2. Adrenal Gland Flashcards
Describe the location and structure of the adrenal glands
Adjacent to kidneys in retroperitoneum
Two functionally distinct zones;
i. Adrenal Cortex; glomerulosa, fasciculata, reticularis
ii. Adrenal Medulla
Describe the function of the adrenal zones
Adrenal Cortex: essential for life, produces 3 classes of steroid hormone;
i. glomerulosa: mineralocorticoids e.g. aldosterone
ii. fasciculata: glucocorticoids e.g. cortisol
iii. reticularis: androgens e.g. DHEAs, androstenedione
Adrenal Medulla: part of sympathetic NS, produces catecholamines, e.g. adrenaline/noradrenaline
What are the key hormones produced by the adrenal cortex?
Glucocorticoid: cortisol (from fasciculata)
Mineralocorticoid: aldosterone (from glomerulosa)
What are glucocorticoids and what is their function? Give an example of a glucocorticoid
Glucocorticoids = steroid hormones that bind glucocorticoid receptor (present on almost all vertebrate cells)
Functions:
- immunological: part of feedback mechanism reducing some immune functions
- e.g. inflammation: upreg anti/ downreg pro inflammatory proteins
- role in development + homeostasis of T cells
- metabolic: involved in glucose metabolism
E.g. cortisol
How is cortisol synthesised and regulated?
As part of the hypothalamic-pituitary-adrenocortical axis
Hypothalamus releases corticotrophin releasing hormone (CRH)
Pituitary is stimulated by CRH to produce adrenocorticotrophic hormone (ACTH)
Adrenal gland synthesises cortisol in response to ACTH stimulation
Cortisol exhibits negative feedback on ACTH release from pituitary + CRH from hypothalamus
Which hormone is an important precursor to ACTH and what adrenal disease symptom does it contribute to?
POMC (pro-opiomelanocortin) is a precursor to MSH (melanocyte stimulating hormone) + ACTH
Produced by anterior pituitary
Primary adrenal hypofunction (Addisons) = no cortisol synthesis from adrenal = increasing ACTH as no negative feedback;
- overproduction of POMC = MSH = hyperpigmentation in Addison’s disease
How can glucocorticoids (cortisol) be used therapeutically?
Adrenal insufficiency: low dose (physiologic replacement)
Immunosuppression: high doses;
- allergic
- inflammatory: asthma (inhaled 2nd line)/pain relief (except tendinopathies)
- autoimmune disorders
- post transplant: GvHD/rejection
- heart failure
- potential use in sepsis
What are the current findings on glucocorticoid therapy in CVD?
Link b/n heart disease + GC resistance;
- polymorphism A3669G in exon 9 of GR gene associated with GC resistance
- these pts have increased risk of coronary heart disease, enlarged hearts, systolic dysfunction, heart failure
Debate around use of GCs in;
- decompensated heart failure to enhance response to diuretics (esp patients with refractory diuretic resistance with large doses loop diuretic)
- treatment of patients with atrial fibrillation
- can have beneficial cardiac effects e.g. improved contractility, inflammation reduction
- strong risk factor for hypertension, atherosclerosis, diabetes mellitus, sodium and fluid retention
What is cortisol?
- glucocorticoid
- end product of HPA axis
- medication = hydrocortisone
When is cortisol released?
In response to stress or low-blood glucose concentration
What are the functions of cortisol?
Range of physiogical functions
Metabolic; to regulate blood glucose
- increased gluconeogenesis = raised blood sugar
- increased hepatic glycogen storage
- increased break down of plasma + muscle protein to amino acids (proteolysis)
- increased release of glycerol + FFAs from adipose tissue (lipolysis) (some studies found suppression of lipolysis?)
Immunologic;
- antiinflammatory effects
- can weaken immune system
What is gluconeogenesis (GNG)?
Generation of glucose from non-carbohydrate carbon substrates
What is glycogenesis?
Formation of glycogen
How does cortisol increase GNG?
Enhances enzyme expression
How does cortisol increase glycogen storage?
Early fasting state: has indirect role in glycogenolysis: glycogen>glucose.
Late fasting state: increases glycogenesis = liver takes up glucose not used by tissues for glycogen stores in case of starvation state.
How does cortisol have antiinflammatory effects?
Prevents release of pro-inflammatory substances
Increases release of anti-inflammatory substances
Believed to be protective to prevent overactivation of inflammatory response to infections (sepsis)
How does cortisol weaken the immune system?
Prevents T cell proliferation
Creates negative feedback loop on IL-1 - central roles in regulating immune responses
What is the steroid metabolism pathway for cortisol?
Cholesterol
v
Pregnenolone > 17a-hydroxypregnenolone
v v
Progesterone > 17a-hydroxyprogesterone
v
Cortisol
How is cortisol found in the body and why is it measured in the urine?
95% blood cortisol bound (mainly) to TRANSCORTIN (cortisol binding globulin)
Normal level free cortisol v. small (filtered at kidneys = excreted in urine)
Transcortin almost fully saturated at normal concentration: excess production = greatly increased excretion in urine
- 24H urine collection sensitive for increased cortisol secretion (BUT NOT DECREASED)
Both urine + serum cortisol measured by immunoassay
When should cortisol testing occur and why?
Cortisol levels fluctuate greatly but there is marked diurnal rhythm: morning=high/ night=low
Therefore blood draw 0800-0900h (peak levels)
Sometimes draw at 2300h (should be low) to detect loss of diurnal variation - early feature of Cushings
Are random cortisol levels of any use?
Random cortisol levels of little use but high levels exclude adrenal failure in sick pt
What factors may affect cortisol tests other than illness?
Stress during collection = increased levels
Use of synthetic glucocorticoids - interfere with some immunoassays
Time - marked diurnal variation
What type of assay is used to measure urine + serum cortisol?
Immunoassay
What is the basic principle of cortisol testing?
Hyperfunction tested by measuring cortisol during suppression
Hypofunction tested by measuring cortisol during stimulation
What is a mineralocorticoid? Give an example.
Steroid hormone - aldosterone (glomerulosa)
What is the main function of aldosterone?
Promote sodium reabsorption + potassium excretion in kidney
How are aldosterone levels controlled?
Primarily controlled through the renin-angiotensin system
But also;
- ACTH can stimulate production to limited degree (minor role in normal secretion)
- synthesis sensitive to changes in circulating potassium levels
Describe the renin-angiotensin-aldosterone system (RAAS)
Renin released from juxta glomerular cells (kidney) in response to various stimuli;
- hypotension/decreased renal blood flow
- hyperkalemia
- hyponatremia
Renin catalyses conversion of angiotensinogen in plasma to angiotensin I
Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II during passage through lungs
Angiotensin II stimulates aldosterone release from adrenal cortex
Aldosterone corrects hypotension/hyperkalemia/hyponatremia
How is aldosterone measured and what factors must be considered during test?
Plasma aldosterone varies with posture - measure after pt recumbent overnight + sometime after being upright
Plasma renin often measured with aldosterone (both measured by immunoassay)
What is Addison’s disease?
Primary adrenal insufficiency/hypocortisolism
Long term endocrine disorder - adrenal glands do not produce enough steroid hormone
Usually occurs slowly/can be acute (medical emergency)
What are the signs + symptoms of Addision’s disease?
Usually gradual development + non-specific
- fatigue/weakness
- anorexia/weight loss
- dizziness/postural hypotension
- hyperpigmentation (inc areas not exposed to sun)
What are the signs and symptoms of an acute adrenal crisis?
Severe hypovolaemia
Shock
Hypoglycaemia
What causes hyperpigmentation in primary adrenal sufficiency and why does it not occur in other forms?
Hyperpigmentation caused by melanocyte stimulating hormone (MSH)
POMC (pro-opiomelanocortin) is the precursor molecule for ACTH + MSH
POMC and therefore MSH are overproduced when there is no cortisol synthesis to provide negative feedback to reduce ACTH/CRH
In secondary and tertiary forms of adrenal hypofunction there is underproduction of POMC/ACTH/CRH
What are the causes of primary adrenal hypofunction (Addison’s)?
Autoimmune destruction of adrenal gland Tuberculosis Tumour metastasis in adrenal Adrenal hemorrhage Amyloidosis Hemochromatosis Removal of adrenals Meningicoccal septicaemia
What are the most common causes of primary adrenal hypofunction (Addison’s)?
Autoimmune destruction of adrenal gland
- 90%
- most common cause in developed world
Other causes total 10%
Tuberculosis is most common in developing world
What causes autoimmune destruction of the adrenal gland in primary adrenal hypofunction?
Immune reaction against enzyme 21-hydroxylase (cytochrome p450) involved in biosynthesis of steroids aldosterone + cortisol
What are the causes of secondary adrenal hypofunction?
Sudden withdrawal of GC drugs/failure to increase GC during stress (e.g. illness/surgery)
Hypopituitarism = decreased ACTH stimulation
Why does suddenly withdrawing from GC drugs or failure to increase them during times of stress result in secondary adrenal hypofunction?
Treatment suppresses normal function of H-P-A axis
It takes a long time to become self-sufficient in GC production again
Will not produce enough excess for stress
What are the clinical differences between primary and secondary adrenal hypofunction?
No hyperpigmentation (ACTH low) No renal Na wasting (only cortisol deficient not aldosterone)
How is Addison’s disease treated?
Maintenance;
- replace missing cortisol = hydrocortisone/prednisone tablets/prednisolone
- replace missing aldosterone = fludrocortisone
- i.e. lifelong GC/MC replacement therapy mimicking physiologic concentrations
Carry med-alert bracelet etc in case of emergency
Carry injectable cortisol kit for emergencies
Increase medicine in times of illness/surgery/dental
Acute crisis;
- IV GCs, large volumes saline solution with dextrose (glucose)
- usually rapid improvement, wean to maintenance dose
What are the biochemical features of adrenal hypofunction and what causes them?
Hyponatremia/hyperkalemia: related to aldosterone deficiency
Hyperuremia (urine excretion products in blood): loss of sodium at kidneys = ECF volume depletion/dehydration = no urine output
Hypoglycaemia: related to cortisol deficiency
How is adrenal hypofunction diagnosed?
9am plasma cortisol;
- <50nmol/L virtually diagnostic of adrenal failure
- > 450nmol/L excludes adrenal failure
SynACTHen = synthetic ACTH analogue;
- used to test capacity of adrenal cortex response to ACTH (stimulation test)
Further testing to establish primary or secondary;
- long/depot synACTHen test = cortisol increased in secondary not primary
- measurement of ACTH levels = increased in primary/ decreased in secondary
Describe the process in a synACTHen stimulation test for hypofunction diagnosis
- measure basal cortisol level
- administer synACTHen
- cortisol measured 30 mins later
- cortisol should rise >450nmol/L
What is adrenocortical hyperfunction and what two syndromes result?
Adrenocortical hyperfunction is the overexpression of the products of the adrenal cortex
Causing;
- overproduction of GCs (cortisol) = Cushing’s syndrome
- overproduction of MCs (aldosterone) = Conn’s syndrome
What is Cushing’s syndrome?
A collection of signs + symptoms due to prolonged exposure to cortisol/other GCs
Primarily excess cortisol
What are the clinical features of Cushing’s?
Depend on aetiology but primarily excess cortisol
Cortisol + precursors have some MC activity;
- excess MC = hypertension (hypernatremia), hypokalemic acidosis (hypokalemia)
- synthetic GCs have no MC activity = these features not present in iatrogenic Cushing’s
Excess androgen symptoms e.g. hirsuitism in females
Generally;
- baldness/facial hair in females
- acne
- moonface/plethoric cheeks
- buffalo hump
- hypertension
- osteoporosis
- skin thinning
- easy bruising
- poor wound healing
- increased abdominal fat
- abdominal striae
- avascular necrosis of femoral head
- muscle weakness
List the causes of Cushing’s syndrome
Pituitary adenoma: ACTH secreting tumour (60-70%)
Ectopic ACTH secretion by various tumours e.g. bronchial carcinoma + carcinoid tumours
Adrenal adenoma/carcinoma: excess GC
Iatrogenic Cushing’s: exogenous GC therapy
What are the difficulties with Cushing’s diagnosis?
Cushingoid features common in general public (hypertension, obesity)
Cushing’s relatively rare (<5million/year)
Pseudo-cushing’s can occur in alcoholism + severe depression
- pt appears cushingoid but also exhibits similar biochem abn
Exclude iatrogenic cause - need thorough drug history
What are the 2 steps of a Cushing’s diagnosis?
- Initial screening tests to identify hypercortisolism
2. Tests to find cause of high cortisol
Name the tests used to screen for hypercortisolism
3 main tests;
- 24H urinary free cortisol (UFC)
- normal <210nmol/24H
- usually used by GPs in NI - Overnight dexamethasone suppression test
- 48H low dose dexamethasone suppression test
- both normal = plasma cortisol <50nmol/L @0900h
What other useful screening tests can be used for hypercortisolism? Describe them.
Insulin hypoglycaemia test;
- cortisol should rise >500nmol/L in response to hypoglycaemia
- rise not seen even in mild cushings
- pseudocushings do respond
- hypoglycaemia-associated risks = contraindicated in various pts
Loss of cortisol secretion diurnal pattern;
- 11pm cortisol <100nmol/L excludes cushings
- 11pm test must be done as inpt + stress avoided to prevent false positives (not practical for screen test)
- pulsatile secretion in both normal + abn states = false positives + negatives common
Describe the UFC screening test for hypercortisolism
Increased UFC (>210nmol/24H) seen in cushings but also pseudocushings + extreme obesity
Care needed as incomplete collection = falsely low levels
Measurement of cortisol:creatinine ratio may help avoid problems with inaccurate urine collections
Describe the dexamethasone suppression tests used to screen for hypercortisolism
Dexamethasone: synthetic GC
- binds cortisol receptors in pituitary = suppression of ACTH release
- in normal pt suppression of ACTH release = suppression of cortisol by adrenals
Overnight dexa supp test;
- 1mg dexa tablet @ 11pm
- 9am cortisol measured: <50nmol/L normal
- failure to suppress = cushings/false positive (pseudo-cushings/stress)
48H low dose dexa supp test;
- 0.5mg dexa every 6hrs for 2 days
- cortisol measured morning after last dose
- levels normally suppress <50nmol/L
- fewer false positives with this method
What 3 main tests are used to find the cause of hypercortisolism/cushings?
- High dose dexamethasone suppression test
- Plasma ACTH measurement
- Cortico-trophin releasing hormone (CRH) test
Describe the high dose dexamethasone test used to find the cause of cushings
Patient given 2mg dexa every 6hrs for 48hrs
Plasma cortisol measured;
- day 1: 0900h before 1st dose (basal level)
- day 2: 0900h
- day 3: 0900h 6hr after last dose
Cushing’s disease (pit tumour) = cortisol usually suppresses to <50% of pretreatment value
Failure to suppress = adrenal tumour/ectopic ACTH source
Describe the plasma ACTH measurement used to find the cause of cushings
Ectopic ACTH source = very high ACTH
Cushings disease (pit tumour) = moderately elevated
Adrenal tumour = low
Describe the CRH test used to find the cause of cushings
Used to distinguish b/n cushings disease (pit tumour) + ectopic ACTH secretion
Pt given dose of IV CRH then ACTH + cortisol measured at intervals; -15, 0, 15, 30, 45, 60, 90, 120 mins
Interpretation;
- pituitary source: cortisol rise from basal to peak >20%
- pituitary source: ACTH rise from basal to peak >50%
- ectopic ACTH secretion (+adrenal tumours): usually no response
Problems;
- 10% pts with cushings disease do not respond to CRH but usually show suppression to HDDST
- 10% of ectopic ACTH syndrome may respond to CRH but fail to suppress with dexa
What other useful tests help determine cause of hypercorticolism?
Imaging;
- adrenal/abdominal CT
- pituitary MRI scan
- chest x-ray for tumours
Selective venous sampling for ACTH to reveal source of secretion (1977 paper);
- selective catheterisation + venous sampling
- localises ACTH secretion
- samples pit venous drainage using Seldinger technique from a femoral approach
- ACTH determined in L + R inferior petrosal sinuses + compared to peripheral venous samples drawn at same time
- increased conc. ACTH in neck vs peripheral suggests pit source
How is Cushings treated?
Depends on cause.
Adrenal adenoma/carcinoma = surgically removed/resected
Cushing’s disease (pit adenoma);
- transphenoidal hypophysectomy
- or if adrenals semi-autonomous: bilateral adrenalectomy + pituitary irradiation
- appropriate steroid/replacement therapy needed after both
Presurgery/if not amenable to surgery = drugs to block cortisol synthesis, e.g. metyrapone
Ectopic ACTH = treat cause, e.g. tumour removal
Iatrogenic cushing’s = review/adjust treatment
What is Conn’s syndrome?
Primary hyperaldosteronism
Rare condition (1 million/year)
What are the clinical features of Conn’s?
Hypertension (accounts for up to 10% of hypertension)
- due to sodium retention at kidneys
Muscle weakness Tetany (spasms) Paraethesiae (pins + needles) Polydipsia + polyuria - all due to hypokalemia as a result of increased renal potassium excretion
Many pts asymptomatic: identified by hypokalemia during hypertension investigation
What are the causes of primary aldosteronism (Conn’s)?
Adrenal adenoma (majority ~75%)
Bilateral hyperplasia of zona glomerula (~2/3 pts in some studies)
Adrenal carcinoma (rare)
GC-suppressible hyperaldosteronism;
- rare autosomal dominant inherited condition
- aldosterone secretion under control of ACTH
Other causes;
- mimicked by excess liquorice/carbenoxone ingestion
Why does excess liquorice ingestion cause Conn’s?
Liquorice = carbenoxone
Inhibits 11B-hydroxysteroid dehydrogenase that converts cortisol to inactive cortisone
Excess cortisol exerts MC effects
What causes secondary hyperaldosteronism?
More common than primary aldosteronism
Overactivity of renin-angiotensin-aldosterone system (RAAS)
Common causes;
- heart failure
- liver cirrhosis
- nephrotic syndrome
Less common;
- renal artery stenosis
- Na wasting nephritis
- Barrter’s syndrome
- Renin-secreting tumour
What other names are primary and secondary hyperaldosteronism known by?
Primary = hyporeninemic hyperaldosteronism (release of aldosterone from adrenal despite no renin stimulation)
Secondary = hyperreninemic hyperaldosteronism (overactive RAAS system)
What are the typical lab findings in Conn’s?
Hypokalemia (excreted in urine)
- urine K+ inappropriately high (>30mmol/24H) for low serum K+ in pt not on diuretics
Plasma sodium usually high-normal/slightly above ref range (usually lower in secondary)
How is Conn’s diagnosed?
Recumbent + ambulatory plasma aldosterone + renin;
- basal measurement taken after 8h recumbency on waking in morning
- Conn’s = high plasma aldosterone/low plasma renin activity
Measurement after ambulatory for 4 hrs useful in distinguishing cause
Imaging techniques;
- CT scan of adrenals
Selective blood sampling
What is the treatment for Conn’s?
Dependent on cause
Adrenal adenoma/carcinoma;
- surgically removed/resected
- pts awaiting sirgery given spironolactone
Bilateral adrenal hyperplasia;
- treated w/ spironolactone (diuretic that antagonises action of aldosterone)
GC-suppressible hyperaldosteronism;
- treated with dexamethasone
What is CAH?
Congenital adrenal hyperplasia (CAH) = a group of metabolic disorders of adrenal steroid hormone synthesis
What causes CAH?
Mutation of enzymes mediating biochem synthesis of steroids
What are the features of CAH?
Depends on enzyme deficiency
What is the most common cause of CAH?
95% due to 21-hydroxylase deficiency (1 in 15000 live births in UK)
Describe 21-hydroxylase deficiency
21-hydroxylase converts progesterone into aldosterone precursor + 17a-hydroxyprogesterone into cortisol precursor
- deficiency = no/little cortisol + aldosterone
21-hydroxylase deficiency may be partial/complete;
- complete presents shortly after birth = severe salt losing state due to deficient cortisol/aldosterone
Lack of cortisol = lack of negative feedback to pit = increased ACTH = drives androgen synthesis
What causes 21-hydroxylase deficiency?
Autosomal recessive disease (male=female frequency)
How can 21-hydroxylase deficiency be diagnosed in the lab?
High levels of 17a-hydroxyprogesterone secreted
Describe the signs and symptoms of classical CAH (21-hydroxylase deficiency)
Lacks cortisol + aldosterone
- predisposes 3/4 severely affected to adrenal crisis with dehydration/shock/death if not properly diagnosed + treated
Excess adrenal androgen production begins in early fetal life;
- may lead to virulisation/ambiguous genitalia in baby girls
- continued androgen excess = precocious puberty in boys
Describe the signs and symptoms of non-classical CAH (21-hydroxylase defiency)
Partial enzyme deficiency;
- some cortisol production
- normal aldosterone
- lower levels adrenal androgens
Milder, non-life threatening form of CAH
Manifests later in childhood/young adult life;
- no ambiguous genitalia in girls
- premature development of pubic hair
- menstrual irregularities
- hirsuitism
- severe acne
- ~10% fertility problems
Ashkenazi jews = highest prevalence
What other rarer forms of CAH exist and how rare are they?
Other forms account for <5% CAH cases
11B-hydroxylase deficiency (5%)
- increased MC + androgen
- hypertension due to accumulation of 11-deoxycorticosterone + excessive androgen production
17-hydroxylase (v rare)
- increased MC, decreased androgen
18-hydroxylase (v rare)
- decreased MC + androgen
3B-hydroxyhydrogenase ( v rare)
Delta5 isomerase (v rare)
How is CAH diagnosed?
Hormone measurement
Clinical evaluation: history + PE
Newborn screening (USA): high false +ve rate
How is CAH treated?
Generally steroid replacement therapy;
- GC - oral hydrocortisone/prednisolone/dexamethasone
- MC - fludrocortisone (classical CAH)
- restores inhibition = decreased androgens
Additional treatments to optimise growth by delaying puberty/bone maturation
What conditions can affect the adrenal medulla?
Pheochromocytoma
What is a pheochromocytoma?
A tumour of the adrenal medulla (usually) secreting catecholamines
- usually noradrenaline (some = large amounts adrenaline)
- rare but treatable cause of hypertension (0.5%)
Where are pheochromocytomas found?
Usually in the adrenal medulla (90%)
Extra adrenal: 10%
Are pheochromocytomas malignant?
10% are malignant
What are the signs + symptoms of a pheo?
- Hypertension associated with vasomotor symptoms (anxiety/sweating/palpitations)
- Headache
- Pallor
- Tremor
- Abdominal pain
What are the major clinical effects of a pheo?
If increased noradrenaline;
- v high BP
- slow heart rate
- increased sweating
- increased blood glucose
If increased adrenaline;
- slightly increased/decreased BP
- rapid heart rate
- increased sweating
- apprehension
- increased blood glucose
How is a pheo diagnosed?
Measurement of urinary metanephrines (BHSCT);
- 1x 24H urinary metanephrine collection
- used to require 2x 24H for urinary catecholamines
- if +ve but potentially interfering drugs: repeat after drug washout
- if still abn then measure plasma metanephrines + confirm with clonadine
Clonadine suppression test;
- 97% sensitivity
- pt must be relaxed
- insert IV cannulae
- after 30 minutes baseline sample collected for plasma catecholamines
- administer 0.3mg clonadine orally
- collect blood for catecholamines after 3 hours
- requires decrease of >50% in plasma adrenaline + noradrenaline
What is clonadine + what does it do?
Clonadine;
- drug that stimulates alpha 2 receptors in brain stem
- binding has sympathetic effect
- suppresses release of noradrenaline
What is the treatment for a pheochromocytoma?
Surgical removal of tumour
