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Year 2 - T2 Theme 1 > L9 - The hypothalamic pituitary adrenal axis - clinical aspects > Flashcards

L9 - The hypothalamic pituitary adrenal axis - clinical aspects Flashcards

1
Q

Activating pathway between hypothalamus and target organ

A

Hypothalamus –releasing factors–> pituitary –tropic hormones –> target organ

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2
Q

Effect of target organ hormones on the hypothalamic-pituitary axis

A

Target organ has inhibitory effects on the hypothalamic-pituitary axis(negative feedback) and also inhibitory effects on bioaminergic or peptidergic neurons

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3
Q

Where are peptidergic hormones released

A

Neurosecretory cells release peptidergic hormones(median eminence, hypothalamus) - transported in blood via pituitary portal system

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4
Q

Path of pituitary stalk and pituitary portal vessels

A
  • Pituitary stalk and pituitary portal vessels pass down through the dura mater which roofs the pituitary fossa
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5
Q

What are parvocellular neurosecretory cells

A

Parvocellular neurosecretory cells are small neurons within paraventricular nucleus (PVN) of the hypothalamus

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6
Q

Where do parvocellular neurosecretory cells project to

A

The axons of the parvocellular neurosecretory cells of the PVN project to the median eminence, at the base of the brain, where their neurosecretory nerve terminals release peptides into blood vessels in the hypothalamo-pituitary portal system

The blood vessels carry the peptides to the anterior pituitary gland, where they regulate the secretion of hormones into the systemic circulation

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7
Q

What do parvocellular neurosecretory cells stimulate the release of

A
  • Hypophyseotropic hormones released
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8
Q

Effect of hypophyseotropic hormones

A
  • Stimulation or inhibition of anterior pituitary hormone release
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9
Q

Adrenal cortex hormone production

A 
• GLUCOCORTICOID
○ CORTISOL
• MINERALOCORTICOID
○ ALDOSTERONE (renin-angiotensin-aldosterone system)
• SEX STEROIDS
○ ANDROGENS
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10
Q

What percentage of cortisol is bound to cortisol binding globulin

A
  • 90%
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11
Q

Type of receptors for glucocorticoids and mineralocorticoids

A
  • Intracellular glucocorticoid and mineralcorticoid receptors(GR and MR)
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12
Q

What is 11-b-hydroxysteroid dehydrogenase (11- b-HSD)

A

11β-Hydroxysteroid dehydrogenase (HSD-11β or 11β-HSD) is a family of enzymes that catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa,[1] thus regulating the access of glucocorticoids to the steroid receptors

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13
Q

Effects of glucocorticoids

A
  • Maintenance of homeostasis during stress
    • e.g. haemorrhage, infection, anxiety
  • Anti-inflammatory
  • Energy balance / metabolism
    • ­ / maintain normal [glucose]
  • Formation of bone and cartilage
  • Regulation of blood pressure
  • Cognitive function, memory, conditioning
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14
Q

Circadian rhythm - cortisol levels

A
  • rise during the early morning
  • peak just prior to awakening
  • fall during the day
  • are low in the evening
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15
Q

Ultradian vs circadian rhythms

A
  • Ultradian rhythm is a recurrent period or cycle repeated throughout a 24-hour day. In contrast, circadian rhythms complete one cycle daily, while infradian rhythms such as the human menstrual cycle have periods longer than a day
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16
Q

Features of the ultradian rhythm

A
  • Spontaneous pulses of varying amplitude
  • Amplitude decreases in the circadian trough
  • It is hard to distinguish the stress response
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17
Q

Where is ACE mainly located

A

It is located mainly in the capillaries of the lungs but can also be found in endothelial and kidney epithelial cells

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18
Q

What can stimulate the renin-angiotensin aldosterone system

A
  • Decrease in renal blood flow
  • Decrease in Na+ levels
  • Increase in K+ levels
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19
Q

What stimulates the release of renin

A
  • Juxtaglomerular (JG) cells associated with the afferent arteriole entering the renal glomerulus are the primary site of renin storage and release.
  • A reduction in afferent arteriole pressure causes the release of renin from the JG cells
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20
Q

What is the macula densa

A

Specialized cells (macula densa) of distal tubules lie adjacent to the JG cells of the afferent arteriole. The macula densa senses the concentration of sodium and chloride ions in the tubular fluid

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21
Q

What causes inhibition of renin release

A

When NaCl is elevated in the tubular fluid, renin release is inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells

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22
Q

Functions of angiotensin II

A

Constricts resistance vessels (via AII [AT1] receptors) thereby increasing systemic vascular resistance and arterial pressure

Stimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing sodium and water retention by the body

Acts on the adrenal cortex to release aldosterone, which in turn acts on the kidneys to increase sodium and fluid retention

Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by the kidneys

Stimulates thirst centers within the brain

Facilitates norepinephrine release from sympathetic nerve endings and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function

Stimulates cardiac hypertrophy and vascular hypertrophy

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23
Q

Breakdown of angiotensin II

A

Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues

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24
Q

What is an androgen

A
  • An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics
25
Q

What is DHEAS

A

Dehydroepiandrosterone Sulphate (DHEAS) is the sulphated form of a weak androgen, DHEA, a male sex hormone that is present in the blood of both men and women

26
Q

Function of DHEA as an androgen

A

DHEA and other adrenal androgens such as androstenedione, although relatively weak androgens, are responsible for the androgenic effects of adrenarche, such as early pubic and axillary hair growth, adult-type body odor, increased oiliness of hair and skin, and mild acne

27
Q

What can DHEA be converted to

A

DHEA is potentiated locally via conversion into testosterone and dihydrotestosterone (DHT) in the skin and hair follicles

28
Q

What is androstenedione

A

It is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA)

29
Q

What is the enzyme that converts testosterone into oestrogen

A
  • Aromatase
30
Q

What is the enzyme that converts testosterone into dihydrotestosterone

A
  • 5-alpha-reductase
31
Q

Anti-inflammatory action of glucocorticoids

A
  • Glucocorticoids are potent anti-inflammatories, regardless of the inflammation’s cause; their primary anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.)
  • glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes
32
Q

Mineralocorticoid receptor affinity for aldosterone vs cortisol

A
  • Same affinity for aldosterone and cortisol

- Specificity is conferred by a ‘pre-receptor’ mechanism

33
Q

Effect of 11-b-HSD-2 in the kidney

A
  • Inactivates cortisol, enabling aldosterone to bind the MR
34
Q

Tissue specificity of 11-beta-HSD enzymes

A
  • ‘gating’ of GC access to nuclear receptors

- ‘amplification’ of GC signal in target cells

35
Q

What is cushing’s syndrome

A
  • Cushing’s syndrome is a collection of signs and symptoms due to prolonged exposure to cortisol
36
Q

Signs and symptoms of cushing’s syndrome

A
  • Weight gain
  • Central obesity
  • Hypertension
  • Insulin resistance
  • Neuropsychiatric problems
  • Osteoporosis
37
Q

Cushing’s syndrome - pathogenesis

A

Excess cortisol:
• Pituitary adenoma: ACTH-secreting cells (‘Cushing’s disease’)
• Adrenal tumour: adenoma (or carcinoma)
• ‘Ectopic ACTH’: carcinoid, paraneoplastic
• Iatrogenic: steroid treatment (‘Cushingoid’)

38
Q

Clinical features of cushing’s syndrome

A
  • Central obesity with thin arms and legs
  • Fat deposition over upper back (‘buffalo hump’)
  • Rounded ‘moon’ face
  • Thin skin with easy bruising, pigmented striae
  • Hirsutism
  • Hypertension
  • Diabetes
  • Psychiatric manifestations
  • Osteoporosis
39
Q

What is addison’s disease

A

Addison’s disease, also known as primary adrenal insufficiency and hypocortisolism, is a long-term endocrine disorder in which the adrenal glands do not produce enough steroid hormones

40
Q

Patient presentation - Addison’s disease

A

Patient:

  • Gradually falls off in general health
  • Becomes languid and weak
  • Indisposed to either bodily or mental exertion
  • The body wastes
  • Slight pain is referred to the stomach
  • There is occasionally actual vomiting
  • Discoloration of the skin
41
Q

Addison’s disease - pathogenesis

A
  • Primary adrenal insufficiency
  • Usually autoimmune in UK
  • Rare causes include metastases or TB
  • Decrease in production of all adrenocortical hormones
42
Q

Other causes of hypoadrenalism

A
  • Secondary to pituitary disease (rare)

- ‘iatrogenic’ - patients on high dose, long term steroid Rx, which is suddenly stopped at a time of stress

43
Q

Clinical features of addison’s disease

A
  • Malaise, weakness, anorexia, weight loss
  • Increased skin pigmentation(knuckles, palmar creases, around/inside the mouth, pressure areas, scars)
  • Hypotension/postural hypotension
  • Hypoglycaemia
44
Q

Features of autoimmune polyendocrine syndrome type 1

A
  • Rare
  • Onset in infancy
  • Ar (AIRE gene)
  • Common phenotype(addison’s, hypoparathyroidism, candidiasis)
45
Q

Features of autoimmune polyendocrine syndrome type II

A
  • More common than type 1 (still rare)
  • Infancy to adulthood
  • Polygenic
  • Common phenotype (addison’s disease, T1 diabetes, autoimmune thyroid disease)
46
Q

Autoimmune conditions that may occur together

A
  • Type 1 diabetes
  • Autoimmune thyroid disease (hypo- or hyper-) (also gestational/post-partum thyroiditis)
  • Coeliac disease
  • Addison’s disease
  • Pernicious anaemia
  • Alopecia
  • Vitiligo
  • Hepatitis
  • Premature ovarian failure
  • Myasthenia gravis
47
Q

Clinical implications of autoimmune polyendocrine syndromes

A
  • High index of suspicion for additional autoimmune endocrine disorders
  • Consider screening in patients with T1 DM and/or addison’s disease (coeliac screen, thyroid function tests)
48
Q

Basal assessment tests of the HPAA

A

Basal:

  • Blood - cortisol, ACTH
  • Urine - cortisol
  • Saliva - cortisol
49
Q

Dynamic tests of the HPAA

A
  • Simulated - ACTH, CRH, STRESS Hypoglycaemia

- Suppressed - Dexamethasone - synthetic glucocorticoid

50
Q

Timing - Basal blood test for assessment of the HPAA

A
  • Circadian rhythm
  • Ultradian rhythm
  • Stress
51
Q

Timing - urine basal test for assessment of the HPAA

A
  • 24 hour collection

- area under curve

52
Q

Test results with too much cortisol

A 
• 24 hour urinary free cortisol
	• ‘AREA UNDER THE CURVE’
• Midnight cortisol (blood / saliva)
	• ‘TROUGH’
• 9 a.m. ACTH (with paired cortisol)
	• PITUITARY / ADRENAL / ECTOPIC?
		○ NEGATIVE FEEDBACK AT PITUITARY
• DEXAMETHASONE SUPPRESSION
	• Sensitivity to GC negative feedback at pituitary
53
Q

Test results with too little cortisol

A 
• 9 a.m. cortisol
	• ‘PEAK’
• SynACTHen test
	• Adrenal response to ACTH
		○ Trophic effect ACTH on adrenals
• Insulin tolerance test
	• Response to hypoglycaemic stress
		○ Can be dangerous!
• U & E (¯Na, ­K) in Addison’s disease
	• Due to mineralocorticoid deficiency
	• Can measure renin & aldosterone concentrations
• ¯ glucose
54
Q

What should you consider once you have confirmed that a patient has cushing’s syndrome

A
  • CXR
  • MRI pituitary
  • CT adrenals
  • Patients with addison’s disease seldom need imaging unless you are concerned they may have TB/metastatic cancer
55
Q

Management of cushing’s syndrome

A 
• Management
	• Surgical (depending on the cause)
		○ Transphenoidal adenectomy
		○ Adrenalectomy
	• Pituitary radiotherapy
56
Q

Management of addison’s disease

A

• Steroid hormone replacement therapy (‘glucocorticoid’):
○ Usually hydrocortisone (sometimes prednisolone)
• Patients with primary adrenal insufficiency also need mineralocorticoid replacement therapy (fludrocortisone).
• Patients with secondary adrenal insufficiency will often be taking other hormone replacement therapy (do not need fludrocortisone).

  • Dose of glucocorticoids needs to be increased to cover ‘stresses’:
    • Intercurrent illnesses (e.g. ‘flu)
  • Operations / post-op period
    • Recommendations depend on the procedure
  • Patients need IV / IM steroid if unable to take their tablets:
    • Vomiting
    • ‘Nil by mouth’
57
Q

What are steroids usually being used for

A
  • Anti-inflammatory/immunosuppressive effects
  • Conditions include severe asthma/COPD, temporal arteritis./polymyalgia rheumatica
  • These patients may look cushingoid, especially those with COPD
58
Q

Effect of long-term dose steroid therapy on endogenous adrenal function

A

• The endogenous adrenal function of patients on long-term high dose steroid therapy may be suppressed:
○ They may not mount an adequate ‘stress response’.
○ Their steroid treatment should not be stopped suddenly.
○ If they need a major procedure / an operation, they require increased steroid cover as described.
○ They should be given a ‘Steroid Treatment Card’ to remind them (& their doctors) about this.

Year 2 - T2 Theme 1 (20 decks)

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