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Phase 2A > Endocrinology Part 1 > Flashcards

Endocrinology Part 1 Flashcards

1
Q

What are the major endocrine system out there?

A

a) Pituitary
b) Thyroid
c) Parathyroid
d) Adrenal
e) Pancreas
f) Ovary
g) Testes

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2
Q

What is Endocrinology?

A

Study of hormones (and their gland of origin), their receptors, the intracellular signalling pathways, and their associated diseases

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3
Q

What does hormone action depend on?

A

a) blood level of hormone
b) numbers of target cell receptors
c) affinity for receptors

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4
Q

State the 3 types of hormone actions.

A

a) Endocrine – blood-borne, acting at distant sites
b) Paracrine – acting on adjacent cells
c) Autocrine – feedback on same cell that secreted hormone

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5
Q

What type of hormones are stored in vesicles and what type of hormones are synthesised on demand?

A

Peptides/monoamines – stored in vesicles
Steroids – synthesised on demand

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6
Q

What type of hormone is protein-bound?

A

Fat-soluble hormone is protein bound while water-soluble hormone is unbound

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7
Q

What type of hormone binds to cell surface and what type of hormone diffuse into cell?

A

water-soluble hormone binds to cell surface receptor, fat soluble hormone diffuse into cell

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8
Q

What type of hormone has long half-life and what type of hormone has short half-life?

A

Water-soluble hormone has short half-life (fast clearance) because it is unbound while fat-soluble hormone has long half-life (slow clearance).

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9
Q

Provide examples of water-soluble hormone.

A

Peptides, monoamine

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10
Q

Provide examples of fat-soluble hormone.

A

Thyroid hormone, steroids

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11
Q

Talk about hormone class: Peptide

A

Vary in length – TRH: 3 amino acids, Gonadotrophins: 180 amino acids

Linear or ring structures

Two chains and may bind to carbohydrates e.g LH,FSH

Stored in secretory granules, hydrophilic, water-soluble

Released in pulses or bursts

Cleared by tissue or circulating enzymes

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12
Q

Talk about the 4 processes of granular store in peptide hormones.

A
  1. Synthesis: Preprohormone - prohormone
  2. Packaging: Prohormone - Hormone
  3. Storage: Hormone
  4. Secretion: Hormone
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13
Q

Talk about surface receptor and secondary messenger activation on insulin receptor.

A
  1. Binding of insulin to receptor protein
  2. Phosphorylation of receptor; activation of tyrosine kinase
  3. Phosphorylation of signal molecules; Cascade of effects; Glucose uptake and anabolic reactions
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14
Q

For hormone class: amine, talk about the steps that form epinephrine.

A

L-phenylalanine > L-tyrosine > L- dopa > Dopamine > Norepinephrine > Epinephrine

Phenylalanine derivatives
Secreted by medulla
Neurotransmitters
Rate limiting step is the conversion to l-DOPA
Cortisol potentiates conversion of norepin to epin
Amines: water soluble, stored in secretory granules, release pulsatile, rapid clearance,
Bind to alpha and beta receptors or D1 and D2
Alpha receptors: vasoconstriction, dilated pupil, alertness, contraction of stomach, bowel, anal sphincter
Beta adrenoceptors: vasodilatation, increased heart rate, bronchial and visceral smooth muscle relaxation

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15
Q

Talk about hormone class: Iodothyronines

A

Thyroid hormones are not water soluble; 99% is protein bound

Only 20% of T3 in the circulation is secreted directly by thyroid

Secretory cells release thyroglobulin into colloid – acts as base for thyroid hormone synthesis

Incorporation of iodine on tyrosine molecules to form iodothyrosines

Conjugation of iodothyrosines gives rise to T3 and T4 and stored in colloid bound to thyroglobulin

TSH stimulates the movement of colloid into secretory cell, T4 and T3 cleaved from thyroglobulin

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16
Q

Talk about the synthesis of T4 and T3.

A
  1. Thyroglobulin is synthesised and discharged into the follicle lumen.
  2. Iodide (I-) is trapped (actively transported in)
  3. Iodide is oxidised into iodine.
  4. Iodine is attached to tyrosine in colloid, forming DIT and MIT.
  5. Iodinated tyrosines are linked together to form T3 and T4.
  6. Thyroid globulin colloid is endocytosed and combined with a lysosome.
  7. Lysosomal enzyme cleaves T3 and T4 from thyroglobulin and hormone diffuse into the blood stream.
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17
Q

Give examples for the 3 types of hormone receptor locations.

A

1) Cell membrane (peptide)

2) Cytoplasm (steroid)
> Glucocorticoids - cortisol
> Mineralocorticoids - aldosterone
> Androgens - testosterone
> Progesterone

3) Nucleus (thyroid)
> Oestrogen
> Thyroid Hormone
> Vitamin D

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18
Q

Talk about hormone class: Cholesterol derivatives and steroids : Vitamin D

A
  • Fat-soluble
  • Enters cells directly to the nucleus to stimulate mRNA production
  • Transported by Vitamin D binding protein
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19
Q

State the steps of production of Vitamin D.

A

7-dehydrocholesterol(sunlight & skin)
Cholecalciferol (Vitamin D3)
(liver)
25-hydroxyvitamin D3
(kidney)
1,25-dihydroxyvitamin D3

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20
Q

Talk about hormone class: Cholesterol derivatives and steroids: Adrenocortical and gonadal steroids

A

> 95% protein bound
After entering cell
Pass to nucleus to induce response
Altered to active metabolite
Bind to a cytoplasmic receptor

Not too rapid inactivation
- In liver by reduction and oxidation, or conjugation to glucoronide and sulphate groups

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21
Q

Talk about steroid action, intracellular steroid pathway.

A

> Steroid hormone diffuses through plasma membrane and binds to receptor
Receptor-hormone complex enters nucleus
Receptor-hormone complex binds to GRE
Binding initiates transcription of gene to mRNA
mRNA directs protein synthesis

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22
Q

Talk about control of hormone secretion.

A

Basal secretion – continuously or pulsatile

Superadded rhythms e.g day-night cycle – ACTH, prolactin, GH and TSH

Release inhibiting factors – dopamine inhibiting prolactin, sum of positive and negative effects (GHRH and somatostatin on GH)

Releasing factors

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23
Q

State the 3 types of releasing factors that affect hormone secretion.

A
  1. Humoral stimulus (Low Ca2+ and parathyroid secretion)
  2. Neural stimulus (action potential & adrenal medulla for epinephrine and norepinephrine)
  3. Hormonal stimulus (hormone from hypothalamus)
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24
Q

What is
a) hormone metabolism
b) hormone receptor induction
c) hormone receptor down-regulation
d) synergism
e) antagonism

A

Hormone metabolism – increased metabolism to reduce function

Hormone receptor induction – induction of LH receptors by FSH in follicle

Hormone receptor down regulation – hormone secreted in large quantities cause down regulation of its target receptors

Synergism – combined effects of two hormones amplified (glucagon with epinephrine)

Antagonism - one hormone opposes other hormone (glucagon antagonizes insulin)

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25
Q

What are the contents of cavernous sinus?

A

Oh, COAT,
that stands for the
> Oculmotor nerve (III),
> Internal Carotid artery,
> Ophthalmic nerve (V1),
> Abducens nerve (VI),
> Trochlear nerve (IV).

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26
Q

Talk about posterior pituitary secretion.

A

Hypothalamic neurons synthesize oxytocin or ADH.

Oxytocin and ADH are transported down the axons of the hypothalamic-hypophyseal tract to the posterior pituitary.

Oxytocin and ADH are stored in axon terminals in posterior pituitary.

When hypothalamic neurons activated, hormones released.

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27
Q

Oxytocin functions?

A
  • uterine contraction during labour
  • milk ejection
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28
Q

What are the 6 hormones from anterior pituitary gland?

A
  1. Thyrothropin-releasing hormone
  2. Growth hormone-releasing hormone
  3. Gonadotropin-releasing hormone
  4. Corticotropin-releasing hormone
  5. Dopamine
  6. Somatostatin
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29
Q

What happens in pituitary dysfunction?

A
  1. Tumour mass effect
  2. Hormone excess
  3. Hormone deficiency

Investigations:
> Hormonal tests
If hormonal tests
abnormal or tumour
mass effects perform
MRI pituitary

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30
Q

What are the direct actions and indirect actions of growth hormone?

A
  1. Indirect actions:
    - growth promoting
    - Insulin-like Growth Factors (IGF-1)
    - Skeletal (Increase cartilage formation and skeletal growth)
    - Extraskeletal ( Increased protein synthesis, cell growth and proliferation)
  2. Direct actions:
    - metabolic, anti-insulin
    - fat metabolism (increase fat breakdown and release)
    - carbohydrate metabolism (increase blood glucose and other anti-insulin effect)
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31
Q

Talk about thyroid hormone function.

A

> Accelerates food metabolism
Increases protein synthesis
Stimulation of carbohydrate metabolism
Enhances fat metabolism
Increase in ventilation rate
Increase in cardiac output and heart rate
Brain development during foetal life and postnatal development
Growth rate accelerated

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32
Q

What is the half-life of T4 and T3?

A

In periphery T4 converted to T3
Half life T4 – 5 to 7 days
Half life T3 – 1 day

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33
Q

Talk about the structure of adrenal gland.

A
  1. Cortex
    > Zona Glomerulosa
    > Zona Fasciculata
    > Zona Reticularis
  2. Medulla
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34
Q

What does adrenal gland secrete?

A

A) In the cortex:
Steroids
1. Mineralocorticoids
- aldosterone
2. Glucocorticoids
- cortisol androgens
3. Androgens
- androstenedione
- dihydroepiandrosterone
(DHEA)
B) In the medulla:
1. Epinephrine
2. Norepinephrine

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35
Q

Talk about “Renin- Angiotensin- Aldosterone” system.

A

Angiotensin (Liver)
(Renin from kidney act on it)
Angiotensin-1
(ACE from lung)
Angiotensin-2

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36
Q

Talk about adrenal hormones in short-term stress.

A

> Stress in hypothalamus
Nerve impulse
Spinal cord
Preganglionic sympathetic fibres
Adrenal Medulla
Epinephrine & Norepinephrine

Short-term stress response
> Heart Rate increases
> Blood pressure increases
> Bronchioles dilate
> Liver convert glycogen to glucose and releases glucose to blood
> Blood flow changes, reduces digestive system activity and urine output
> Metabolic Rate increases

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37
Q

Talk about adrenal hormones in long-term stress.

A

> Stress in hypothalamus
Corticotropin-releasing hormone (CRH)
Corticotropic cells of anterior pituitary gland
Adrenal cortex

Long-term stress response:
> Kidneys retain sodium and water
> Blood volume and blood pressure rise
> Proteins or fats converted to glucose or broken down for energy
> Blood glucose increases
> Immune system suppressed

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38
Q

For gonas, what does FSH and LSH act on>

A

FSH - Granulosa Cell
LH - Theca cell

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39
Q

What is appetite?

A

desire to eat food

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40
Q

What is hunger?

A

need of eating

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41
Q

What is Anorexia?

A

lack of appetite

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42
Q

What is satiety?

A

feeling of fullness -
disappearance of appetite after a meal

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43
Q

What is body mass index? (BMI)

A

wt (kg)/ht (m2)

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44
Q

List the BMI range for
a) Underweight
b) normal
c) overweight
d) obese
e) morbidly obese

A

<18.5 underweight
18.5 - 24.9 normal
25.0 - 29.9 overweight
30.0 - 39.9 obese
>40 morbidly obese

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45
Q

What are the risks of being obese (what will it cause?)

A

Type II diabetes
Hypertension
Coronary artery disease
Stroke
Osteoarthritis
Obstructive sleep apnoea
Carcinoma
Breast
Endometrium
Prostate
Colon

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46
Q

What does weight regulation depend on?

A

Environment + gene -> which contribute to normal fat mass ( and there is negative feedback mechanism too)

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47
Q

Talk about the simplified scheme of appetite regulation.

A

Energy expenditure vs. Energy intake in
1) GI Tract
2) Brain
3) Adipose Tissue

In an individual weight is normally remarkably constant
- hardwired to maintain a specific weight

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48
Q

Why do we eat?

A

Internal physiological drive to eat
Feeling that prompts thought of food and motivates food consumption

External psychological drive to eat
Sometimes even in the absence of hunger (e.g buffet)

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49
Q

State the 2 centres in hypothalamus when Hypothalamus plays a central role
in appetite regulation

A
  1. Lateral hypothalamus - hunger centre
  2. Ventromeidal hypothalamic nucleus - satiety center
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50
Q

What are the factors that control appetite?

A
  • psychological factors
  • neural afferent (vagal)
  • Gut peptides (CCK, ghrelin, PYY)
  • Metabolites (glucose, ketones)
  • Hormones (leptin, insulin, cortisol)
  • Cultural factors

Central controllers of appetite
- Increase appetite (NPY, AgRP)
- Decrease appetite (CART, GLP-1, Serotonin)

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51
Q

Talk about integration in hypothalamus for the regulation of appetite.

A

Leptin
- Inhibits NPY and AgRP
- Stimulates POMC and CART

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52
Q

Talk about Leptin.

A

Expressed in white fat
Binds to leptin receptor
- cytokine receptor family
- in hypothalamus

Switches off appetite and is
immunostimulatory

ob/ob mouse - leptin deficient
hyperphagic
hyperinsulinaemic
very obese
Blood levels increase after meal
Blood levels decrease after fasting

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53
Q

Talk about peptide YY in appetite regulation.

A
  • 36 amino acids
  • Structurally similar to NPY
  • Binds NPY receptors
  • secreted by neuroendocrine cells in ileum,
  • pancreas and colon in response to food
  • inhibits gastric motility
  • reduces appetite
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54
Q

Talk about CCK (Cholecystokinin)

A

Receptors in pyloric sphincter
- delays gastric emptying
- gall bladder contraction
- insulin release

and via vagus - satiety

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55
Q

Talk about ghrelin.

A

28 amino acid
Acyl side chain
Expressed in stomach

Action: stimulates - Growth hormone release
- appetite - orexigenic

Blood levels high when fasting, fall on re-feeding

Levels lower after gastric bypass surgery

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56
Q

What are the 3 signs and symptoms for POMC deficiency?

A
  1. Pale skin
  2. Adrenal Insufficiency
  3. Hyperphagia and Obesity
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57
Q

Talk about the action of Leptin and Insulin.

A
  1. Stimulate- POMC/CART neurons > increases CART and alpha-MSH levels
  2. Inhibit NPY/AgRP neurons > decrease NPY and AgRP

Net effect : ↑ Satiety and decrease Appetite

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58
Q

Talk about ghrelin

A

stimulates NPY/AgRP > increase NPY and AgRP secretion
- ↑ Appetite

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59
Q

Talk about PYY

A

PYY3-36 is a homolog of NPY

Binds to an inhibitory receptor on NPY/AgRP , decrease secretion of NPY and AgRP - decrease Appetite

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60
Q

Talk about AMPK

A

During fasted state,
NPY increases
Glucose decreseas
Insulin decreseases
Ghrelin increases
Leptin decreases
alphaMSH decreases
AgRP increases

go toes AMPK
decreases Malonyl CoA

2 enzyme involded -
a) Acetyl CoA Carboxylase
b) Malonyl CoA Decarboxylase

increase appetite and vice versa

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61
Q

Role of Incretins in Glucose Homeostasis and Appetite Suppression?

A

> Decrease gut motility
Increase satiety, decrease appetite
Increase glucose uptake by muscles
Decrease blood glucose

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62
Q

What happen during fasting state in regulation of CHO metabolism in non diabetic humans?

A

all glucose comes from liver (and a bit from kidney)

Breakdown of glycogen

Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol)

Glucose is delivered to insulin independent tissues, brain and red blood cells
Insulin levels are low

Muscle uses FFA for fuel

Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat

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63
Q

What happen after feeding (postprandial) in regulation of CHO metabolism in non diabetic humans?

A

After feeding (post prandial) - physiological need to dispose of a nutrient load

Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon

40% of ingested glucose goes to liver and 60% to periphery, mostly muscle

Ingested glucose helps to replenish glycogen stores both in liver and muscle

High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall

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64
Q

What are the site of insulin and glucagon secretion of the endocrine pancreas?

A

beta cells ans alpha cells respectively

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65
Q

What kind of substances can be used as fuel for a short period of time?

A

ketone

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66
Q

What is paracrine cross-talk in endocrine pancreas?

A

paracrine ‘crosstalk’ between alpha and beta cells are physiological, i.e. local insulin release inhibits glucagonan effect lost in diabetes

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67
Q

Talk about the insulin secretion mechanism from the beta cells.

A
  1. Glucose entry through GLUT2 transporter and glucokinase
  2. Potassium channel closes and depolarises cell membrane
  3. calcium channels open and calcium influx
  4. insulin secretion
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68
Q

Talk about insulin action in muscle and fat cells.

A
  1. Insulin binds to insulin receptor on plasma membrane of muscle or fat cells
  2. Intracellular cascades - intracellular GLUT$ vesicles
  3. GLUT4 vesicle mobilization to plasma membrane
  4. GLUT4 vesicle integration into plasma membrane
  5. Glucose entry into cell via GLUT4
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69
Q

Talk about insulin in carbohydrate metabolism.

A

> Supresses hepatic glucose output
 Glycogenolysis
 Gluconeogenesis
Increases glucose uptake into insulin sensitive tissues (muscle, fat)
Suppresses
- Lipolysis
- Breakdown of muscle

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70
Q

Talk about glucagon in carbohydrate mechanism.

A

> Increases hepatic glucose output
 Glycogenolysis
 Gluconeogenesis
Reduce peripheral glucose uptake
Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs)
Lipolysis
Muscle glycogenolysis and breakdown

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71
Q

What is diabetes mellitus?

A

A disorder of carbohydrate metabolism characterised by hyperglycaemia

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72
Q

How can diabetes mellitus cause morbidity and mortality through?

A

Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State )

Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)

Side effects of treatment- hypoglycaemia

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73
Q

Diabetes is associated with serious complications. What are they?

A
  1. Diabetic retinopathy
    - Affects over one-third of people with diabetes; leading cause of vision loss in working-age adults1
  2. Diabetic nephropathy
    - Leading cause of
    end-stage renal disease
  3. Stroke
    - Diabetes increases risk of stroke by 2- to 6-fold
  4. Cardiovascular Disease
    - Most common cause of death and disability among people with diabetes
  5. Diabetic Neuropathy
    - Up to 28% of foot ulcers may result in some
    form of lower extremity amputation
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74
Q

What are the different types of diabetes?

A
  • Type 1
  • Type 2
  • Includes gestational and medication-induced diabetes
  • Maturity onset diabetes of youth (MODY), also called monogenic diabetes
  • Pancreatic diabetes
  • “Endocrine Diabetes” (Acromegaly/Cushings)
  • Malnutrition related diabetes
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75
Q

What is the definition of diabetes?

A

> Symptoms and random plasma glucose > 11 mmol/l
Fasting plasma glucose > 7 mmol/l
No symptoms - GTT (75g glucose) fasting > 7 or 2h value > 11 mmol/l (repeated on 2 occasions)
HbA1c of > 48mmol/mol (6.5%)

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76
Q

Talk about the pathogenesis of Type 1 Diabetes.

A

> An insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction

> Beta cells express antigens of HLA histocompatability system perhaps in response to an environmental event (?virus)

> Activates a chronic cell mediated immune process leading to chronic ‘insulitis’

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77
Q

Talk about glucose metabolism and type 1 diabetes.

A

> Failure of insulin secretion leads to:
- Continued breakdown of liver glycogen
- Unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
- Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake

> Rising glucose concentration results in increased urinary glucose losses as renal threshold (10mM) is exceeded

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78
Q

What does failure to treat with insulin leads to?

A

> Increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose
perceived ‘stress’ leads to increased cortisol and adrenaline
progressive catabolic state and increasing levels of ketones

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79
Q

What are the symptoms of diabetes?

A

> feeling very thirsty
peeing more frequently than usual, particularly at night
feeling very tired
weight loss and loss of muscle bulk
itching around the penis or vagina, or frequent episodes of thrush
cuts or wounds that heal slowly
blurred vision

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80
Q

Talk about glucose metabolism and Type 2 diabetes.

A

> A consequence of insulin resistance and progressive failure of insulin secretion (but insulin levels are always detectable)
- Impaired insulin action leads to
Reduced muscle and fat uptake after eating
- Failure to suppress lipolysis and high circulating FFAs
- Abnormally high glucose output after a meal

> Even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive

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81
Q

Summarise type 1 diabetes in 1 sentence.

A

Severe insulin deficiency due to autoimmune destruction of the cell (initiated by genetic susceptibility and environmental triggers)

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82
Q

Summarise type 2 diabetes.

A

Insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors (obesity and lack of physical activity)

Recent research indicates lipid deposition in liver and pancreas lead to both insulin resistance and impaired insulin secretion

83
Q

Talk about the principle of treatment for diabetes in general.

A

Control of symptoms

Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states

Identification and prevention of long-term microvascular complications

Limited evidence yet that glucose control per se reduces cardiovascular events (confirmed by recent clinical trials, ACCORD, ADVANCE) in the short-term

But long-term follow-up indicates a modest reduction in IHD from tight glucose control if started at diagnosis

HbA1c 50mmol/mol (6.5%) (as low as possible in those not on insulin or sulphonylureas)

84
Q

What is the different drugs for type 2 diabetes? (just the names)

A
  1. Sulphonylureas (gliclazide, glibenclamide)
  2. Thiazolidinediones (pioglitazone - ACTOS)
  3. GLP-1 analogues
  4. DPP-IV inhibitors (oral)
  5. SGLT2 - inhibitors

> Metformin first line
Sulphonylureas are no longer the second line agents of choice
DPP-IV inhibitors, GLP1 analogues, SGLT-2 inhibitors are replacing sulphonylureas
Use of glitazones rarely used

85
Q

Talk about Sulphonylureas (gliclazide, glibenclamide)

A
  • stimulate insulin release by binding to -cell receptors
  • Improve glycaemic control (1-2% in HbA1c) at the expense of significant weight gain
  • Do not prevent the gradual failure of insulin secretion
  • Can cause hypoglycaemia (occasionally prolonged and fatal, particularly in the elderly and when renal function is impaired)
  • Use gliclazide in most people
    > Warn and document the risks of hypoglycaemia
86
Q

Talk about Thiazolidinediones (pioglitazone - ACTOS).

A

> Bind to the nuclear receptor PPAR (peroxisome proliferator-activated receptor)
Activate genes concerned with glucose uptake and utilisation and lipid metabolism
Improve insulin sensitivity
Need insulin for a therapeutic effect
Glitazones relatively rarely used but may be useful in some sub-groups
-Increase weight
- Increase the risk of heart failure
- Increase the risk of fractures

87
Q

What are the criteria for an ideal drug in type 2 diabetes?

A
  • Reduce appetite and induce weight loss
  • Preserve beta-cells and insulin secretion
  • Increase insulin secretion at meal time
  • Inhibit counterregulatory hormones which increase blood glucose such as glucagon
  • Not increase the risk of hypoglycaemia during treatment
88
Q

What are the effects of GLP-1?

A
  • stimulates insulin secretion
  • suppresses glucagon secretion
  • slows gastric emptying
  • reduces food intake
  • increases beta cell mass and maintains beta cells function
  • improves insulin sensitivity
  • enhances glucose disposal
89
Q

Native GLP-1 is rapidly degraded by what?

A

DPP-IV

90
Q

What are some examples of GLP-1?

A

Exenatide(BYETTTA) twice daily
Once weekly exenatide (BYDUREON)
Liraglutide (VICTOZA) once daily
Lixisenatide (LYXUMIA) once daily
Dulaglutide (TRULICITY) once weekly
Semaglatide (OZEMPIC) once weekly
Oral semaglutide (RYBELSUS) daily

Lower glucose Reduce weight and CVD independent of glucose lowering

91
Q

What are some examples of DPP-IV inhibitors (oral) ?

A

Oral agents but modest glucose lowering effect, no effect on CVD or weight

Vildagliptin (GALVUS)
Sitagliptin (JANUVIA)

92
Q

Talk about SGLT2- inhibitor.

A

SGLT2 inhibitors block the reabsorption of glucose in the kidney, increase glucose excretion, and lower blood glucose levels

Agents include empagliflozin, canagliflozin, dapagliflozin

May have specific benefit in reducing CV mortality

Side effects, genital thrush, increased risk of euglycaemic ketoacidosis including in type 2 diabetes, now licensed in type 1 diabetes

93
Q

Why doesn’t DKA occur in Type 2 diabetes?

A

It is rare because the low insulin levels are sufficient to suppress catabolism and prevent ketogenesis. It can occur if hormones such as adrenaline rise to high levels (eg during an MI)

94
Q

Why does obesity cause Type 2 diabetes?

A

Obesity (particularly central) impairs insulin action. In those, already insulin resistant due to genetic factors and who have progressive impairment in insulin secretion this brings out diabetes at an early stage.

95
Q

Why does insulin secretion become impaired in Type 2 diabetes?

A
  • not entirely clear, possibly related to
    > genetic predisposition (i.e. abnormalities of insulin secretion in first degree relatives)
    > ‘glucotoxicity’ hyperglycaemia inhibits insulin secretion
  • Main factor is lipid deposition in the pancreatic islets which prevent normal section of insulin
96
Q

What is HBA1C test ?

A

HbA1C - excellent test, prickle the blood - just tell you the blood thats happening NOW, but we want to know what happened 3 months ago, RBC can survive 3 months, that’s why test HbA1C test (if you have huge blood loss previously then its not reliable, sickle cell, thalassemia, can also affect the result)

test for blood glucose level btw

97
Q

Why high level of glucose causes macro or microvascular complications?

A

Because the glucose tends to stick to the blood vessels

97
Q

Why high level of glucose causes macro or microvascular complications?

A

Because the glucose tends to stick to the blood vessels

98
Q

Will we get diabetic ketoacidosis in Type 2 diabetes?

A

for type 2 diabetes, we dont get ketoacidosis thats easily, since its very sensitive to insulin, but will still get hyperglycemiae (DKA can be at late stage of diabetes type 2; for type 1 u will get DKA at the get go; for type 2 like after 10 plus years, we can have DKA ; type 2 - hyperosmolar hyperglycaemia)

99
Q

Why does the pancreas fail to work in Diabetes?

A

not only does the pancreas fail because its working super hard, but the high level of glucose is directly toxic to the beta cells (direct glucose toxicity)

100
Q
A
101
Q

What are the differences between Type 1 and Type 2 diabetes?

A

Type 1 DM
- Autoimmune condition (β-cell damage) with genetic component
- Profound insulin deficiency

Type 2 DM
- Insulin resistance
- Impaired insulin secretion and progressive β-cell damage but initially continued insulin secretion
- Excessive hepatic glucose output
- Increased counter-regulatory hormones including glucagon

102
Q

Talk about Modern insulin therapy in T1D.

A

> Separation of basal from bolus insulin to mimic physiology
Pre-meal rapid acting boluses adjusted according to pre-meal glucose and carbohydrate content of food to cover meals
Basal insulin should control blood glucose in between meals and particularly during the night
Basal insulin given as either twice daily insulin levemir (basal analogue or once daily degludec) adjusted to maintain fasting blood glucose between 4–7 mmol/L

103
Q

Tight control of diabetes reduces the complication of the eyes and kidneys, but at what expense?

A

at the expense of hypoglycemia

104
Q

What are the Different insulin approaches in diabetes ?

A
  1. Once-daily basal insulin (only used in
    Type 2 diabetes)
  2. Twice-daily mix-insulin (used both types of diabetes)
  3. Basal-bolus therapy (mostly Type 1 diabetes but somtimes Type 2)
105
Q

What are the advantages and disadvantages of Basal insulin in type 2 diabetes .

A

Advantages:
> Simple for the patient, adjusts insulin themselves, based on fasting glucose measurements
> Carries on with oral therapy, combination therapy is common
> Less risk of hypoglycaemia at night

Disadvantages:
> Doesn’t cover meals
> Best used with long-acting insulin analogues which are considered expensive.

106
Q

What are the advantages and disadvantages of pre-mixed insulin in diabetes?

A

Advantages:
> Both basal and prandial components in a single insulin preparation
> Can cover insulin requirements through most of the day

Disadvantages:
> Not physiological
> Requires consistent meal and exercise pattern
> Cannot separately titrate individual insulin compononents
> Increase risk for nocturnal hypoglycaemia
> Increase risk for fasting hyperglycaemia if basal component does not last long enough
> Often requires accepting higher HbA1c goal of <7.5% or ≤8% (<58 or ≤64 mmol/mol)

107
Q

What are the current classification of hypoglycemia?

A

Level 1:
- Alert value
> Plasma glucose <3.9 mmol/l (70 mg/dl) and > no symptoms

Level 2:
- Serious biochemical
> Plasma glucose <3.0 mmol/l
(55 mg/dl)

Level 3 (Severe & Non-severe)
- Non-severe: Patient has symptoms but can self-treat and cognitive function is mildly impaired

  • Severe: Patient has impaired cognitive function sufficient to require external help to recover (Level 3)
108
Q

Hypoglycaemia has pathophysiological effects on multiple organs and systems, such as?

A
  1. Brain
    - Cognitive dysfunction
    Blackouts, seizures, comas
    Psychological effects
  2. Heart
    - Increased risk of myocardial ischaemia
    Cardiac arrhythmias
  3. Musculoskeletal
    - Falls, accidents, driving accidents
    Fractures
    Dislocations
  4. Circulation
    - Inflammation
    Blood coagulation abnormalities
    Haemodynamic changes
    Endothelial dysfunction
109
Q

What are the common hypoglycemia symptoms?

A
  1. Development of the symptoms
    a) Autonomic
    - Trembling
    - Palpitations
    - Sweating
    - Anxiety
    - Hunger

b) Neuroglycopenic
- Difficulty concentrating
- Confusion
- Weakness
- Drowsiness
- Dizziness
- Vision changes
- Difficulty speaking

c) Non-specific
- Nausea
- Headache

  1. Low blood glucose (<3.9 mmol/l)*
  2. Response to treatment with carbohydrate
110
Q

At what level of blood glucose there will be symptoms onset of Autonomic–Neuroglycopenic? (during hypoglycemia)

A

3.2–3.0 mmol/L

111
Q

At what level of blood glucose there will be glucagon secretion and adrenaline secretion during hypoglycemia?

A

3.8 mmol/L; 3.5 and 2.5 mmol/L

112
Q

What are the causes of hypoglycemia?

A
  • Long duration of hypoglycemia
  • Tight glycaemic control with repeated episodes of non-severe hypoglycaemia
  • Increasing age
  • Use of drugs (prescribed/ alcohols)
  • Sleeping
  • Increasing physical activity
113
Q

What are the risk factors that should be taken into consideration when we are doing hypoglycemic screening?

A

Low HbA1c; high pre-treatment HbA1c in T2DM
Long duration of diabetes
A history of previous hypoglycaemia
Impaired awareness of hypoglycaemia (IAH)*
Recent episodes of severe hypoglycaemia
Daily insulin dosage >0.85 U/kg/day
Physically active (e.g. athlete)
Impaired renal and/or liver function

114
Q

What is impaired awareness of hypoglycemia?

A

So you know when you have low glucose or hypoglycemia, usually what happened is that your Ventromedial hypothalamus will fire sympathetic system to release adrenaline to break down more glucose for you, however, in long term, the brain wont be able to sense the low level of glucose anymore, thats why the adrenaline is functioning, just that the brain is not sensing, so there is hypoglycemia.

115
Q

What are the other strategies to prevent hypoglycemia?

A
  1. Patient education
    > Discuss hypoglycaemia risk factors and treatment with patients on insulin or sulphonylureas
    > Educate patients and caregivers on how to recognize and treat hypoglycaemia
    > Instruct patients to report hypoepisodes to their doctor/educator
  2. Consider enrolling patients with frequent hypoglycaemiain a blood glucose awareness training programme
116
Q

Talk about the treatment of hypoglycemia.

A
  1. Recognize symptoms so they can be treated as soon as they occur
  2. Confirm the need for treatment if possible (blood glucose <3.9 mmol/l is the alert value)
  3. Treat with 15 g fast-acting carbohydrate to relieve symptoms
  4. Retest in 15 minutes to ensure blood glucose >4.0 mmol/l and re-treat (see above) if needed
  5. Eat a long-acting carbohydrate to prevent recurrence of symptoms
117
Q

What are the effects of parathyroid hormone (PTH)?

A
  1. Kidney
    - Increase Ca2+ reabsorption
    - decrease phosphate reabsoprtion
    - increase hydroxylation of 25-OH vit D
  2. Bone
    - Increase bone remodelling
    - Bone resorption > Bone formation
  3. Gut (not a direct effect)
    - Increase Ca2+ absorption
    - because of increased 1,25 (OH) 2 vit D
118
Q

What are the summarised PTH response to decreased serum calcium?

A
  1. Increase bone resorption in the bone
  2. Increase Ca2+ absorption in the gut
  3. Increase Ca2+ reabsorption in the kidney
119
Q

Talk about calcium homeostasis and negative feedback.

A

Return serum ionised calcium back to the set point of about 1.1 mmol/

120
Q

Why is maintaining the Ca2+ level that important?

A

Functioning of nerves and muscles

121
Q

What is the formula of corrected serum level?

A

total serum calcium + 0.02 * (40 – serum albumin)

122
Q

What is the consequence of hypocalcemia?

A

Parasthesia
* Muscle spasm
o Hands and feet
o Larynx
o Premature labour
* Seizures
* Basal ganglia calcification
* Cataracts
* ECG abnormalities
o Long QT interval

> Chvostek’s Sign
Tap over the facial nerve
Look for spasm of facial muscles

> Trousseau’s Sign
Inflate the blood pressure cuff
to 20 mm Hg above systolic
for 5 minutes

123
Q

What are the causes of hypoparathyroidism?

A
  • Syndromes
    > Di George (Hypoparathyroidism, Thymic aplasia, Immunodeficiency, Cardiac defects
    Cleft palate, Abnormal facies)
  • Genetic
    > Recessive
    > Dominant
    > X-linked
  • Surgical
  • Radiation
  • Autoimmune
    > isolated
    > polyglandular type 1
  • Infiltration
    > Haemochromatosis
    > Wilson’s disease
  • Magnesium deficiency
124
Q

State the effect on PTH, Calcium, Phosphate level as well as the appropriate/inappropriate response of the Hypoparathyroidism.

A
  • increase PTH
  • decrease calcium
  • decrease phosphate
  • appropriate PTH response
125
Q

What is pseudohypoparathyroidism?

A
  • Resistance to parathyroid hormone
    o Type 1 Albright hereditary osteodystrophy
    – mutation with deficient Gα subunit
  • Short stature
  • Obesity
  • Round facies
  • Mild learning difficulties
  • Subcutaneous ossification
  • Short fourth metacarpals
  • Other hormone resistance
126
Q

State the effect on PTH, Calcium, Phosphate level as well as the appropriate/inappropriate response of the pseudohypoparathyroidism?

A
  • decrease PTH
  • decrease calcium
  • increase phosphate
  • inappropriate PTH response
127
Q

What can cause hypercalcemia? (like the fake one not the real medical one lmao)

A

Tourniquet on for too long
* Sample old and haemolysed
* The RBC lysed and release calcium

128
Q

Talk about the symptoms and consequences of Hypercalcaemia.

A

Symptoms:
* Thirst, polyuria
* Nausea
* Constipation
* Confusion -> coma

Consequences:
* Renal stones
* ECG abnormalities
* Short QT

129
Q

What are the real causes of hypercalcemia?

A
  • Malignancy (90%)
    o bone mets, myeloma, PTHrP, lymphoma

(hypercalcemia, RBC haemolysed and releasing calcium, if bone is destriyed by cancer cells, will release calcium, some tumours produce PTHrP, or kidney cancer produces it too, act just like pth, lymphoma makes large number of monocyte macrophage which express 1-25 vit d, activate vit d, vit d poisoning → hypercalcemia)

  • Primary hyperparathyroidism
  • Thiazides (diuretic- retain calcium)
  • Thyrotoxicosis
  • Sarcoidosis (sarcoidosis same mechanism as lymphoma)
  • Familial hypocalciuric / benign hypercalcaemia
  • Immobilisation
  • Milk-alkali
  • Adrenal insufficiency
  • Phaeochromocytoma
130
Q

State the effect on PTH, Calcium, Phosphate level as well as the appropriate/inappropriate response of the Hypercalcaemia.

A
  • decrease PTH
  • increase calcium
  • (complicated and not relevant) phosphate
  • appropriate PTH response
131
Q

State the effect on PTH, Calcium, Phosphate level as well as the appropriate/inappropriate response of the Primary Hyperparathyroidism.

A
  • increase PTH
  • increase calcium
  • decrease phosphate
  • inappropriate PTH response
132
Q

What are the consequences of primary hyperparathyroidism?

A

(Bones, Stones, Groans, Moans)
* Bones
o Osteitis fibrosa cystica
o Osteoporosis

  • Kidney stones
  • Psychic groans
    o confusion
  • Abdominal moans
    o Constipation
    o Acute pancreatitis
133
Q

Signs of Xray of primary hyperparathyroidism.

A

> The arrows show sub-periosteal
erosions of the phalanges
The skull shows cysts
‘Osteitis fibrosa cystica

134
Q

Main cause of Primary hyperparathyroidism?

A
  • 80% due to single benign adenoma
135
Q

Where does the pituitary gland lie?

A

within the sella turcica or the hypophyseal fossa

136
Q

What structure lies upward to the pituitary gland?

A

optic chiasm

137
Q

How is growth hormone normally released?

A

pulsatile release

138
Q

KEYPOINT: if we remove the thyroid gland, what will happen to the TSH?

A

the TSH will be elevated because there is lack of negative feedback; thyrotoxicosis - TSH will be suppressed (very important in diagnosis and treatment)

139
Q

Talk about the blood circulation supply for the anterior pituitary gland.

A

The anterior pituitary has no arterial blood
supply but receives blood through a
portal venous circulation from the
hypothalamus.

140
Q

Talk about the function of FSH and LH for male and female.

A

LH stimulate testosterone release, FSH is important for producing sperm, LH -oestradiol, FSH - egg production

141
Q

During menopause, does the FSH and LH increase or decrease?

A

During menopause, failure of the ovary, stop secreting oestrogen, don’t get negative feedback, so FSH and LH goes up, take testosterone (anabolic drugs, feedback and switch of gonadotrophy) during GYM, FSH and LH will decrease

142
Q

Talk about Pituitary – thyroid axis.

A

Hypothalamus (TRH) - Pituitary Gland (TSH) - Thyroid (T3&T4)

T3 and T4 produce negative feedback on both TRH and TSH

143
Q

Talk about the 5 regulations of hormone by the hypothalamus-pituitary gland.

A
  1. GHRH & SMS - GH
  2. GnRH - FSH & LH
  3. CRH - ACTH (glucocorticoid (steroid) hormone cortiso)
  4. TRH - TSH - T3&T4
  5. Dopamine - Prolactin
144
Q

What are the possible diseases of the pituitary?

A
  • Benign pituitary adenoma (Pituitary adenomas are benign tumours of the pituitary gland. Most are located in the anterior lobe (front portion) of the gland) - mostly doesn’t cause harm
  • Craniopharyngioma
  • Craniopharyngiomas result from the growth of cells that, early in foetal development, have failed to migrate to their usual area.
  • Craniopharyngiomas are thought to arise from epithelial remnants of the craniopharyngeal duct or Rathke’s pouch (adamantinomatous type) or from metaplasia of squamous epithelial cell rests that are remnants of the part of the stomadeum that contributed to the buccal mucosa (squamous papillary type).
  • Trauma
  • shaking and rupture of the pituitary stalk - hypopituitary
  • Apoplexy / Sheehan’s
  • Pituitary apoplexy is bleeding into or impaired blood supply of the pituitary gland. This usually occurs in the presence of a tumor of the pituitary, although in 80% of cases this has not been diagnosed previously.
  • Sarcoid / TB
  • cause inflammation of the hypothalamus and hypopituitarism
145
Q

KEYPOINT: What are the 3 vital points?? (What does tumour cause?)

A
  1. Pressure on local structure e.g. optic nerves
    – Bitemporal hemianopia
  2. Pressure on normal pituitary
    – hypopituitarism
  3. Functioning tumour
    – Prolactinoma
    – Acromegaly
    – Cushing’s disease
146
Q

What does pressure in local structure cause?

A
  1. Headache
    - streching of the dura by tumour (upward stretch)
  2. Hydrocephalus (rare) (upwards stretch)
  3. Visual field defect - bitemporal hemianopia
    - nasal retinal fibres compressed by tumours (upward stretch)
  4. Cranial nerve pals & temporal lobe epilepsy
    (lateral extension of tumour)
  5. Cerebrospinal fluid (CSF) rhinorrhea - particularly after surgery
    (downward extension of tumour)
147
Q

Usually what colour of pin does physician use to measure vision field?

A

Measuring the visual fields
with a red pin

148
Q

What 3 conditions does functioning pituitary tumour cause?

A
  • Prolactinoma
  • Acromegaly and Gigantism
  • Cushing’s Disease
149
Q

Low growth hormone, what signs and symptoms it will cause?

A

without growth hormone, can get thin and soft skin because lacking of the hormone, central obesity

150
Q

Talk about acromegaly and gigantism.

A

Gigantism - the reason: the pituitary hormone with growth hormone causes hypopituitarism, doesn’t go through puberty, at the end of puberty, bone seal, but no testosterone, there wont be puberty, so bone continues to grow, if grows after the epiphyseal has sealed - will get acromegaly: big jaw and sweat a lot, heart get big as well

151
Q

Talk about prolactinoma.

A
  • More common in women
  • Present with galactorrhoea / amenorrhoea
    / infertility
  • Loss of libido (reduce sex drive)
  • Visual field defect
  • Treatment dopamine agonist eg
  • Cabergoline or bromocriptine

Treat prolactinoma will make them more fertile, if start treatment should warn them on this

152
Q

Who is the first person that performs transphenoidal surgery on the pituitary gland?

A

Harvey Cushing

153
Q

What is the difference between Cushing syndrome and Cushing disease?

A

Cushing disease occurs when Cushing syndrome is caused by an ACTH-producing pituitary tumor, whereas Cushing syndrome is the set of symptoms that results when there is a surplus of cortisol in the body.

154
Q

Talk about Cushing disease.

A

Cushing disease is pituitary secreting ACTH, too much steroid in childhood will stop growing, if children are fat and tall, obesity, if fat and short might have endocrine issues, striae or stretch mark-quite common during puberty also too much steroid in chusing disease, thin skin, bruising, ulcer, infection.

155
Q

What is the normal adult male testis volume?

A

15-20/25 ml

Orchidometer
measures
testicular volume
in mL

156
Q

What happen when testis not getting bigger than 5ml?

A

Typical germ cell failure

157
Q

Breast budding is a sign of ?

A

Oestrogen

158
Q

Describe puberty.

A

Describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms.

159
Q

What are the definitive signs of puberty in male and female.

A

–Girls - Menarche – first menstrual bleeding.
– Boys - first ejaculation, often nocturnal.
– These do not signify fertility

160
Q

you can only have endometrium when you have what hormone?

A

oestrogen

161
Q

Acidic vaginal pH to protect from?

A

infection

162
Q

What are the Secondary sexual characteristics ?

A

Girls:
* Ovarian oestrogens regulate the growth of
breast and female genitalia
* Ovarian and adrenal androgens control pubic and axillary hair

Boys:
* Testicular androgens
–External genitalia and pubic hair growth
–enlargement of larynx and laryngeal muscles -> voice deepening

163
Q

Talk about Tanner Stages in Boys.

A

Stage 1:
* Prepubertal: No pubic hair
* Testicular length <2.5 cm
* Testicular volume <3.0 mL

Stage 2:
* Sparse growth of slightly curly pubic hair, mainly base of penis
* Testes > 3 mL (>2.5 cm in longest diameter)
* Scrotum thinning and reddening

Stage 3:
* Thicker, curlier hair spread to mons pubis
* Growth of penis in width and length; further growth of testes

Stage 4:
* Adult-type hair, not yet spread to medial surface of thighs
* Penis further enlarged; testes larger, darker scrotal skin colour

Stage 5:
* Adult-type hair spread to medial surface of thighs
* Genitalia adult size and shape

164
Q

Talk about Tanner’s stages in girl.

A

Stage 1:
* Prepubertal: No pubic hair
* Elevation of papilla only

Stage 2:
* Sparse growth of long, straight or slightly curly, minimally
pigmented hair, mainly on labia
* Breast bud noted/ palpable; enlargement of areola

Stage 3:
*Darker, coarser hair spreading over mons pubis
* Further enlargement of breast and areola, with no separation of contours

Stage 4:
* Thick adult-type hair, not yet spread to
medial surface of thighs
* Projection of areola and papilla to form secondary mound above level of breast

Stage 5:
* Hair adult-type and distributed in classic inverse triangle
* Adult contour breast with projection of papilla only

165
Q

During normal puberty in girls, what are the mean age onset of breast development, pubic hair, menses (menarche)

A
  1. Breast development - 8-10
  2. Pubic hair 8-11
  3. Menses (menarche) 12-13
166
Q

Talk about thelarche - breast development.

A

First visible change of puberty
* Induced by estrogen
* Completed in about 3 years
* Effects of estrogen on the breast
- Ductal proliferation
- Site-specific adipose deposition
- Enlargement of the areola & nipple
* May be unilateral for several months
* Other hormones involved in breast development
- prolactin, glucocorticoids, insulin

167
Q

Compare Prepubertal and Pubertal Uterus and Ovary.

A
  1. Prepubertal
    - uterus
    * Corpus : cervix ratio 1:2
    * Tubular shape
    * Length 2-3 cm
    * Volume 0.4-1.6 ml
    * Endometrium single layer of
    cuboidal cells

ovary: Volume 0.2-1.6 ml
* Non-functional

  1. Pubertal
    Uterus
    * Corpus : cervix ratio 2:1
    * Pear shape
    * Length 5-8 cm
    * Volume 3-15ml
    * Endometrium increased
    thickness

Ovaries
* Volume 2.8-15ml
* Multicystic

168
Q

What does a pelvic ultrasound look for?

A

Are the Mullerian structures present?
* Morphology of uterus?
* Morphology of ovaries?

169
Q

What does a pelvic ultrasound look for?

A

Are the Mullerian structures present?
* Morphology of uterus?
* Morphology of ovaries?

170
Q

Compare the prepubertal and pubertal vagina.

A
  1. Prepubertal
    * Reddish in colour
    * Thin atrophic columnar
    epithelium
    * pH neutral
    *Length 2.5-3.5 cm
  2. Pubertal
    * Dulling of the reddish colour
    * Thickening of the epithelium
    * Cornification of the
    superficial layer
    stratified squamous epithelium
    * pH acidic 3.8-4.2
    * Secretion of clear whitish
    discharge in the months
    before menarche
    * Length 5-8 (-12)cm
171
Q

Talk about the Maturation of the external genitalia.

A

Under the effect of oestrogens:
– Labia majora & minora increase in size & thickness
– Rugation & change in colour of the labia majora
– Hymen thickens
– Clitoris enlarge
– Vestibular glands begin secretion

Adrenal androgens & ovarian androgens:
– Growth of pubic & axillary hair

172
Q

At what age does height spurt in girl and boy?

A

girl - 12
boy - 14

173
Q

Talked about precocious puberty and delayed puberty in males and females.

A
  1. Precocious puberty: onset of secondary sexual characteristics before 8 yrs (girl), 9 yrs (boy)
  • Menarche before 9 yrs may lead to short stature
  1. Delayed puberty: absence of secondary sexual characteristics by 14 yrs (girl), 16 yrs (boy)
    * Delayed puberty leads to reduced peak bone mass
    and osteoporosis
174
Q

Talk about male and female HPG axis.

A

Female HPG axis:
Hypothalamus- Pituitary - Gonad (Ovary)

Male HPG axis:
Hypothalamus - Pituitary - Gonad (Testis)

175
Q

Physical changes during puberty is controlled by what?

A

Physical changes controlled by gonadal and adrenal sex steroids regulated by the
gonadotrophins, LH and FSH

176
Q

Puberty only requires what hormone?

A

hypothalamic GnRH

177
Q

What is Adrenarche?

A

Maturational process of the adrenal gland
* Only observed in humans and in some old
world primates
* Developmental process where a specialized
subset of cells arises forming the androgenproducing zona reticularis (ZR)

Developmentally programmed peripubertal activation of adrenal
androgen production
– Premature or exaggerated adrenarche
up to 2 yrs earlier
* ­ DHEA, DHEA-S
* Mild advanced bone age, axillary
hair, oily skin, mild acne, body odour
* More pronounced in obese children

178
Q

Talk about precocious puberty.

A

Incidence 1 in 5,000 to 10,000
* 90% of patients female
* Idiopathic CPP
– Up to 80% female
– Only 30% male
Rule out brain tumour!

179
Q

Talk about the Differential Diagnosis by GnRH (LHRH) Test.

A

“True” Precocious puberty
Stimulation pubertal range
Stimulated LH:FSH ratio > 1

Precocious pseudopuberty
Stimulation pre-pubertal range or
suppression
Stimulated LH:FSH ratio < 1

180
Q

What are the causes of “True” (Central) Precocious Puberty
(GnRH dependent)

A

Idiopathic precocious puberty:
* CNS tumours
– Optic glioma associated with NF1
– Hypothalamic astrocytoma

  • CNS disorders
    – Developmental abnormalities, hypothalamic
    harmartoma
    – Encephalitis, Brain abscess
    – Hydrocephalus, Myelomeningocele,
    Arachnoid cyst
    – Vascular lesion
    – Cranial irradiation
  • Secondary central precocious puberty
  • Psychosocial, i.e. adoption from abroad
181
Q

What are the causes of Precocious Pseudo-Puberty (GnRH independent)?

A
  • Increased androgen secretion
    – Congenital adrenal hyperplasia (21OHD, 11OHD)
    – Virilizing neoplasm
    – Leydig cell adenoma
    – Familial Male Precocious Puberty – Testotoxicosis
  • Gonadotropin secreting tumours
    – Chorioepitheliomas, germinoma, teratoma
    – Hepatoma, choriocarcinoma
  • McCune-Albright syndrome
  • Ovarian cyst
  • Oestrogen secreting neoplasm
  • (Hypothyroidism)
  • Iatrogenic or exogenous sex hormones
182
Q

What is delayed puberty and what are th types of delayed puberty?

A
  • Idiopathic (constitutional) delay in growth and puberty
    – delayed activation of the hypothalamic pulse generator
  1. Hypogonadotrophic hypogonadism
    – sexual infantilism related to to gonadotrophin deficiency
  2. Hypergonadotrophic hypogonadism
    – primary gonadal problems
183
Q

Talk about the statistic and the consequences of delayed puberty.

A

Occurs in about 3% of children
* In boys, delayed puberty often constitutional
and functional (63%)
* In girls, delayed puberty less common and
often organic
* Delay in puberty leads to delay in acquisition of secondary sex characteristics, psychological problems, defects in reproduction and reduced peak bone mass.

184
Q

Indications for investigation for delayed puberty.

A

Girls
* Lack of breast development by 13 yrs
* More than five years between breas
development and menarche
* Lack of pubic hair by age 14 yrs
* Absent menarche by age 15-16 yrs

Boys
* Lack of testicular enlargement by age 14
yrs
* Lack of pubic hair by age 15 yrs
* More than 5 years to complete genital
enlargement

185
Q

What is the most common cause for delayed puberty in both sexes?

A

Constitutional delay of growth and puberty (CDGP)

Delay in bone maturation, delay in adrenarche
* Frequently family history of late menarche in mother
or sister or delayed growth spurt in father
* Onset of puberty corresponds better with bone age
than chronological age

186
Q

What factors do you take into consideration when taking history for delayed puberty?

A

Totally absent or started and then arrested
* Family history
– constitutional delay
– Infertility
– delayed puberty
* Review of symptoms
* Perinatal history
* Prior medical illness
* Medication
* Psychosocial deprivation

Nutrition, exercise intensity
* Neurologic symptoms
– Headache
– Visual disturbances
– Seizures
– Learning difficulties
– Sense of smell
* Hypoglycaemia
* Cancer history: Radiation, Chemotherapy
* Testicular injury: surgery, radiation, bilateral
torsion, bilateral cryptorchisdism

187
Q

What do you perform in ALL girls with short stature?

A

Karyotyping, CGH array
- might have the common turner’s syndrome

188
Q

What are the laboratory investigations for delayed puberty?

A
  • Complete red blood count
  • U&E, renal, LFT, coeliac ab
  • LH, FSH
  • Testosterone/ Oestradiol
  • Thyroid function, Prolactin
  • DHEA-S, ACTH, Cortisol
  • Karyotying, CGH array
189
Q

Talk about bone age and skeletal maturity

A

> Bone age: skeletal maturity
Delayed bone age in GH deficiency
Advanced bone age in precocious puberty

190
Q

LH is usually dominant in which type of precocious puberty?

A

LH is usually dominant in those with true precocious puberty compared to precocious pseudopuberty

191
Q

ADH medication might lead to precocious or delayed puberty?

A

Delayed puberty

192
Q

In HPG AXIS – Hypogonadism, what does it mean by tertiary, secondary and primary hypogonadism.

A

In primary its the problem with the gonads, in secondary, its the problem with the pituitary, in tertiary, its the problem with the hypothalamus

193
Q

Talk about the type of primary hypogonadism.

A

Hypergonadotropic Hypogonadism
- High GnRH, High FSH & LH,

194
Q

Talk about the type of secondary/tertiary hypogonadism.

A

Hypogonadotropic Hypogonadism

195
Q

What are the common causes of HYPOGONADOTROPHIC HYPOGONADISM?

A
  1. CNS disorders
  2. Isolated Gonadotropin Deficiency
    - Kallmann’s syndrome
    With hyposmia or anosmia
    Without anosmia
  3. Idiopathic and Genetic Forms of Multiple
    Pituitary Hormone Deficiencies
  4. Miscellaneous Disorders
196
Q

Talk about Kallman syndrome.

A

Hypogonadotrophic hypogonadism
* 1 in 10,000 – M:F 4:1
* Anosmia in 75%
* Failure of migration of GNRH neurons
* Multiple generic causes
– X-linked, autosomal recessive or autosomal dominant
– Mutations in Kal-1, FGF-receptor 1, prokineticin
– GnRH-receptor, GPR54 (normoosmic)

197
Q

How to differentiate CHH from CDGP?

A
  • No gold-standard diagnostic test exists to fully
    differentiate CHH from CDGP
  • Inhibin B marker of Sertoli cell number and
    correlates with testicular volume
  • In men with CHH and severe GnRH deficiency
    serum levels of inhibin B are typically very low
  • For partial forms of CHH, inhibin B levels
    overlap with those in patients with CDGP and
    in healthy controls
198
Q

What are the causes of primary gonadal failure, ie HYPERGONADOTROPHIC HYPOGONADISM?

A

Males
Klinefelter’s syndrome (47XXY)

Females
Turner’s syndrome and its variants

199
Q

Talk about Turner’s syndrome.

A

45,X0 GIRLS
* 1 in 2,000 girls
* At birth oedema of dorsa of hands, feet and
loose skinfolds at the nape of the neck
* Webbing of neck, low posterior hairline,
small mandible, prominent ears, epicanthal
folds high ached palate, broad cheast,
cubitus valgus, hyperconvex fingernails
* Hypergonadotrophic hypogonadism,
streak gonads
* Cardiovascular malformations
* Renal malformations (horseshoe kidney)
* Recurrent otitis media
* Short stature

200
Q

Talk about KLINEFELTER SYNDROME.

A
  • Affects approx. 1 in 1,000 males
  • 47, XXY
  • Primary hypogonadism
  • Azoospermia, Gynaecomastia
  • Reduced secondary sexual hair
  • Osteoporosis
  • Tall stature
  • Reduced IQ in 40%
  • 20-fold increased risk of breast cancer
201
Q

Talk about hormone replacement therapy in females.

A
  • Ethinyloestradiol (tablet) or
    Oestrogen (tablets, transdermal)
  • Start with low, gradual increasing doses to
    provide time for pubertal growth and gradual
    breast development
  • Several incremental steps over 2 years until
    full adult replacement dose achieved
  • Once full replacement dose achieved,
    progesterone should be added
202
Q

Talk about hormone replacement therapy in males.

A
  • Testosterone enanthate, IM injection most
    common method of pubertal induction and
    maintenance
  • Increasing use of transdermal testosterone
  • Several incremental steps of 2(-4) years until
    full adult replacement dose achieved
203
Q

Talk about fertility treatment.

A
  • Patients with hypogonadotrophic
    hypogonadism potentially fertile
  • Typical approach to fertility induction is pump
    administered GnRH-TX (requires intact
    pituitary)
  • Or parenteral combination of gonadotrophin
    TX (LH/hCG and FSH)

Phase 2A (11 decks)

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