Adrenal Gland Anatomy and Physiology Flashcards
What are cortioids derived from?
Steroids
Derived from enzymatic modification of cholesterol
Where are steroid enzymes location intracellularly?
Mitochondria and sER
Are steroids permeable or impermeable?
Freely-permeable to membranes
Can steroid enzymes be stored? Where
No. They are synthesised and immediately released
Are steroids water soluble?
No
What time of day is plasma concentration of steroid hormones highest?
Higher in the morning than at night (diurnal rhythm)
How is cortisol circulated?
95% is bound to proteins
- mainly cortisol-binding globulin
Where do the adrenal glands lie?
Between the superiomedial aspects of the kidneys and the diaphragmatic crura
Surrounded by connective tissue and perinephric fat
What are the adrenal glands?
Endocrine glands
What size and weight are the adrenal glands?
4-6cm
6-8geach
How many arteries supply the adrenal glands and where do they branch of?
3
- Superior suprarenal artery - from subphrenic artery
- Middle suprarenal artery - from abdominal aorta near the SMA
- Inferior suprarenal artery - from the renal artery
Describe adrenal venous drainage
Medullary vein emerges from the hilum of each gland forming the suprarenal vein which goings:
IVC on the R
RV on the L
Describe the nerve supply to the adrenal glands
- Colic plexus
- Thoracic splenchnic nerves
Act on the chromaffin cells in the adrenal medulla
- secrete (nor)adrenaline
Describe the histological layout of the adrenal glands
Fibrous capsule
______
Outer Cortex
- Zona glomerulosa
- regulated by Ang II and K+
- secretes mineralocorticoids (aldosterone) and glucocorticoids (cortisol)
__ - Zona fasiculata
- regulated by ACTH
- secretes mineralocorticoids (aldosterone) and glucocorticoids (cortisol)
__ - Zona reticularis
- regulated by ACTH
- secretes: androgens, DHEA, and DHEAs
\_\_\_\_\_ Inner medulla - Chromaffin cells - regulated by nerves: colic plexus and thoracic splanhnic nerves - secretes: nor(adrenaline)
List the adrenal androgens and where are they secreted from?
DHEA Androstenedione DHEA DHEAs Testosterone
- zone reticularis
What areas secreted cortisol and aldosterone?
Zona glomerulosa and zona fasciculata
Sources of cholesterol?
Diet into circulation
De novo via acetyl CoA
What is the rate limiting step of cholesterol synthesis?
HMG-CoA Reductase enzyme
What is the first enzymatic step of steroid hormone synthesis?
Cholesterol –> pregnenolone
Via mitochondria P450 enzyme
What is the rate-limiting step of steroid hormone synthesis?
Transport of free cholesterol from cytoplasm to mitochondria by Steriodogenic Acute Regulatory Protein (StAR)
Where does steroid synthesis take place?
Mitochondria
What causes congenital adrenal hyperplasia?
21-hydroxylase deficiency
or
11-hydroxylase deficiency
Where are steroid receptors found?
Nucleus
How do steroid hormones act?
On nuclear receptors
Initiate transcription factors
What are the domains of the steroid receptors?
A/B - N-terminal: domain controls which gene is activated
C - DNA binding domain
D - hinge-region - controls movement of the receptor to the nucleus
E - ligand binding domain: binds steroid
F - C-terminal domain
Which domain on the steroid receptors do ligands bind?
E
Which domain on the steroid receptors control which gene is activated?
A/B
Describe steroid hormone MOA
- Steroid hormones diffuses through plasma membrane
- Binds to intracellular cytosolic receptor
- Receptor-hormone complex enters the nucleus and binds to a glucotocoid response element (DNA sequence) in the 5’ flanking region of the target gene
- Binding initiates gene transcription to produce mRNA
- mRNA is translocate to protein which mediates the effect-target cell response
What types of steroid receptors are there?
Glucocorticoid receptors (GR) Mineralocoritocoid receptors (MR)
Explains the distribution of steroid receptors
- Glucocorticoid receptors (GR)
- widespread - Mineralocoritocoid receptors (MR)
- distal nephron
- salivary glands
- sweat glands
- large intestine
- brain
- vascular tissue
- heart
Cortisol can bind to MR
and cortisol concentration is higher than aldosterone
What mechanism if used to protect MR from illicit occupation by glucocortocoids?
Enzyme: 11beta-HSD II
- Catalyses the conversion of cortisol (active) to cortisone (inactive)
What is the inactive form of cortisol?
Cortisone
How is cortisol converted to its inactive form?
Cortisone is its inactive form
Converted via 11b-HSDII
What common food can inhibit the enzyme that converts cortisol to its inactive form
Inactive form: cortisone
Converted by 11b-HSD II
Can be inhibited by liquorice
List effects of cortisol
- stimulates gluconeogenesis in liver
- permissive effect on glucagon
- stimulates lipolysis in adipose tissue = FA is released
- acts as insulin antagonist and suppresses the release of insulin
- increases breakdown of skeletal muscle protein
- immune suppression
- changes mood
List actions of aldosterone
- Na+ reabsorption + H2O
- K+ and H+ excretion
Where does aldosterone act?
MR in the principal cells of the DCT and CD in the kidney
What does aldosterone do in the kidney?
- upregulates and activates basolateral Na/K-ATPases
- upregulates ENaC - increasing apical membrane permeability to Na
- stimulates K+ secretion into lumen
- stimulate H+ secretion via H+-ATPase in the intercalated cells of the CD
Describe aldosterone MOA in the kidney
- aldosterone bines to MR
- initiates cascade acting on the nucleus
- transcribes hormonal response elements
- mRNA transcription of ENaC, pumps etc…
- Na+ reabsorption + H2O
+ K+excretion
How is adrenal steroid production regulated
- Cortisol and androgens - HPAA
2. Aldosterone - RAAS and [K+]plasma
What is ACTH
Andogencoricotrophic hormone
What kind or hormone is ACTH
39AA peptide
What is ACTH formed from?
POMC
Pro-opiomelanocortin
What hormones are secreted from POMC?
ACTH
gamma-MSH
Endorphins (lipotropins)
What hormones trigger europhic effects and where are they released from?
B-endophin and met-enkephatin
POMC
What’s the function of gamma-MSH?
Controls melanin pigmentation of the skin
What activates RAAS?
Major regulator of aldosterone production
- activated in response to decrease in BP and [Na+]plasma
What is the direct effects of AngII
Vasoconstriction
What is the indirect effects of AngII?
aldosterone + thirst
What does RAAS do to BP
Increases BP
What is the RAAS pathway?
- decrease in BP and [Na+] detected in JG-apparatus
- renin released from juxtaglomerular cells
- renin converts angiotensinogen to AngI
- ACE converts Ang I to Ang II
- Ang II acts on adrenal cortex to secrete aldosterone
- aldosterone acts on kidneys to retain sodium and water
How does Ang II act on the adrenal medulla?
- GPCR
- Cascade: PLC-PIP2-IP3-DAG
- Increased IC Ca2+
- Transcription of StAR (Steriodogenic Acute Regulatory Protein)
- Cholesterol uptake into mitochondria
- Biosynthesis
What blood biochemical change apart from sodium decrease can trigger aldosterone?
increase [K+]ec
What is primary aldosteronism?
Increase levels of aldosterone
What does primary aldosteronism lead to (biochemically)?
- increase Na reabsorption = hypernaturaemia
- volume expansion
- hypokalaemia
- alkalosis
- low plasma renin activity
- hypertension
What can cause primary aldosteronism?
- aldosterone-producing adenoma (unilateral)
- bilateral adrenal hyperplasia
What syndrome results from increased levels of cortisol?
Cushing’s Syndrome
What are the typical features seen in Cushing’s syndrome
- weight gain
- moon face
- increased BP
- red raddy face
- buffalos hump
- stomach strech striae
What are the cause of Cushing’s syndrome?
ACTH-producing pituitary adenoma
What, apart from pituitary adenoma, can cause hypersecretion of cortisol?
Cortisol-producing adrenal adenoma
or
Iatrogenic
What is Addison’s disease?
Primary adrenal insufficiency or hypoadrenalism
Autoimmune
Inability of adrenal gland to make cortisol and aldosterone
What are the common clinical characteristics of Addison’s?
Fatigue Cachexia Low mood Loss of appetite Weight loss Increased thirst Pigmentation
Give a few examples of what can cause primary adrenal insufficiency
Autoimmune (Addison’s)
TB
Viral
Malignancy
What is primary adrenal insufficiency
Inadequate adrenocortical function
Inability to increase steroid hormone production
What are the characteristics of congenital adrenal hyperplasia
- ambiguous genitalia
- precocious puberty
- hirsutism
- amenorrhea
- mentrural irregularities
What kind of disease is congenital adrenal hyperplasia?
Autosomal recessive
lack of 21-hydroxylase activity
deficiency of cortisol and aldosterone
increased adrenal androgens
What biochemical feature would you expect in congenital
adrenal hyperplasia
Increase ACTH - in an attempt to compensate but this drives cholesterol biosynthesis down 17-hydroxylase pathways generating increased androgens
Decreased cortisol and aldosterone
How is secondary adrenal insufficiency caused?
- lack of ACTH stimulation
- iatrogenic (excess exogenous steroid)
- pituitary/hypothalamic disorders
What is Addison’s disease?
Commonest cause of primary adrenal insufficiency
- autoimmune destruction of adrenal cortex
How much of the adrenal cortex would be destroyed in Addison’s before patient is symptomatic?
> 90%
What are the common clinical features of Addisons
Anorexia Weight loss Fatigue/lethargy Dizziness Decreased BP Abdominal pain Vomiting Diarrhorea Skin pigmentation
Why do you get an increased ACTH in Addison’s?
Amplified negative feedback of cortisol due to lack of cortisol production
Dx Addison’s
- Suspicious biochemistry: decreased Na+, increased K+, hypoglycaemia, acidosis
- Impair cortisol response to synthetic ACTH (syn-ACTH-en)
- Elevated ACTH causes skin hyperpigmentation (POMC)
- Adrenal autoantibodies
- Increased renin
- Decreased Aldosterone
What is the biochemistry of addisons
- Suspicious biochemistry: decreased Na+, increased K+, hypoglycaemia, acidosis
Describe the synthetic ACTH test
Impaired cortisol response test
synACTHen
- measure plasma cortisol before and 30minutes after IV injection
Normal (cortisol levels):
- baseline: >250nmol/L
- post-ACTH >480nmol/L
Why is there hypotension and electrolyte imbalance in Addisons
Mineralocorticoid deficiency
- Decrease aldosterone = Decreased Na+ and increase K+
- Decreased water reabsorption = hypovolaemia = hypotension
*dehydration is the most common cause of orthostatic hypotension
What causes hyperpigmentation in Addisons?
Increased ACTH
Increased POMC
POMC = pro-opiomelanocortin
What causes hypoglycaemia in Addisons
Decreased cortisol
What natural conditions could give rise to cortisol?
Pregnancy and contraceptive pill
Tx Addisons
- Hydrocortisone (cortisol replacement)
- Fludrocortisone (aldosterone replacement)
What clinical feature distinguishes between primary and secondary adrenal insufficiency?
In secondary there is no increase in ACTH (there’s a lack of ACTH) so there is no hyperpigmentation (POMC)
And during an aldosterone production test, aldosterone is working as its regulated by RAAS
What are the causes of Cushing’s syndrome?
MAIN: oral steroids
Endogenous causes are rare
- 80% are due to increase ACTH - pituitary adenoma (Cushing’s disease)
- ACTH-dependent
1. pituitary adenoma
2. ectopic ACTH - carcinoid/carcinoma
3. Extopic CRH - ACTH-independent: decreased ACTH due to negative feedback
1. adrenal adenoma
2. adrenal carcinoma
3. nodular hyperplasia
Why is random plasma cortisol not an effective way to Dx Cushing’s?
May be misleading as illness, time of day, and stress (e.g. venepuncture) influence cortisol levels
How would you Dx Cushing’s?
Step 1: establish cortisol excess
- Overnight dexamethasone suppression test
- 1mg oral steroid
- if normal: should decrease ACTH and cortisol due to negative feedback
- in Cushing’s: No cortisol is suppressed - 24-hour urinary free cortisol (alternative)
- excess cortisol will exceed availability plasma capacity of plasma binding globulin (cortisol binding globulin)
- unbound cortisol is filtered freely into urine
- either 24hr assessment or cortisol:Cr ratio - Midnight salivary test of cortisol
- 11pm-midnight
- in normal people cortisol level is very low at this time
- in cushings it is very high due to loss of circadian rhythm
Step 2: Establish the source of cortisol excess
- undetectable ACTH
- adrenal CT = positive adrenal adenoma/carcinoma - normal/high ACTH
- do CRH stimulation test
a) no change in ACTH = CT chest/abdominoplevic region = actopic ACTH
b) exaggerated rise in ACTH = pituitary MRI = adenoma
Tx Cushing’s Syndrome?
- medical
- inhibit cortisol production (Metyrapone) - Surgical
- Trans-sphenoidal pituitary surgery
- laproscopic adrenalectomy
- excise ATCH source
What is the 2nd commonest cause of hypertention?
Primary aldosteronism
What causes primary aldosteronism?
Single or bilateral adrenal adenoma
Dx primary aldosteronism
- biochemistry:
- increase aldosterone
- decrease renin
- decreased K+
- increased Na+ - suppression test
- IV saline
- attempt to suppress aldosterone - Adrenal CT
Management primary aldosteronism
- Surgical
- adrenal adenoma: unilateral laparoscopic adrenalectomy
- cures hypokalaemia
- cures hypertension (30-70% cases) - Medical
- in bilateral adrenal hyperplasia
- MR antagonist - spironolactone
- amiloride (inhibit ENaC)
What is phechromocytoma?
Catecholamine-secreting tumours of the adrenal medulla
What is the clinical consequence of phechromocytoma?
Hypertension Headaches Palpitations Pallor Sweating
Dx phechromocytoma
- Measure urinary catecholamines and metabolites
- CT adrenals
Tx phechromocytoma
alpha1 +/- beta1 antagonists
