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WEEK 8 Flashcards

1
Q

What is steroidogenesis?

A

Production of steroids via pathways of reactions involving enzymes-cholesterol is extremely important

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2
Q

What are corticosteroids?

A

Lipid soluble molecules that bind to specific intracellular receptors, altering gene transcription

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3
Q

Describe the process that causes cortisol to cause its effect on target cells

A

Cortisol moves into the cell, binds to cortisol receptor which causes HSP (heat shock protein) release, causes dimerisation of receptor, receptor moves into nucleus and activates GRE (glucocorticoid response element), transcription occurs with help from coactivators (increased RoT)

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4
Q

What is an example of glucocorticoids?

A

Cortisol

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5
Q

Where are glucocorticoids produced and released?

A

Zona Fasciculata (middle)

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6
Q

What are the actions of glucocorticoids?

A

Increase glucose metabolism (augment gluconeogenesis, amino acid generation and increases lipolysis)
Maintenance of circulation (vascular tone and salt+water balance)
Immunomodulation (dampens immune response)
=importance in stress response

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7
Q

How is the large proportion of glucocorticoids transported?

A

Bound to proteins (90% to Corticosteroid-Binding Globulin, 5% to albumin, 5% free=bioavailable)

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8
Q

In clinical practice, how are glucocorticoid levels measured?

A

Using ‘total’ rather than ‘free’ circulating glucocorticoid

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9
Q

What happens to CBG levels due to inflammation?

A

Decrease due to being cleaved, releasing cortisol and therefore increasing ‘free’ cortisol levels

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10
Q

Describe the hypothalamic-pituitary-adrenal (HPA) axis with respect to cortisol and stress

A

‘Stress’ cytokines cause neurotransmitters to cause CRH secretion from hypothalamus, ACTH secreted from anterior pituitary gland, cortisol secreted from zona fasciculata which inhibits hypothalamus and pituitary gland

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11
Q

What effect does ACTH deficiency have on adrenal gland size?

A

Adrenal atrophy (shrinking)

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12
Q

What effect does ACTH excess have on adrenal gland size?

A

Adrenal hyperplasia (enlargement)

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13
Q

What is cortisol circadian rhythm?

A

Daily rhythm with low cortisol levels at night, massive increase in the morning, then decrease until meals where levels rise

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14
Q

Define stress

A

The sum of the body’s responses to adverse stimuli

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15
Q

What is the effect of stress on cortisol levels?

A

Increase and disruption to Circadian/diurnal rhythm

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16
Q

Give 6 examples of stress

A

1) infection
2) trauma
3) haemorrhage
4) medical illness
5) psychological
6) exercise/exhaustion

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17
Q

Where are mineralocorticoids produced and released?

A

Zona Glomerulosa (outermost)

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18
Q

What are the two main mineralocorticoids?

A

Aldosterone and DOC (11-deoxycorticosterone)

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19
Q

What is the main action of mineralocorticoids?

A

Regulation of salt and water balance in kidney, colon, pancreas, salivary and sweat glands

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20
Q

Where is the site of action of aldosterone?

A

Distal convoluted tubule of kidneys

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21
Q

What are two non-classical effects of aldosterone?

A

Myocardial collagen production

Role in cardiac fibrosis/remodelling

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22
Q

What is the specific action of aldosterone?

A

Reabsorption of Na+ and water into the blood, causing K+ secretion into urine which increases circulating blood volume

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23
Q

How does aldosterone cause its action?

A

Binding to mineralocorticoid receptors (MR) on principal cells in DCT, increasing permeability of apical (luminal) membrane to K+ and Na+ and activates basolateral Na+/K+ pump

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24
Q

Describe the feedback loop of the renin-angiotensin-androgen-system (RAAS)

A

Aldosterone stimulates renal perfusion pressure at the vascular level of kidneys, this suppresses renin release from the juxtaglomerular cells, renin stimulates angiotensin->angiotensin 1 (in liver), angiotensin 1->angiotensin 2 via ACE (angiotensin-converting enzyme), A2 stimulates aldosterone release-increasing circulating blood volume and therefore renal perfusion

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25
What is meant by mineralocorticoid receptor specificity?
Both cortisol and aldosterone have an equal affinity to mineralocorticoid receptor
26
How is cortisol changed to not have affinity to MRs and how is this inhibited?
Cortisol->Cortisone via 11beta-HSD2 enzyme | Inhibition of 11beta-HSD2 due to liquorice ingestion
27
Where are adrenal androgens produced and released?
Zona Reticularis (innermost)
28
What is the most abundant adrenal steroid?
DHEA (dehydroepiandrosterone)
29
Give four examples of adrenal androgens
Testosterone DHEA Androstenedione Oestrogen (women)
30
What are the three major actions of androgens?
1) Increased frequency of sexual thought 2) Increased sexual interest 3) Increased satisfaction with physical and mental aspects of sex life
31
How are adrenal androgens regulated?
ACTH rather than gonadotropins (FSH/LH)
32
Where do androgens act?
Ovary theca cells and testis leydig cells and in peripheral tissues
33
How is the Adrenal Medulla different from the Adrenal Cortex?
Influenced by sympathetic pre-ganglionic innervation via the autonomic nervous system rather than hormones
34
What does the Adrenal Medulla synthesise and release?
Catecholamines (main site for adrenaline synthesis)
35
What is the relative production of catecholamines?
80% adrenaline/epinephrine to 20% noradrenaline/norepinephrine
36
What is normal catecholamine synthesis reliant on?
High cortisol levels (permissive effect)
37
What is the relationship between adrenaline and noradrenaline?
Adrenaline is formed from noradrenaline metabolism via phenylethanolamine N-methyltransferase
38
What is the result of sympathetic stimulation on the Adrenal Medulla?
``` stimulation of: tyrosine hydroxylase (tyrosine->DOPA) dopamine beta-hydroxylase (dopamine->noradrenaline) ```
39
What is the result of cortisol induction on the Adrenal Medulla?
stimulation of: tyrosine hydroxylase (tyrosine->DOPA) phenylethanolamine N-methyltransferase (noradrenaline->adrenaline)
40
Why do the actions of catecholamines differ?
Due to different adrenergic receptors
41
What is the main action of catecholamines?
"fight or flight" preparing the body for physical activity via redistribution of circulating blood volume from digestive/excretory/reproductive systems
42
What is the action of alpha1 adrenergic receptors?
smooth muscle contraction
43
What is the action of alpha2 adrenergic receptors?
smooth muscle contraction in pancreas | inhibits transmitter release
44
Where is the action of beta1 adrenergic receptors?
The heart
45
What is the action of beta2 adrenergic receptors?
smooth muscle relaxation in the bladder, uterus and bronchi
46
Define Adrenal insufficiency?
Where the adrenal glands fail to produce enough hormones (mainly cortisol but also aldosterone and DHEA)
47
What are the major symptoms of adrenal insufficiency?
``` Fatigue Weakness Nausea and vomiting Anorexia Abdominal pain Loss of libido (women) ```
48
What are the signs of adrenal insufficiency?
``` Weight loss Hyperpigmentation (patches of darker skin due to increased melanocytes in areas of friction) Hypotension Vitiligo (white integumental patches) Hyponatremia (low Na+ levels in blood) Hyperkalaemia (high K+ levels in blood) Hypoglycaemia Uraemia (raised blood urea) Anaemia (low level of RBCs/haemoglobin) Loss of pubic hair (women) ```
49
What is adrenal insufficiency also known as?
Addison's disease/hypoadrenalism
50
What are the main causes of primary adrenal insufficiency?
Autoimmune adrenalitis (Pts often have other autoimmune conditions-autoimmune polyendocrine syndrome)-most frequent Tuberculosis Congenital adrenal hyperplasia
51
What are the lesser causes of primary adrenal insufficiency?
Bilateral adrenalectomy Bilateral metastasis destroying adrenal glands Bilateral adrenal haemorrhage Drugs
52
What are the three stages of diagnosing primary adrenal insufficiency?
Indicative signs Lab tests The Short Synacthen Test (SST)
53
What would the results of the lab test show if someone had primary adrenal insufficiency?
Low serum Na+ High serum K+ High serum urea Low serum cortisol, high serum ACTH (diagnostic pair) Low serum aldosterone, high serum renin (diagnostic pair)
54
What is the Short Synacthen Test (SST)?
250micrograms of ACTH(1-24) (SYNACTHEN)-i.v. or i.m. measure serum cortisol 30 mins before and after expected cortisol increase >400-500mmol/L
55
What are the main causes of secondary adrenal insufficiency?
Hypopituitarism (low ACTH levels) | Iatrogenic due to exogenous glucocorticoid treatment
56
What is the difference between primary and secondary adrenal insufficiency?
Primary=cortisol not produced by adrenal glands but ACTH produced by pituitary Secondary=ACTH not produced by pituitary gland
57
How would you differentiate diagnosis of primary adrenal insufficiency?
if antibody negative and male patient: measure very long chain fatty acids (exclude adrenoleukodystrophy/adrenomyeloneuropathy) if both negative: CT adrenals and exclude TB exclude congenital adrenal hyperplasia
58
How would you differentiate diagnosis of secondary adrenal insufficiency?
check if RAAS is intact: no aldosterone replacement needed | check if other hypothalamic-pituitary axes are affected
59
What are the two functions of 11beta-HSD2?
1) Converts cortisol/hydrocortisone (active) to cortisone/cortisone acetate (inactive) 2) Converts prednisolone (active) to prednisone (inactive)
60
What are the two functions of 11beta-HSD1?
1) Converts cortisone/cortisone acetate (inactive) to cortisol/hydrocortisone (active) 2) Converts prednisone (inactive) to prednisolone (active)
61
Why is the active form, cortisol/hydrocortisone, preferred over cortisol/cortisone acetate?
Variable 11beta-HSD1 activity
62
What is the effect of using the active form (cortisol) over the inactive form (cortisone)?
Lower cortisol dose required
63
What is the effect of using the active form (prednisolone) over the inactive form (prednisone)?
Lower prednisolone dose required
64
Why are prednisolone and dexamethasone (synthetic) longer-acting and what is the result of this?
Greater affinity to glucocorticoid (GC) receptor, therefore a lower dose is required
65
What are therapeutic corticosteroids?
Corticosteroids given as replacement therapy (hydrocortisone/prednisolone/dexamethasone)
66
What is 100 mineralocorticoid units (MCU) equivalent to?
100micrograms of fludrocortisone (aldosterone equivalent) | 40mg of hydrocortisone
67
What should be paused if daily hydrocortisone dose is greater than 50mg?
Fludrocortisone (aldosterone equivalent)
68
How does dexamethasone differ from other corticosteroids given therapeutically?
It has no mineralocorticoid activity
69
What is the long-term treatment of adrenal insufficiency?
Replace glucocorticoid-hydrocortisone: 15mg AM/10mg PM Replace mineralocorticoid-fludrocortisone: 100-200micrograms/day (only in primary adrenal insufficiency) Adrenal androgens-DHEA (in women with low libido/energy)
70
What is the acute treatment of adrenal insufficiency (in medical emergency)?
Treat shock: generous saline infusion, immediate injection of hydrocortisone (100mg) followed by continuous hydrocortisone infusion (200mg/24hr)
71
What is the first step in crisis prevention in adrenal insufficiency patients?
Steroid card and/or medic-alert bracelet to identify exogenous steroid dependence
72
What is sick day rule 1 treatment in crisis prevention in adrenal insufficiency patients?
Double daily glucocorticoid dose
73
What is sick day rule 2 treatment in crisis prevention in adrenal insufficiency patients?
100mg hydrocortisone (i.v.), followed by continuous infusion of 200mg/24hr hydrocortisone and fluid resuscitation
74
What is the cause of sick day rule 1?
Moderate stress-fever, infection requiring antibiotics, minor surgery under LA
75
What is the cause of sick day rule 2?
Severe stress-trauma, major surgery, persistent vomiting, colonoscopy, active labour
76
What is adrenal crisis?
A life-threatening medical emergency caused by insufficient cortisol levels
77
What are the signs and symptoms of adrenal crisis?
``` Nausea and vomiting Severe weakness Reduced consciousness Syncope (fainting) Fever Confusion Hypovolemic shock Abdominal guarding ```
78
What is the follow up after adrenal crisis?
6-12 monthly evaluations of signs and symptoms: - periodical reinforcement of sick day rules - check steroid card, emergency kit and injection training - measure body weight and blood pressure - blood tests: Na+/K+/renin - screen for other autoimmune conditions in patients with autoimmune adrenalitis
79
Define Cushing's syndrome
Too much cortisol
80
Give four examples of more Cushing-specific signs and symptoms
Easy bruising Reddish/purple stretch marks Proximal myopathy (gluteal and femoral muscles) Central obesity
81
Give five examples of less Cushing-specific signs and symptoms
``` Depression Hair thinning Menstrual irregularity Poor wound healing Hypertension ```
82
Give three examples of ACTH-dependent Cushing syndrome signs and symptoms
Acne Hirsutism (male hair growth in females) Hyperpigmentation
83
Give two examples of generalised signs and symptoms of Cushing's syndrome
Weight gain | Fatigue
84
What are the causes of too much glucocorticoid?
Iatrogenic (exogenous glucocorticoid use) ACTH-dependent Cushing's syndrome ACTH-independent Cushing's syndrome
85
What are the two variations of ACTH-dependent Cushing's syndrome?
1) Pituitary-dependent Cushing's syndrome=Pituitary adenoma | 2) Ectopic Cushing's due to ectopic ACTH secretion=small cell lung carcinoma/carcinoids
86
What is the cause of ACTH-independent Cushing's syndrome?
Adrenocortical adenoma/carcinoma
87
What are three methods of diagnosing Cushing's syndrome?
1) Dexamethasone overnight suppression test 2) 24hr urinary free cortisol (>130micrograms/24hr) 3) "midnight cortisol" (above late night reference range)
88
What is the process of the dexamethasone overnight suppression test?
1mg dexamethasone tablet at 11pm, measure serum cortisol at 8-9am, cortisol levels remain high (>50nmol/L)
89
What is the role of dexamethasone in the dexamethasone overnight suppression test?
It mimics cortisol effects by binding to GC receptors in hypothalamus and pituitary gland which causes downregulation of ACTH and suppression of endogenous cortisol->Cushing's patients not responsive to this suppression
90
What is the first stage of differential diagnosis for Cushing's syndrome?
9am Plasma ACTH ACTH suppressed=adrenal ACTH normal/high=pituitary/ectopic
91
What is the second stage of differential diagnosis for Cushing's syndrome?
High Dose Dex Test and CRH test=pituitary adenoma responds, ectopic tumours don't Inferior petrosal sinus sampling
92
What happens when response to High Dose Dex Test and CRH test occurs?
MRI to identify pituitary adenoma
93
What happens when no response to High Dose Dex Test and CRH test occurs?
CT scan of chest and abdomen to identify ectopic tumours
94
What is the third stage of differential diagnosis for Cushing's syndrome?
Imaging-CT adrenals/MRI pituitary
95
What are the surgical treatments for Cushing's syndrome?
Pituitary=transsphenoidal surgery Bilateral adrenalectomy: Adrenal adenoma=laparoscopic adrenalectomy Adrenocortical adenoma=open adrenalectomy
96
What are the actions of drug treatments for Cushing's syndrome?
Block cortisol-producing adrenal enzymes Block glucocorticoid receptor (GC antagonist) Disrupt adrenal redox balance and thereby steroidogenesis and cell proliferation
97
What is the treatment for Cushing's syndrome due to exogenous steroid use?
Causative agent slowly withdrawn
98
What is the follow up after Cushing's syndrome treatment?
Surgery: review regularly until HPA axis recovery and monitor for recurrence Non-surgical Rx: review regularly for safety and efficacy Ensure CV, metabolism and bone health are protected long-term

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