
in clotting factor VIII hemophilia A and
vWD type I
Vitamin D calcitriol Rocaltrol increased osteoclast action; hypocalcemia, metallic taste, epigastric hypercalcemia
MCCQE 2002 Review Notes

renal Ca2+ absorption, bone osteodystrophy, discomfort, nausea and
resorption, Ca2+ and PO4 osteoporosis vomiting
absorption from gut;
increased serum Ca2+ and PO4
COMMON MEDICATIONS
Bisphosphonates 1. pamidronate Aredia (APD) osteoclast inhibitor tumour induced infusion site reaction hypersensitivity
disodium hypercalcemia transient decrease in Ca2+
2. alendronate Fosamax osteoclast inhibitor osteoporosis GI upset, esophagitis severe renal dysfunction
. . . CONT.
3. etidronate Didrocal osteoclast inhibitor Paget’s disease; severe renal dysfunction

used in cyclic fashion
for osteoporosis
as it may inhibit
bone formation
4. risedronate Actonel osteoclast inhibitor osteoporosis arthralgia, diarrhea,

headache
Steroids
A. Glucocorticoids 1. prednisone many anti-inflammmatory effect adrenal insufficiency, electrolyte disturbances, systemic fungal infection
(5 mg) via unclear mechanisms autoimmune fluid retention, immuno-
disorders, COPD/ suppression, muscle
with equivalent 2. methyl- Solumedrol asthma, ITP, weakness, impaired
PO doses prednisolone nephrotic syndrome, wound healing,
(4 mg) dermatological PUD, menstrual
disorders, cerebral irregularities, psychosis,
3. hydrocortisone Solucortef edema, prevention osteoporosis, AVN,
(25 mg) of organ transplant many drug interactions
rejection, gout,
4. dexamethasone Decadron chemotherapy,
(0.75 mg) ocular inflammation
B. Mineralo- fludrocortisone Florinef adrenocortical less severe then above systemic fungal infectoin
corticoids insufficiency
(Addison’s),
hypoaldosteronism,
CAH
Endocrinology – E43
Illustrated by Angela Handforth

Endocrine Notes - All in One File

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Endocrine Notes - All in One File

Uploaded by

Copyright:

Available Formats

System: Endocrinology

Families of Chemical Messengers:

Synthesis of Chemical Messengers:

Endocrine (diffuse) Glands:

Classical Endocrine Glands:

Long or Short Range?

Levels of Feedback Loops:

- Hierarchical Classification of Hypothalamo-Pituitary Axis Disorders:

Testing for an Endocrine Disorder:

- Pituitary Hormones & their Target Tissues/Organs

Major Hormones involved with Growth:

The Growth Hormone Axis:

Anterior Pituitary Hormone of Growth:

Defects in Endocrine Control of Growth:

Anatomy of Thyroid Gland:

Physiology of the Thyroid Gland:

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

Blood [Glucose] Range:

Major Endocrine Organs that Regulate Metabolism:

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

Insulin Independent Tissues:

Mechanism of Insulin Action (Glucose Uptake):

T F S Directly After a Meal:

Why Maintain Fluid & Electrolyte Balance?:

Regulation of Water Intake (Thirst) Hypothalamic Triggers:

Regulation of Water Output:

Absence of ADH Presence of ADH (+Aldosterone)

- Atrial Natriuretic Peptide (ANP) Water Output:

Adrenal (AKA: Suprarenal) Anatomy & Physiology:

Why Maintain Electrolytes

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

Parathyroid Anatomy & Physiology

- Parathyroid Hormone (PTH):

Functions of Calcium & Phosphate:

Hormonal Regulation of the Ovarian Cycle:

Disorders of Fluid/Electrolyte-Regulating Hormones:

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

Adrenocortical Insufficiency (Hyporadrenal) Syndromes:

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

- CUSHING S DISEASE/SYNDROME (Hypercortisolism):

progesterone 17-OH-pregnenolone DHEA-S

11-deoxycorticosterone 17-OH-progesterone androstenedione

corticosterone 11-deoxycortisol testosterone

aldosterone cortisol estradiol dihydrotestosterone

Mineralocorticoids Glucocorticoids Sex Steroids

1 17-hydroxylase 2 3-ß-dehydrogenase 3 21-hydroxylase

Figure 4. Pathways of Major Steroid Synthesis in the

MCCQE 2002 Review Notes Endocrinology – E25

volume depletion volume expansion

stimulation of JGA inhibition of JGA

Angiotensinogen Angiotensin I Angiotensin II*

Aldosterone release renal Na+ retention, K+ excretion

JGA - juxtaglomerular apparatus ACE - angiotensin converting enzyme

Figure 5. Renin-Angiotensin-Aldosterone Axis

E26 – Endocrinology MCCQE 2002 Review Notes

Short Cosyntropin Stimulation Test

MCCQE 2002 Review Notes Endocrinology – E27

CONT. buffalo hump red cheeks, acne, moon face

thin arms and legs

poor wound healing

Figure 6. Cushing’s Syndrome

E28 – Endocrinology MCCQE 2002 Review Notes

clinical features suspicious for hypercortisolism