Adrenal Flashcards
Adrenal gland, function, control axis affects and pathology
Location of Adrenal gland
The adrenal (or suprarenal) gland sits on top of the kidney (ad – near, supra – above, renal –kidney).
Divisions of Adrenal Gland
Zona glomerulosa(cortex) Zona fasciculata(cortex) Zona reticularis(cortex) Adrenal Medulla
What does zona fasiciculata produce and what enzyme does it lack
glucocorticoid cortisol
lacks aldosterone synthase
What does zona reticularis produce and what enzyme does it lack
lacks aldosterone synthase
adrenal androgens
androstenedione
dehydroepiandrosterone acetate (DHEA)
What is Acth derived from
ACTH derived from pro-opiomelanocortin
POMC
What other products do you get from POMC breakdown
g-lipotrophin (g-LPH),b-MSH ACTH main ones
REGULATION OF SYNTHESIS of cortisol brief outline involving axis
hypothalamus releases CRH, causes anterior pituitary corticotrophs to release acth, causes cortex to synthesis and release cortisol. negatuve feedback from cortisol to hypothalamus and pituitary
What molecule are all steroid hormones derived from
Chlesterol
What receptor does ACTH act on
ACTH acts on a G-protein coupled receptor
(melanocortin 2 receptor, MC2R) to activate adenyl
cyclase which leads to an increase in cAMp level and activation of PKA
What enzymes are involved in synthesis of cortisol in zona fascicuclata
cholesteryl ester hydrolase (CEH)
cholesterol 20,22-hydroxylase also referred to as
desmolase
What enzyme is the rate limiting step in cortisol synthesis
desmolase
Describe action of the enzymes in synthesis of cortisol
All steroid hormones are derived from cholesterol.
ACTH acts on a G-protein coupled receptor
(melanocortin 2 receptor, MC2R) to activate adenyl
cyclase which leads to an increase in cAMP levels.
This in turn activates protein kinase A which activates
cholesteryl ester hydrolase (CEH) which liberates
cholesterol from lipid droplets. There is also stimulation
of cholesterol 20,22-hydroxylase also referred to as
desmolase which is the first enzyme in the pathway and
is the rate limiting step. This leads to increased synthesis
of cortisol.
Name the five steroid hormones produced by adrenal gland
cortisol, corticosterone, aldosterone, DOC(Deoxycorticosterone), DHEA(Dehydroepiandrosterone)
How is cortisol transported in the blood plasma
CBG corticosteroid binding globulin 75% , albumin 15% , free 10%
How is aldosterone transported in the blood plasma
free 40%, albumin bound 40% and CBG 20%
When steroid hormone binds to cytoplasmic receptor what protein dissociates from receptor
Steroid hormone enters cells by diffusion and binds to
cytoplasmic receptor. This leads to dissociation of Heat
Shock Protein (hsp90) from the receptor.
Once steroid hormone has bound to cytoplasmic receptor outline what occurs
The hormone-receptor complex dimerises and is
translocated to nucleus. The complex binds to hormone
responsive element (HRE) on DNA which leads to an
increase in mRNA production and subsequently to
increased protein synthesis.
Why is steroid action have a slower effect on the body
The complex binds to hormone
responsive element (HRE) on DNA which leads to an
increase in mRNA production and subsequently to
increased protein synthesis.
Protein sythesis is slow
EFFECTS OF GLUCOCORTICOIDS (cortisol) on glucose
decrease glucose uptake
decrease glucose use
increase gluconeogenesis
“hyperglycaemia”
EFFECTS OF GLUCOCORTICOIDS (cortisol) on proteins
decrease protein synthesis
increase protein breakdown
“muscle wasting”
EFFECTS OF GLUCOCORTICOIDS (cortisol) on calcium
decrease Ca2+ absorption in gut increase Ca2+ excretion in kidney decrease activity of osteoblasts increase activity of osteoclats "osteoporosis"
EFFECTS OF GLUCOCORTICOIDS (cortisol) on inflammatory early phase
anti-inflammatory effects
early phase
reduce redness, heat, pain, swelling
EFFECTS OF GLUCOCORTICOIDS (cortisol) on inflammatory late phase
late phase
reduce wound healing, repair, proliferation
EFFECTS OF GLUCOCORTICOIDS (cortisol) on immune response
decreases expression of COX2 (cyclo-oxygenase 2) cytokine production complement in plasma nitric oxide (NO) production histamine release IgG production
How is cortisol action on mineralcorticoid recptors prevented
cortisol has higher affinity for mineralocorticoid receptor than glucocorticoid receptor 11bHSD cortisol ------→cortisone active inactive 11bHSD 11bhydroxysteroid dehydrogenase 11bHSD2 isoform expressed in aldosterone sensitive tissues converts cortisol ---→ cortisone 11bHSD1 isoform expressed in liver,adipose, muscle converts cortisone ---→ cortisol
What causes Cushing syndrome
Cushing syndrome due to prolonged exposure to elevated levels of cortisol or exogenous glucocorticoid drugs
What symptoms associated with cushing syndrome
Osteoporosis Negative nitrogen balance Increased appetite Obesity Increased susceptibility to infection
What drugs can be used to treat cushing syndrome and how do they work
Metyrapone 11b hydroxylase inhibitor • Ketoconazone (withdrawn in Europe) inhibits steroid biosynthesis • Pasireotide (somatostatin analogue) SSTR5 agonist ● Cabergoline (dopamine D2 agonist) ● Mifeprestone glucocorticoid receptor antagonist progestogen receptor antagonist
What causes Addison disease
Low cortisol- Chronic adrenal insufficiency
Symptoms associated with Addisons
Hypotension, weight loss, hyperpigmentation,gastro disturbances
What androgen do adrenal glands secrete and which zone does this occur in
zona reticularis DHEA
and its sulphate, and
androstenedione
What happens to androgens secreted by adrenal gland in periphery
n 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.
In the post-menopausal woman, with the regression of
the ovary, the main oestrogen in oestrone. As peripheral
conversion takes place in adipose tissue the production
of oestrone is higher in the obese postmenopausal
woman than in the thin woman.
What is function of aldosterone (mineralococortoid)
Aldosterone Effects in distal tubule & collecting duct in kidney Increased number of sodium channels in apical membrane (ENaC epithelial Na channel) Increase in Na + /K +ATPase in basolateral membrane Increased Na/K exchange
What drug can be used to reduce aldosterone action
Spironolactone
Aldosterone antagonist
Used as K+ sparing diuretic
Adrenaline and Nora adrenaline are examples of
Catecholamines
Hypofunction of the adrenal gland causes which pathology
Addisons
Hyperfunction of adrenal gland causes which pathologyies
– Cushing’s (high cortisol)
– Pheochromocytoma
– Conn’s / hyperaldosteronism (high aldosterone)
Primary Hypoadrenalism (issue at adrenal level) caused by
Autoimmune, Abrupt discontinuation of exogenous steroids, body system out of sync, tubercolosis, surgery, Haemorrhage/ infarction – Meningococcal septicaemia (Waterhouse Friderichsen Syndrome) • Infiltration – Malignancy, amyloid
symptoms of primary hypoadrenalism
weight loss, diahorrea, nausea/vomiting, hypotension, myalgia
signs of hypoadrenalism
Pigmentation – new scars buccal palmar creases • Postural hypotension • Wasting • Dehydration • Loss of body hair
how do you investigate suspected hypoadrenalism
Random cortisol • Short synacthen test • Plasma ACTH • Urea and electrolytes • Adrenal antibodies
How do you treat adrenal failiure
Emergency, life-threatening adrenal crisis – ICU care – Fluids, sodium – IV hydrocortisone @ high dose • Maintenance treatment – Glucocorticoid (hydrocortisone, prednisolone) – Mineralcorticoid (fludrocortisone) – ?DHEA
If high cortisol is ACTH dependent at what level is the issue with axis likely to be at
pituitary, Cushing’s disease
If high cortisol is ACTH independent at what level is issue with axis likely to be at
Adrenal level, potential adrenal adenoma or carcinoma
Taking too many steroids can cause what pathology
hyperadrenalism
What are the signs of Cushings
Hypertension Osteoporosis Pathological # Kyphosis Buffalo hump Striae Oedema Proximal myopathy Diabetes mellitus
How can you diagnose cushings or high cortisol
Dynamic Investigations
TO CONFIRM DIAGNOSIS
• Low dose dexamethasone suppression test
• 24 hour urinary cortisol
• Loss of diurnal rhythm (mid-night cortisol).
test conc of acth,
how do you treat hyperadrenalism
Laparoscopic adrenalectomy
• Replacement GC (after removing part of adrenal gland you can become hypo)
– Hydrocortisone
– Periodic withdrawal
• Many of the features improve
– BP, diabetes, psychological disturbance may
continue
What is Phaeochromoctoma
Tumour of the adrenal medulla. Increase of NA and Adr can be bilateral or malignant
How does Phaeochromoctoma present
Headaches • Palpitations • Sense of Doom • Chest pain • Sweating • Weight loss SNS Over stimulation
How does Phaeochromoctoma get diagnosed
Diagnosis with • 24 HOUR – urine catecholamines • OR • Metanephrines either 24 HOUR urine • OR plasma
How does Phaeochromoctoma get treated
Surgical removal after
– Pretreatment with alpha and B blockade
• Phenoxybenzamine
• Doxazosin
what does aldosterone do to BP and serum potassium
• Raised BP and low serum potassium
Conn’s syndrome= primary
hyperaldosteronism chracterised by
Hypertension, hypokalaemia, alkalosis
Treatment of Conn’s syndrome?
Remove the adenoma – Laparoscopic • Drug treatment – Spironolactone – Eplerenone
