Adrenal Flashcards
What is the average size and weight of an adrenal gland?
average size: 2-3cm wide, 4-6cm long and 1cm thick
mean weight: 4g irrespective of age, sex or weight
- At autopsy the adrenal gland may weigh up to 22g
What hormones are made in the adrenal gland in each region?
medulla: adrenaline and noradrenaline
cortex - steroid hormones:
● Zona glomerulosa - mineralocorticoid - aldosterone
● Zona fasciculata - glucocorticoid cortisol cortisol
● Zona reticularis - adrenal androgens - androstenedione dehydroepiandrosterone acetate (DHEA), (testosterone?)
What happens to the adrenal androgens?
Converted in to sex hormones in the periphery
How is cortisol synthesis regulated?
- hypothalamus: CORTICOTROPIN RELEASING HORMONE (CRH) (41aa’s). CRH stimulates corticotrophs in anterior pituitary to produce to produce ADRENOCORTICOTROPIC HORMONE (ACTH) (39 amino acids).
- ACTH stimulates the adrenal cortex to synthesize and release cortisol.
- Cortisol feeds back on the corticotrophs of the anterior pituitary to decrease ACTH release and on the hypothalamus to inhibit release of CRH.
How are steroid hormones synthesised?
All steroid hormones - derived from cholesterol.
ACTH - G-protein coupled receptor - activates adenyl cyclase - - - increase in cAMP levels.
- activates protein kinase A
- activates cholesteryl ester hydrolase (CEH) which liberates cholesterol from lipid droplets.
- also stimulation of cholesterol 20,22-hydroxylase (desmolase) which is the first enzyme in the pathway and is the rate limiting step. This leads to increased synthesis of cortisol
Why can’t the zona glomerulosa synthesise cortisol?
Zona glomerulosa - lacks - 17-alpha-hydroxylase enzyme - Needed to make cortisol
Is the mitochondria involved in the synthesis of cortisol?
Yes
What percentages of cortisol in plasma are free, CBG bound, Albumin bound?
10%
75%
15%
What percentages of aldosterone in plasma are free, CBG bound, Albumin bound?
30-50%
5-10%
25 – 50%
What the mechanism of steroid receptor activation
- Steroid hormones interact with nuclear receptors.
- Steroid hormone enters cells by diffusion
binds to cytoplasmic receptor. - This leads to dissociation of Heat Shock Protein (hsp90) from the receptor.
- The hormone-receptor complex dimerises and is translocated to nucleus.
- The complex binds to hormone responsive element (HRE) on DNA
- increase in mRNA production and subsequently to increased protein synthesis.
What are the metabolic effects of glucocorticoids
- decrease glucose uptake
- decrease glucose use
- increase gluconeogenesis
- hyperglycaemia
- decrease protein synthesis
- increase protein breakdown - muscle wasting
- decrease Ca2+ absorption in gut
- increase Ca2+ excretion in kidney
- decrease activity of osteoblasts
- increase activity of osteoclasts - osteoporosis
What a the anti inflammatory effects of glucocorticoids?
early phase: vs. redness, heat, pain, swelling late phase: vs. wound healing, repair, proliferation - decreases: expression of COX2 (cyclo-oxygenase 2) cytokine production complement in plasma nitric oxide (NO) production histamine release IgG production increases: annexin-1 (lipocortin-1) which inhibits phospholipase A2 (PLA2)
How is the prevention of cortisol activation of mineralocorticoid receptors achieved?
cortisol and aldosterone have same affinity for mineralocorticoid receptor
11betaHSD converts cortisol to cortisone (inactive)
11betaHSD - 11-beta-hydroxysteroid dehydrogenase
11betaHSD2 isoform expressed in aldosterone sensitive tissues
What are the adverse affects of glucocorticoids?
suppression of response to infection suppression of endogenous glucocorticoid production metabolic effects osteoporosis iatrogenic Cushing's syndrome
What Is the difference between Cushing’s disease and Cushing’s syndrome?
Cushing’s disease - ectopic tumour - ACTH, cortisol
Cushing’s syndrome - more common - drug induced
What are the clinical manifestations of Cushing’s syndrome?
easy bruising poor wound healing muscle wasting thinning of skin increased abdominal fat buffalo hump moon face osteoporosis obesity increased appetite increased susceptibility to infection cataracts
What are the percentage frequencies of the following clinical features of Cushing's disease or syndrome? Obesity Hypertension Hirsutism Striae Acne Bruising Neuropsychiatric effects Menstrual disorders Impotence Glucose intolerance Diabetes
Obesity 90 Hypertension 85 Hirsutism 75 Striae 50 Acne 35 Bruising 35 Neuropsychiatric effects 85 Menstrual disorders 70 Impotence 85 Glucose intolerance 75 Diabetes 20
What are the treatments for Cushing’s syndrome?
- Metryrapone 11-beta-hydroxylase
- Ketoclonazone inhibits steroid biosynthesis
- Pasireotide (somatostatin analogue) SSTR5 agonist (Receptors highly expressed in tumours - shut down ACTH production) - Mifeprestone - glucocorticoid receptor antagonist
What are the clinical manifestations of Addison’s disease?
muscular weakness low blood pressure depression anorexia loss of weight Fatigue Gastrointestinal disturbances hypoglycaemia Hyper pigmentation Salt cravings Postural symptoms
What are the percentage frequencies of these clinical manifestations of Addison’s disease?
Weakness, fatigue, anorexia, weight loss
Hyper-pigmentation
Hypotension
Gastrointestinal disturbances
Salt craving
Postural symptoms
Weakness, fatigue, anorexia, weight loss 100 Hyperpigmentation 92 Hypotension 88 Gastrointestinal disturbances 56 Salt craving 19 Postural symptoms 12
In pre-menopausal women what percentage of androstenedione is derived from the adrenal and is converted in peripheral tissue to oestrogen and testosterone?
What effect can excess androgen secretion have in women?
In the pre-menopausal woman 50% of androstenedione is derived from the adrenal and is converted in peripheral tissue to oestrogen and testosterone. Excess secretion of these androgens in women can lead to hirsutism and virilisation.
What ‘advantage can obesity have in post-menopausal women?
In the post-menopausal woman, with the regression of the ovary, the main oestrogen in oestrone, peripheral conversion of androgen to oestrogen takes place in adipose tissue
- the production of oestrone is higher in the obese postmenopausal woman than in the thin woman.
- obese women suffer less from high testosterone in Cushing’s
What are the effects of aldosterone and what is spironolactone?
Effects in kidney
Increased number of sodium channels in apical membrane
Increase in Na +/K +ATPase in basolateral membrane
Spironolactone: Aldosterone antagonist , Used as K+ sparing diuretic
See table on synthetic steroid in adrenal - basic notes
-
4 classifications of adrenal disorders
– Hypofunction
– Hyperfunction
– Cancer
– Genetic conditions
3 Types of hypofunction adrenal disease
– Hypothalamo-pituitary disease
– Primary adrenal failure
(Addison’s disease - destruction of cortex)
– Congenital adrenal hyperplasia
How does an adrenal gland appear on a CT scan?
Thin structure with lateral and medial limbs
From where do the cells of the adrenal medulla originate?
Migratory neural crest cells
Aetiology of Adrenal Failure/ Primary adrenal insufficiency?
9 causes
- Autoimmune (polyglandular failure)
- Granulomatous infiltration (TB, sarcoid etc)
- Haemorrhage
- Fungal infection Fungal
- AIDS
- Congenital adrenal hyperplasia
- Metastatic disease
- Adrenalectomy
- Toxic drugs
Causes of secondary adrenal insufficiency?
- Cessation of exogenous steroids
* Hypothalamo-pituitary hypofunction - Surgery - Radiotherapy - Tumours - Genetics
What are the common features of Addison’s disease?
Weakness - 100% Weight loss - 100% Pigmentation - 95% Postural hypotension - 25% Anorexia - 95% Nausea - 95% Abdominal pain - 30%
What are the uncommon features of Addison’s disease?
Vitiligo - 20%
Salt craving - 15%
Hypoglycaemia - (in adults) - less than 1%
Aches and pain - 10%
Treatment of adrenal failure?
• Emergency, life-threatening adrenal crisis:
– ICU care
– Fluids, sodium IV hydrocortisone @ high dose
– IV hydrocortisone @ high dose
• Maintenance treatment
– Glucocorticoid (hydrocortisone, prednisolone)
– Mineralcorticoid (fludrocortisone)
– ?DHEA
What is Congenital adrenal hyperplasia CAH and what are its consequences?
• Recessive defect in cortisol biosynthesis leading to:
- elevated ACTH
- adrenomegaly
- excess androgens
Commonest defect = 21 OH enzyme – Commonest defect
Features:
– Salt-wasting crises
– Precocious puberty in boys
– Masculinisation of females leading to ambiguous genitalia at birth
List the clinical manifestations of congenital adrenal hyperplasia CAH
Classic CAH - presents in neonate Non-classic CAH - presents in adolescence or adulthood Urogenital sinus Labial fusion Scotilization of labia majora Clitoromegaly Penile enlargement Precocious adrenarche Bone age advancement Rapid growth Acne Hirsutism Menstrual abnormalities Infertility - this is the spectrum
How is CAH treated?
- In utero ideally
- Use glucocorticoids to suppress ACTH
- Antiandrogens
- Mineralocorticoid
- Genitoplasty – Controversial wrt age, degree of operation – Gender assignment
What are the clinical manifestations of Addison’s disease (glucocorticoid deficiency)?
Muscle fatique and chronic weakness Depression psychosis Nausea anorexia Hypoglycemia
What are the clinical manifestations of Cushing’s disease (glucocorticoid excess)?
Hyperglycemia Elevated blood pressure Obesity (thin limbs, fat trunk) Wasting of skeletal muscle Poor wound healing Mood swings (depression/euphoria) hallucinations
What is the aetiology of Cushing’s disease/syndrome?
ACTH - dependent 80%:
– Pituitary adenoma (Cushing’s disease)
– Ectopic (neuroendocrine tumour)
ACTH - independent 20%:
– Adrenal adenoma
– Adrenal carcinoma
– Carney’ syndrome (PPNAD)
Diagnosis of adrenal Cushing’s syndrome?
• Circadian serum cortisol (nmol/l) – 0900 604 – 1800 626 – 2400 677 • Plasma ACTH levels (ng/l) – 0900 s so ACTH stays high
What is the treatment of Cushing’s?
Treatment
• Laparoscopic adrenalectomy
• Replacement GC – Hydrocortisone
– Periodic withdrawal
• Many of the features improve – BP, diabetes, psychological disturbance may continue
What effect does noradrenaline have on force of myocardial contraction,Systolic blood pressure and Diastolic pressure?
Increases them all
What effect does adrenaline have on force of myocardial contraction,Systolic blood pressure and Diastolic pressure?
Increases the first 2
Usually little effect on latter
What affect do adrenaline and noradrenaline have on heart rate?
Adrenaline: increases
Noradrenaline: decreases because of reflexes
What is the effect of adrenaline on the blood flow to skin, mucous membranes, gut, brain, skeletal muscle?
skin - decreases mucous membranes - decreases gut - decreases brain - increases skeletal muscle - increases
What is the effect of noradrenaline on the blood flow to skin, mucous membranes, gut, brain, skeletal muscle?
skin - decreases mucous membranes - decreases gut - decreases brain - may increase slightly skeletal muscle - little or no effect
Does adrenaline affect anxiety?
Yes - increases the sensation of anxiety
Does noradrenaline affect anxiety?
No
What affect does adrenaline have on the blood levels of glucose, lactic acid, fatty acids?
- Glucose: Raised
- Lactic acid: Markedly increased
- Fatty acids: Somewhat increased
What affect does noradrenaline have on the blood levels of glucose, lactic acid, fatty acids?
- Glucose: Little effect
- Lactic acid: Slightly increased
- Fatty acids: Increased
STIMULI WHICH CAUSE EPI/NORAdrenaline RELEASE?
- Stressful situations
- Hypoglycemia (dietary or disease induced)
- Postural hypotension
- Exercise
What is Phaeochromoctoma and what is its aetiology?
• Tumour of the adrenal medulla(typically benign, typically cystic?) – Secreting NA or A – 10 % bilateral - 10 % malignant – 10 % part of a genetic condition: • MEN 2 • Von Hippel Lindau • NF- 1 SDH
How does Phaeochromoctoma present?
- Headaches
- Palpitations
- Sense of Doom
- Chest pain
- Sweating
- Weight loss
How can you diagnose Phaechomoctoma?
• Plasma or urine assessment of levels of A, NA or their products – VMA / HMMA
– Metanephrins - almost exclusively used
– Imaging
• Nuclear medicine – MIBG
• Radiology – CT/ MRI
Treatment of Phaechomoctoma?
- Surgical removal after – Pretreatment with alpha and B blockade • Phenoxybenzamine
- Doxazosin first then propranolol
PHYSIOLOGICAL EFFECTS OF ALDOSTERONE?
Regulation of water and electrolyte balance - Decreases cellular K+ - increases cellular Na+ in kidney: - Increases Na+ reabsorption - Decreases K+ reabsorption - Increases H+ secretion
Volume-feedback loop between angiotensin 2 and aldosterone?
• Action of angiotensin II on aldosterone results in negative feedback • 2 critical systems are regulated: – 1) sodium homeostasis ) – 2) regulation of arterial pressure: • Vasular smooth muscle • NA release • ADH • Volume expansion
What is the action of aldosterone?
• Aldosterone binds to the type 1 mineralocorticoid receptor
– Increasing the number of “open” sodium channels channels
- Increased sodium resorption
• Negative gradient in the lumen – Consequent secretion of K and H
What are the clinical features of Conn’s syndrome (primary hyperaldosteronism)?
– Hypertension, often difficult, younger people
– Spontaneous or diuretic associated hypokalaemia
– Oedema = rare
• Hypernatraemia, hypomagnesaemia, alkalosis, DI, neuromuscular symptoms
What are the features of aldosteronism?
- Often non-specific, hypertension
- Hypokalaemia related to renal potassium wasting
- Classical: hypertension, hypokalaemia & alkalosis
What causes secondary aldosteronism?
–Renovasular
–Gitelmans, Barrters pseudo, nephrotic, cirrhotic, CCF
What are the usual clinical manifestations do primary hyperaldosteronism?
- Hypertension
- Hypokalemia
- Hypervolemia (without peripheral edema)
- Metabolic alkalosis
What are the ‘other’ clinical manifestations/effects do primary hyperaldosteronism?
-Due to hypertension:
•Headaches •Retinopathy (rare)
-Due to hypokalemia:
•Neuromuscular symptoms (cramps, paresthesias, weakness) •Nephrogenic diabetes insipidus
•Cardiac arrhythmia
•Glucose intolerance / impaired insulin secretion
-Due to direct actions of aldosterone on the cardiovascular system:
•Cardiac Hypertrophy/Fibrosis
•Vascular smooth muscle hypertrophy
•Due to a reset osmostat
•Mild hypernatremia
What are the subtypes of Primary hyperaldosteronism?
- Aldosterone producing adenoma (60%)
- Bilateral adrenal hyperplasia (30-40%)
- Glucocorticoid-remediable aldosteronism (1-3%)
- Unilateral adrenal hyperplasia
- Adrenal carcinoma
What do you know about Aldosterone producing adenoma?
- Small – 0.-2 cm
- Women > men
- Histology- difficult= benign cortical adenoma
- CT appearance- low HU
Diagnosis of primary aldosteronism?
• Biochemical screening – PRA, aldosterone= PA/ PRA
Confirmation of primary hyperaldosteronism?
- Measurement of PRA (suppressed) and aldosterone (high) in salt-replete individuals
- Salt loading
- Suppression with fludorocortisone
- Catheter studies for selective venous sampling
Treatment of Conn’s syndrome?
• Remove the adenoma – Open or laparoscopic • Drug treatment: – Spironolactone – Eplerenone – Amiloride + others
