PBL 11- Cushings/Addisons Flashcards
(147 cards)
1
Q
What is the definition of Cushings syndrome?
A
The symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoid
2
Q
What are some causes of Cushings syndrome?
A
Excess adrenal secretion ○ ACTH dependent § Pituitary § Non-pituitary § Increased CRH secretion ○ ACTH independent § Functioning adrenal tumours § Other rare syndromes
Iatrogenic
Steroids such as in asthma
3
Q
What is the normal hypothalamic pituitary adrenal axis?
A
○ Various stressors, low levels of circulating cortisol and the body’s circadian rhythm stimulated the hypothalamus
○ Hypothalamus secretes corticotrophin releasing hormone (CRH) into the hypophyseal portal system ○ CRH is transported to the anteriorituitary where it stimulates the cleaving into Adrenocorticotropic Hormone (ACTH) ○ ACTH is released by the corticotroph cells of the anterior pituitary and acts as the pivotal regulator of cortisol synthesis in the adrenal gland
ACTH also has short term effects on the mineralocorticoid and adrenal androgen synthesis
4
Q
What are the three steroid hormones produced by the adrenal cortex and where are they produced?
A
○ Mineralocorticoids = Zona Glomerulosa
○ Glucocorticoids = Zona Fasciculata
Androgens = Zona Reticularis
5
Q
What is the basic action of ACTH?
A
○ ACTH stimulates secretion of steroid hormones in the adrenal cortex
○ It especially works in the Zona Fasciculata by binding to the cell surface ACTH receptors (G protein coupled) ○ Influences steroid hormone secretion by both rapid short-term mechanisms that take place within minutes and then slower long-term actions
6
Q
What are the rapid short term actions of ACTH?
A
○ Stimulation of cholesterol delivery to the mitochondria cholesterol side chain cleavage enzyme (CYP11A1) is located
○ The enzyme catalyses the first step of steroidogenesis which is the cleavage of cholesterol to form pregnenolone ○ ACTH also stimulates lipoprotein uptake into the adrenal cortical cells increasing the bioavailability of cholesterol in these cells
7
Q
What are the long term actions of ACTH?
A
○ Stimulation of the transcription of genes coding for the steroidogenic enzymes, especially CYP11B1 and their electron transfer proteins
○ This is observed over several hours ○ Also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems ○ These are necessary for the supply of the increased energy needs of the adrenocortical cells stimulated by ACTH
8
Q
Describe the ACTH receptor:
A
○ It is a seven membrane spanning G protein coupled receptor
○ Stimulate adenyl cyclase which leads to increase in intracellular cAMP
Activation of protein kinase A
9
Q
What are the ACTH dependent causes of Cushings?
A
○ Cushings disease ( ACTH secreting pituitary adenoma)
○ Ectopic ACTH syndrome
○ CRH Hypersecretion
10
Q
What is Cushings Disease?
A
○ 70% of non–iatrogenic cushings syndrome
○ Located in the anterior pituitary
○ M: F = 1:6
○ Age : 20-40
○ Basophilic corticotroph cell pituitary adenoma (usually less than 10mm)
○ Bilateral adrenocortical hyperplasia
○ Hyperplasia is usually micronodular
○ Slow progressive course over many years
11
Q
What is Ectopic ACTH syndrome?
A
○ A non-pituitary tumour synthesizes and hyper secretes biologically active ACTH or a ACTH like peptide
○ Most commonly caused by small cell and non-small cell carcinomas of the lung
○ More common in men 3:1
○ 15% of non - iatrogenic Cushing’s syndrome
○ Age: 40-60
○ Bilateral adrenocortical hyperplasia
○ Course and prognosis is of the underlying neoplasm
12
Q
What is CRH hypersecretion?
A
○ Very rare condition where patients have diffuse hyperplasia of the pituitary corticotroph cells which results in hypersecretion of ACTH
○ Due to either:
○ Hypersecretion of CRH by the hypothalamus
○ Non-hypothalamic tumours that secrete ectopic CRH (bronchial carcinoids, medullary carcinoma of the thyroid, prostate carcinoma)
○ Chronic CRH hypersecretion does not cause pituitary adenomas
13
Q
What are ACTH Independent Causes of Cushings Syndrome?
A
○ Functioning adrenocortical tumours (the main causes)
○ ACTH independent macronodular hyperplasia
○ Primary pigmented nodular adrenal disease
○ McCune-Albright Syndrome
14
Q
What are functioning adrenocortical tumours?
A
○ Adenomas and carcinomas that produce cortisol autonomously
○ More common in women
○ 40 years of age
○ Prognosis depends on the underlying neoplasm
Adrenal Adenomas
○ Responsible for about 8% of non iatrogenic cushings syndrome
○ 1-6 cm in diameter
○ Encapsulated and consist mainly of zona fasciculata cells
○ Relatively inefficient producers of cortisol
○ Clinical features are only mind and androgenic effects usually absent
○ Onset is gradual
○ Only elevated Cortisol
Adrenal Carcinomas
○ 7% of Cushings syndrome
○ Large
○ Often palpable as an abdominal mass by the time the syndrome manifests
○ Highly vascular with areas of necrosis, haemorrhage, cystic degeneration and calcification
○ Highly malignant tumours and invade the adrenal capsule, neighbouring organs and blood vessels
○ Metastasize to the liver and lungs
○ Rapid onset and progression
○ Marked elevations of glucocorticoids, Mineralocorticoids and androgens
15
Q
What is ACTH independent macronodular hyperplasia?
A
○ Rare but notable cause of adrenal cortisol excess
○ Characterised by the ectopic expression of receptors not usually found in the adrenal gland
○ Examples of present receptors are: LH, ADH, Serotonin, IL-1 and GIP- the cause of food dependent cushings
○ Activation of these receptors results in upregulation of Protein Kinase A signalling which is the same as what happens in ACTH
○ Subsequently this results in increase in cortisol production
16
Q
What is primary pigmented nodular adrenal disease?
A
○ Mutations in the regulatory subunit R1A of Protein Kinase A
○ This is part of Carneys complex- a multiple neoplasia condition associated with cardiac myxomas, hyperientiginosis, sertolis cell tumours and PPNAD
17
Q
What is McCune-Albright Syndrome?
A
○ Very rare
○ Associated with polyostotic fibrous dysplasia
○ Unilateral cage-au-lait spots and precocious puberty
○ Activating mutations in GNAS-1
18
Q
What are the Clinical manifestations of Cushings syndrome?
A
○ Glucose intolerance ○ Muscle Wasting ○ Obesity and redistrubution of body fat ○ Weight gain ○ Moon face ○ Supraclavicular fat pads ○ Truncal obesity ○ Buffalo hump ○ Sparing of the extremities ○ Skin Changes ○ Cutaneous atrophy ○ Easy brusing ○ Abdominal striae ○ Cigarette paper skin ○ Poor wound healing ○ Hirsutism and acne ○ Pigmentation ○ Osteopenia ○ Back pain and fractures ○ Nephrolithiasis ○ Gonadal dysfunction ○ Females have menstrual irregularity ○ Males have less testicular testosterone ○ Hypertension ○ Psychiatric disturbances ○ Ocular involvement ○ Glaucoma, cataracts, exophthalmos ○ Visual field defects (pituitary macroadenoma) ○ Impaired immune response ○ Growth Retardation
19
Q
Why does Cushings cause Glucose intolerance?
A
○ Cortisol excess promotes the synthesis of glucose in the liver from amino acids liverated by protein catabolism
○ This increased gluconeogenesis occurs via stimulation of the enzyme Glucose 6 phosphatase and phosphoenolpyruvate carboxykinase ○ Cortisol also antagonises the actin of insulin in peripheral glucose utilisation possibly by inhibiting glucose phosphorylation
20
Q
What are the characteristics of Diabetes in Cushings syndrome?
A
○ Overt diabetes occurs in 10-15% of patients with Cushings syndrome
○ They have insulin resistances, ketosis and hyperlipidaemia
○ Acidosis and microvascular complications are rare
21
Q
What causes Muscle wasting in Cushings syndrome?
A
○ Result of excess protein catabolism
○ Decreased protein synthesis
○ Induction of insulin resistance in a muscle via a post insulin receptor defect
○ Proximal muscle weakness occurs in about 60% of cases
○ Usually manifested by difficulty in climbing stairs or rising from a chair or bed without arms
○ Fatigue when combing the hair is also seen.
22
Q
Why is there increased weight gain in Cushings syndrome?
A
○ Result of excess protein catabolism
○ Decreased protein synthesis
○ Induction of insulin resistance in a muscle via a post insulin receptor defect
○ Proximal muscle weakness occurs in about 60% of cases
○ Usually manifested by difficulty in climbing stairs or rising from a chair or bed without arms
○ Fatigue when combing the hair is also seen.
23
Q
Why is there increased weight gain in Cushings syndrome?
A
○ Plasma leptin levels are significantly elevated- probably as a result of the visceral obesity
○ Glucocorticoids may act on adipose tissue to increase leptin synthesis and secretion
○ Chronic hypercortisolism may also have an indirect effect via associated insulin resistance
○ Intra abdominal fat seems to have a higher density of glucocorticoid receptors
24
Q
Why are there skin changes in Cushings Syndrome?
A
○ Glucocorticoid excess inhibits fibroblasts leading to loss of collagen and connective tissue
○ This leads to thinning of the skin, abdominal striae, easy bruising and poor wound healing
○ Atrophy leads to a translucent appearance of the skin
○ Cutaneous atrophy is best appreciated as a fine cigarette paper wrinkling on the hand or over the elbow
○ On the face corticosteroid excess causes perioral dermatitis
○ Small follicular papules on an erythematous base around the mouth and rosacea like eruption
○ Central facial erythema
○ Loss of subcutaneous tissue with hypercortisolism leads to facial telangiectases and plethora over the cheeks
○ Striae also caused from increased subcutanous fat deposition that stretches the thin skin and ruptures subdermal tissues- they are depressed below the skin surface because of the loss of subcutanous connective tissue
○ In ectopic ACTH syndrome- hyperpigmentation can occur because some of the elevated ACTH is converted to melanocyte stimulating hormone- rare in cushings.
25
Why do people get osteopenia in Cushings Syndrome?
○ Excessive glucocorticoids inhibits bone formation and accelerates bone resorption
○ Exert direct effects on the main cell types that regulate bone metabolism
○ Inhibit osteoblast differentiation
○ Induce osteoblast and osteocyte apoptosis whilst prolonging osteoclast survival
○ Leads to a state of hypogonadism which reduces the beneficial effects of sex hormones on bone strength
○ Decreases intestinal Ca absorption and increases urinary excretion by inhibiting the effects of vitamin D as well as decreased hydroxylation of vitamin D in the liver
○ Secondary increase in PTH secretion accelerating bone resorption
○ Combination of decreased bone formation and increased resorption leads to loss in bone mass (osteoporosis) and increased risk of fracture
26
Why do people get kidney stones in cushings syndrome?
○ Excess glucocorticoids leads to increased Ca resorption from bone and to its increased excretion in the urine.
○ Kidney stones occur in about 15% of patients causing such patients to present with renal colic
○ Also reduce the renal tubular reabsorption of phosphate leading to phosphaturia and reduced phosphorus concentrations
27
Why do people get Gonadal dysfunction in Cushings?
○ Females get menstrual irregularity due to inhibition of hypothalamic GnRH
○ due to increased adrenal androgens and cortisol
○ Males have decreased testicular testosterone leading to decreased libido and impotence as well as loss of body hair due only to increased cortisol
○ Due to inhibition of hypothalamic GnRH which then inhibits normal LH and FSH pulsatility
28
Why do people get hypertensive in Cushings syndrome?
○ Occurs in 80% of cushings
○ Increased alt and water retention from the mineralocorticoid effects of the excess glucocorticoid - in high concentrations they escape inactivation by the kidney
○ Increased secretion of angiotensinogen - due to direct stimulatory effect of glucocorticoids on the hepatic synthesis (Renin levels are normal or suppressed in cushings )
○ Increased Endothelin and a decrease in nitric oxide predisposing to vasoconstriction
○ Increase a-adrenergic receptor density
29
What are the psychiatric disturbances that people experience in Cushings disease and why?
○ Depression, irritability, emotional lability
○ Euphoria, hypomania
○ Psychosis
○ Impaired cognitive function
○ Sleep disorders
○ Mechanism not well understood
Possibly loss of synapses in the prefrontal lobe. Decrease in neurogenesis and increase in olgiodendrogenesis
30
Why do people get Ocular involvement in Cushings syndrome?
○ Mild to moderate elevations of intraocular pressure and glaucoma related to swelling of collagen strands in the trabecular meshwork
○ This interferes with aqueous humour drainage
○ Posterior sub capsular cataracts may develop
○ Pituitary adenomas may also put pressure on the optic chiasm
○ Microadenomas should not cause visual field defects.
31
Why do people with Cushings syndrome have an impaired immune response?
○ Glucocorticoid excess suppresses the normal inflammatory response
○ Patients are more susceptible to infections especially those with a cell mediated immune response such as TB, fungal or pneumocystis infections
32
Why do children with Cushings get Growth Retardation?
○ Direct inhibition of bone cells and a decrease in growth hormone and TSH secretion as well as decreased somatomedin generation
○ Glucocorticoids suppress growth by exerting direct effects on the growth plate
○ Inhibits mucopolysaccharide production resulting in reduced cartilaginous bone matrix and epiphyseal proliferation
33
What is the diagnostic process for cushings syndrome?
○ Do they have consistent clinical features that are multiple and progressive?
○ Exclude exogenous glucocorticoids
○ Perform the following tests
○ 24 hour urinary free cortisol (repeated 3 x)
○ Midnight salivary cortisol level (repeated 3 x)
○ Low dose dexamethasone suppression test
○ If both tests are negative = unlikely but can re test in 6 months if pre test probability is high
○ If one is abnormal- causes for the syndrome should be sought
○ If both abnormal the diagnosis is confirmed and further investigations should be undertaken to find the cause
○ High dose Dexamethasone suppression testing (8mg)
○ CRH test
○ Imaging
○ MRI for a pituitary adenoma
○ MRI/CT for ectopic ACTH syndrome
○ CT for Adrenal Tumour
34
What is a urinary free cortisol excretion test and how is it done?
○ Measures unbound cortisol - not effected by conditions and medications that alter cortisol binding globulin (such as oral oestrogen)
○ Requires an accurate 24 hour collection of urine- total volume and creatinine
○ False negatives occur once the eGFR is < 60mL/min
○ Interpretation of result depends on upper limit of normal for the particular assay being used
○ Due to variability it should be repeated 3 times
35
What's the normal circadian rhythm of cortisol?
○ Level begins to rise at 3-4am and then reaches a peak at 7-9am
○ Falls for the rest of the day to very low levels when the person in unstressed and asleep at midnight
36
What are the circadian abnormalities of cortisol in cushings syndrome and how can they be used in tests?
○ There is a loss of rhythm with the absence of the late night cortisol low
○ This is the basis for the measurement of midnight salivary cortisol level
○ The morning cortisol peak is unable to be suppressed by supra-physiological doses of glucocorticoid
○ This forms the basis of the dexamethasone suppression test.
37
What is the salivary cortisol test?
How is it performed?
What is the normal value?
○ Biologically free cortisol in the blood is equal to that in the saliva
○ Salivary production does not appear to change the concentration
○ Normal subjects have a midnight level of < 4nmol/L
○ Values > 4 are consistent with Cushings syndrome
○ Easily performed and non invasive
○ Collected either by passive drooling into a tube or placing a cotton bud in the mouth and chewing for 1-2 minutes
○ Should be performed on 3 separate occasions
38
What is a Dexamethasone suppression test?
○ Two forms of low dose dexamethasone suppression test which give roughly the same results
○ Overnight 1mg test
○ Given at midnight
○ Blood drawn at 8-9am the next day
○ Normal response is < 50nmol/L because the early morning circadian peak is suppressed
○ 48 hour 2mg/day test
○ Oral administration of 0.5mg at 6 hourly intervals
○ Followed by drawing of blood for cortisol level, 6 hours after the last dose at 9am
○ Normal response is < 50 nmol/L due to early morning circadian peak suppression
39
How can a Dexamethasone suppression test be used to determine cause of problem?
○ Normal anterior pituitary coricotrophs , pituitary basophilic adenomas and non pituitary neoplasms can secrete ACTH
○ Cells in each of these tissues vary in their responsiveness to ciruclating cortisol
○ Normal pituitary cells are extremely sensitive and are suppressed by physiological amounts of Glucocorticoid ie 1mg
○ Pituitary adenomas are still composed of corticotrophs- but they are less sensitive. They can still be suppress by glucocorticoids however they need about 8mg
○ Non pituitary neoplasms that produce ACTH are not composed of corticotrophs and therefore are NOT suppressed by any mount of Glucocorticoid
40
How much of cortisol is bound to plasma proteins?
90%
41
Once Cushings syndrome has been confirmed what is the next investigation that should be performed?
How would the results be interpreted?
What would the results be in Cushings DISEASE?
What would the results be with autonomous adrenal tumours?
○ A 9am plasma ACTH level to determine if the cause is ACTH dependent or independent
○ An elevated or inappropriately normal ACTH level is consistent with ACTH dependent causes
○ Undetectable or low-normal ACTH level is consistent with an ACTH independent (usually adrenal) cause
○ In cushings disease, 50% of people have ACTH within the normal range, 50% is ELEVATED
○ In patients with autonomous adrenal tumours the plasma ACTH is undetectable
42
If 9am plasma ACTH is elevated what would the possible diagnosis be?
How would you distinguish them from each other?
○ ACTH secreting adenoma (cushings disease)
○ Ectopic ACTH syndrome
Can be distinguished by using
Dexamethasone suppression test
○ In cushings disease there is an element of negative feedback so high doses of dexamethasone suppresses ACTH and therefore cortisol
○ In 90% of cushings disease the second plasma level will be <50% of the baseline level
○ Unfortunately 10% of patients with ectopic ACTH syndrome will have the same result
Corticotrophin releasing hormone test
○ This test stimulates the pituitary secretion of ACTH and hence cortisol
○ In cushings disease this response is exaggerated ie a 100% increase in ACTH and a 50% increase in cortisol
○ In ectopic ACTH syndrome or adrenal neoplasms this dramatic response is ABSENT
43
What is inferior petrosal sinus sampling
When would you use it?
What do the results mean?
○ This is the most robust way of distinguishing Cushings disease from an ectopic ACTH syndrome
○ Most costly and technically demanding
○ Blood from each half of the pituitary drains into the ipsilateral inferior petrosal sinus
○ Catheterisation of both with sampling can distinguish the cause
○ In cushings disease the sinus ACTH is more than the peripheral and ipsilateral is usually more than contralateral
○ In ectopic ACTH the sinus ACTH is equal to the peripheral
Use:
More making the differential between ACTH dependent cushings syndrome AFTER high dose dex testing and peripheral CRH testing have not been conclusive.
44
What test results would point towards a pituitary ACTH secreting tumour?
What Imaging would you order?
○ If the plasma ACTH is normal or elevated
○ The high dose dexamethasone suppression test shows >50% suppression of the morning cortisol
○ The CRH test causes significant increase in the secretion of ACTH (100%) and cortisol (50)
○ MRI would be ordered
45
What test results would point towards a non pituitary ACTH secreting tumour?
What imaging would you order?
○ The plasma ACTH is elevated
○ The high dose dexamethasone test shows LESS than 50% suppression of the morning cortisol
○ The CRH test causes NO increase in the secretion of ACTH and cortisol
○ A MRI/CT can be ordered
○ 2/3 of the ectopic ACTH secreting tumours occur in the chest so this cavity should be imaged first
46
What test results would point towards a Primary Adrenal tumour?
What imaging would you order?
○ If plasma ACTH is low normal or undetectable
○ CT should be ordered rather than MRI
○ They are large and often associated with metastatic spread at presentation
47
What is the treatment for Cushings Disease?
○ Trans-sphenoidal surgery
○ Remission rate is 75%
○ Recurrence 25% within 10 years
○ Hydrocortisone 25 mg mane
○ In some patients they develop adrenocortical insufficiency following removal of the adenoma and the ACTH and cortisol levels become undetectable
Glucocorticoid replacement therapy is then required until the axis is recovered
○ Monthly measurement of 8am plasma cortisol after the hydrocortisone has been omitted for 24 hours
48
What is the treatment of ectopic ACTH syndrome?
○ Depends on the cause
○ Treatment of the primary tumour
○ Prognosis for small cell lung cancer associated with the syndrome is poor
○ If the source cannot be found then consider bilateral adrenalectomy.
49
What is the treatment of Adrenal Tumours?
○ Adrenalectomy even though metastasis may be present
○ 100% cure rate
○ May take many years for the suppressed adrenal to recover. In these casesglucocorticoid therapy is required
○ Monthly 8am plasma cortisol monitoring when it has been omitted for 24 hours
○ Poor prognosis - most people die within 2 years
50
What are some medical treatments that can be used regardless of the Cushign syndromes cause?
○ Metyrapone
○ Ketoconazole
○ Mitotane (in adrenocortical carcinoma)
○ Act by inhibiting steroid biosynthesis in the adrenal cortex
○ Can be used regardless of the cushings syndromes cause
○ Not curative
○ Lead to rapid improvement in the clinical features of Cushings by reducing the secretion of cortisol
○ This can be used whilst awaiting definitive treatment
○ Aim is to use the smallest dose that will normalise the 24 hour urinary free cortisol
51
What is the broad definition of Addisons Disease?
| What hormones are involved?
* Adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex
* All three groups of hormones are affected- mineralocorticoids, glucocorticoids and androgens
52
What is the Zona Glomerulosa?
| What Hormone does it produce?
* It is the layer of the adrenal gland that is most superficial and lies underneath the capsule
* Produces aldosterone through aldosterone synthase CYP11B2
* The activity of aldosterone synthase is controlled by circulating angiotensin II and to a lesser extend Potassium
* Does not make androgens or cortisol- lacks the enzymes needed.
53
What is the Zona Fasciculata?
| What does it produce?
* The middle and widest later
* Makes up about 75% of the cortex
* Secretes Glucocorticoids - mainly CORTISOL
* Activity is regulated by the hypothalamic-pituitary adrenal axis via ACTH
54
What is the Zona Reticularis?
| What does it secrete?
* The deepest layer of the adrenal cortex
| * Secretes androgens as well as oestrogens in small amounts
55
What are primary and secondary causes of Hypoadrenocorticosteroidism?
Primary Adrenal Insufficiency:
• Dysfunction or destruction of the adrenal cortex itself= Addisons disease
Secondary Adrenal Insufficiency:
* Dysfunction within the hypothalamus with failure to produce enough CRH
* Dysfunction within the anterior pituitary with failure to produce enough ACTH
56
What are some causes of secondary hypoadrenocorticosteroisism?
* Mass lesions- tumours
* Radiation
* Infiltrative lesions such as sarcoidosis or haemachromatosis
* Infection or abscess- TB
* Infarction- sheehans syndrome
* Genetic mutatinons
* Empty sella
* Trauma or stroke
57
How do primary and secondary causes of hypoadrenocorticosteroidism affect aldosterone and androstenedione?
* Primary insufficiency will result in the under secretion of these hormones
* Secondary causes should have little effect
58
What happens to cortisol and ACTH levels in Addisons disease?
How does this effect the skin?
* Decreased production of cortisol
* Less feedback inhibition of hypothalamus and pituitary
* Increase in levels of ACTH
* Increased pigmentation
59
What is the epidemiology of Addisons disease?
* Uncommon
| * Females effected twice as much as males
60
What are some causes of Addisons Disease?
```
• Autoimmune adrenalitis
○ The principal cause of addisons
• Infection
○ TB
○ Fungal infections
○ Cytomegalovirus
○ Infections associated with HIV/AIDs
• Malignancy
○ Uncomon
○ Both glands need to be destroyed
○ Lung, breast, stomach, colon, melanoma and lymphoma
• Haemorrhage/infarction
○ Severe sepsis leading to waterhouse-friderichsen syndrome
○ Coagulopathies- anticoagulants, Anti phospholipid syndrome, DIC
○ Trauma
• Drugs
○ Azole antifungal agents can inhibit CYP enzymes - reversible
○ Metyrapone- used in cushings blocks cortisol
○ Mitotane- used in cushings
• Inborn errors of metabolism
○ Very rare, present in infancy
```
61
What are the different forms of Autoimmune adrenalitis that can cause Addisons disease?
Autoimmune adrenalitis
○ 85% of cases
○ Destruction of the cortex by humoral and cell mediated immune mechanisms
○ Antibodies react with steroidogenic enzymes in all three zones in the cortex CYP 21A2
Isolated autoimmune adrenalitis
○ 40% of cases
○ Autoimmune disturbance is confined to adrenal glands
• Autoimmune polyglandular syndrome type 1
• Autoimmune polyglandular syndrome type 2
Autoimmune polyglandular syndrome type 1
• Rare
• Autosomal recessive disorder
• Mutations in the autoimmune regulator AIRE gene on chromosome 21q22.3
• Important for generation and selection of T cells
• 10% of the autoimmune polyglandular syndromes
• Presents in childhood with chronic mucocutaneous candidiasis
• Followed years later by adrenal insufficiency
• Associated with primary hypoparathyroidism, hypogondaism, alopecia and pernicious anaemia
Autoimmune polyglandular syndrome type 2
• More common that type 1
• Accounts for 55% of cases
• Occurs later in life at 40 years old
• Primary adrenal insufficiency is main feature
• Associated with T1DM, hypogonadism, vitiligo, pernicious anaemia and hypopituitarism due to autoimmune hypophysitis
• DO NOT GET hypoparathyroidism
62
In general what are the differences in clinical features between primary and secondary adrenal insufficiency?
Primary:
• Loss of BOTH glucocorticoid and mineralocorticoid secretion
• Disrupted Androgen secretion
Secondary:
• Loss of glucocorticoid and androgens only
• Still able to be regulated by RAAS system
• May have other endocrine disorders or visual disturbances due to hypothalamic/pituitary disease
63
What are the different features in acute and chronic adrenal insufficiency?
Acute:
* After prolonged period of non specific complaints
* More common in primary adrenal insuficiency
* Postural hypotension may progress to hypovolaemic shock
* Acute abdominal pain
* Nausea
* Comiting
* Fever
* Decreased responsiveness, progressing to stupor and coma
* Can be triggered by intercurrent illness, trauma or stress
Chronic
* Non specific signs and symptoms
* Fatigue and loss of energy
* Often misdiagnosed as depression or anorexia
* Hyperpigmentation in primary adrenal insufficiency
* Hypopigmentation in secondary adrenal insufficiency
64
What are the symptoms/signs in Addisons disease?
| Which hormone are they related to?
Onset is very gradual and symptoms are often non specific - diagnosis is often delayed
Glucocorticoid deficiency:
* Weakness, tiredness and lack of energy
* Anorexia and weight loss
* Myalgia and arthralgia
* Weight loss
* hyperpigmentation
Mineralocorticoid deficiency
* Nausea, vomiting, abdominal pain, change in bowel habit
* Postural hypotension (lack of RAAS regulation and enhancing effect of glucocorticoids)
* Salt craving
*
Adrenal androgen deficiency
* Dry itchy skin
* Loss of libido
* Loss of axillary and pubic hair
* Muscle wasting
65
Why do patients with primary adrenal insufficiency get amenorrhoea?
* Combination of weight loss and chronic ill health
* Autoimmune ovarian failure
* Steroid responsive hyperprolactinaemia
66
Why does Hyperpigmentation occur in Primary Adrenal insufficiency?
In what time frame does it occur?
* Often comes before all other symptoms by months to years
* Caused by high levels of circulating ACTH that bind to the melanocortin 1 receptor on the surface of dermal melanocytes
* When stimulated the cells change the colour of their pigment to dark brown or black
* Usually is generalised- most prominent in the palmar creases on the sun exposed areas of the skin, extensor surfaces, knuckles, knees and elbows
* Can also be found in the mouth along the dento-gingival margins
* Vaginal and perianal mucosa and be effected too
* Chronic mucocutaneous candidiasis can effect the finger nails
67
What are the basic initial laboratory abnormalities expected in Addisons diseae?
Due to glucocorticoid deficiency :
* Anaemia
* Lymphocytosis
* Eosinophilia
* Decreased glucose
Due to mineralocorticoid deficiency:
• LOW Na (Most common abnormality- 90%)
○ Also due to lack of cortisol inhibition of ADH
• HIGH K+
○ Due to aldosterone deficiency
• HIGH urea and creatinine
68
How do you confirm the diagnosis of Addisons disease?
Short Synacthen stimulation test
○ To Demonstrate inappropriately low morning serum cortisol
Plasma ACTH
* To determine if this is dependent on ACTH or independent
* If Eleveated with low cortisol = PRIMARY
* If low/undetectable = Secondary
Serum plasma Renin and aldosterone
* Test the level of mineralocorticoid secretion
* Primary = Increased Renin, Decreased Aldosterone
* Secondary = Normal levels
Imaging
• Secondary causes = MRI
○ Neoplasms or mass lesions
• Primary causes = CT
○ Enlarged glands or calcifications suggest infectious, haemorrhagic or metastatic cause rather than autoimmune
69
What is a Synacthen stimulation test?
• Synacthen is synthetic ACTH
• Performed at 8am
• Blood drawn for a baseline serum cortisol
○ Less than 300 is suggestive of insufficiency but not conclusive
• Give 0.25mg of Synacthen
• One hour later draw blood to see the stimulated cortisol level
• Normal is serum cortisol > 500 before or after synacthen
70
How are results of the Synacthen stimulation test interpreted?
• If the cortisol is inappropriately low after the test this is suggestive of adrenal insufficiency
Need to compare this to a plasma ACTH level to determine primary vs secondary causes
71
How are plasma ACTH used in conjunction with synacthen testing to determine classification of adrenal insufficiency?
• If cortisol is inappropriately low following Synacthen testing
• Plasma ACTH is performed in the morning
• If the ACTH is HIGH - this suggests a PRIMARY cause
○ >12 pmol/L
• If the ACTH is LOW- this suggests a SECONDARY cause due to a problem in the hypothalamic, pituitary adrenal axis.
○ < 4pmol/L
72
What would be the clinical findings from the diagnostic tests in Addisons diseaae?
Short Synacthen stimulation test = inappropriately low morning cortisol
Plasma ACTH = Elevated
Plasma Renin = increased
Plasma Aldosterone = Decreased
73
What imaging modality is used in adrenal insufficiencies?
If suspected Primary cause = CT
| If suspected Secondary cause = MRI
74
When would a Corticotrophin releasing hormone test be used in SECONDARY adrenal insufficiency?
* If MRI does not reveal a cause
* Can distinguish between a hypothalamus or pituitary gland cause.
* Baseline plasma ACTH and Cortisol gathered
* CRH given
* ACTH and cortisol levels taken every 15 minutes for 2 hours
• CRH stimulates the secretion of ACTH by corticotrophs of the anterior pituitary
If the disease s in the hypothalamus =
• Exaggerated and prolonged ACTH response
• Sub normal cortisol level
○ Due to disuse the adrenal cells will have atrophied
If the disease is in the pituitary =
• Subnormal ACTH
○ Corticotrophs unable to respond to CRH
• Sub normal Cortisol
75
What is the prognosis for Addisons Disease?
* When clinically obvious and untreated then 2 year mortality = 85%
* Since introduction of glucocorticoids the prognosis is improved however the mortality is twice that of the normal population
76
Management of Primary Adrenal insufficiency
• Treat cause if possible
• Replace deficient adrenal hormones where required
○ Glucocorticoids
§ Hydrocortisone
○ Mineralocorticoids
§ Fludrocortisone replaces aldosterone
§ Adequate salt intake
○ Adrenal androgens not routinely replaces
○ Catecholamines- not required
• Treat comorbidities
77
What is the Management of secondary Adrenal Insufficiency?
* Treated with glucocorticoid replacement alone
* Mineralocorticoids are not needed because the RAAS axis remains intact
* Treat comorbidities
78
```
Hydrocortisone
What is the oral bioavailability
When is the peak blood level
Half life?
How often does it need to be given
What is the dose?
Where is it absorbed?
```
```
Oral Bioavailability = 100%
Peak blood level = 1 hour
Half life = 2 hours
Needs to be taken 2-3 times daily with a bulk dose in the morning to mimic circadian rhythm
Absorbed in the GIT
Dose = 0.25 mg/Kg of body weight
```
79
How and why is the glucocorticoid replacement monitored?
* Appropriate dose is the lowest dose that relieves the symptoms of deficiency
* Need to avoid the symptoms and signs of excess
* Measurement of plasma ACTH to guide is NOT recommended
* Clinical assessment is used to monitor dose
80
How does management change if someone with insufficiency becomes unwell?
• Glucocorticoid doses need to be increased 2-3 fold
• Should also be increased if the person is undergoing a minor surgery
• This simulates the normal increase in response to stress
• Should be increased when symptoms occur even without consulting a doctor
• This should be continued for the recovery period usually 1-3 days
• If the illness has not resolved for more than 3 days they should seek medical advice
• If there is vomiting then parenteral glucocorticoid is necessary
○ People who live remotely or are going overseas should have vials with them and know how to administer them
• If major illness or surgical procedure then should be given 100mg initially then 50mg every 6 hours until stable
81
```
How is Fludrocortisone absorbed?
What is the half life?
How often is it given ?
When would the dose change?
How is it monitored?
What are its effects on symptoms?
```
```
Absorbed = oraly
Half life = 24 hours
Given = once a day
Dose = 0.1 mg per day
Increased = in hot climates, heavy work or exercise where salt is lost in sweat
Effects on symptoms?
- Normal BP without postural drop
- No oedema
- Normal K
- Plasma renin activity at upper limit of normal
```
Monitored= clinically and by measuring plasma renin, K and BP
Adjustments are not required for stress or illness
82
What should the patient be educated about?
- The nature of the hormonal deficit and the reason for its treatment
- Maintenance medications
- Medication adjustment during minor illnesses and surgery and situations associated with increased sweating
- When to seek medical help
- Recognising the early features of an adrenal crisis
- Carrying and using injectable glucocorticoid when away from medical care
- Wearing an alert bracelet in case of emergency or loss of consciousness
83
What is an Adrenal (Addisonian ) Crisis?
What are the clinical features?
When does it occur?
It is a situation of acute adrenal insufficiency
Can be fatal - is a medical emergency
Due to :
○ Primarily to deficiency of mineralocorticoid
○ Glucocorticoid deficiency can contribute as there is decreased vascular responsiveness to Angiotensin II and Norepinephrine
```
Clinical Features:
○ Hypovolaemic shock
○ Nausea / vomiting
○ Abdominal pain
○ Fever (40) - need to exclude sepsis
○ Confusion/ coma
○ Unexplained hypoglycaemia
○ Poor tissue perfusion
○ Raised serum lactate
```
Causes:
- Undiagnosed patient with primary insufficiency who is unwell or under major stress
- In a known primary patient who does not increase replacement during infection or illness OR who has vomiting
- After bilateral adrenal infarction or haemorrhage
- Patients with secondary adrenal insufficiency during stress- less common- sometimes in situations of cortisol deficiency due to pituitary infarction
- Patietns who are abruptly withdrawn from large doses of glucocorticoids that have secondary adrenal insufficiency
Incidence:
8 % per year. More common in primary insufficiency
84
What are the signs of a bilateral adrenal injury, haemorrhage or infarction causing acute adrenal insufficiency?
Present with:
○ hypovolaemic shock
○ abdominal, flank, back or lower chest pain
○ Fever
○ Anorexia
○ nausea,vomiting
○ abdominal rigidity or rebound tenderness
○ Fall in Hb and progressive hyperkalaemia, hyponatremia
○ Volume contraction
Risk factors:
○ Anticoagulant therapy or coagulopathy
○ Postoperative state
○ Meningococcal and pseudomonas infections (Waterhouse-Friderichsen syndrome)
Must be considered in patients with one or more risk factors
85
What is the management for an adrenal crisis?
○ Blood for urea, creatinine, electrolytes and glucose
○ IV normal saline to correct fluid deficit
○ Hyperkalaemia usually corrects with volume replacement and hydrocortisone
○ IF patient has known primary insufficiency
- Hydrocortisone 100 mg IV then 50 mg IV every 6 hours
○ If patient is not known to have adrenal insufficiency
- Dexamethasone 4mg IV then hydrocortisone 50mg IV every 6 hours
- Draw blood for cortisol, ACTH and rening
- Short Synacthen stimulation test
○ When stable
- Use higher doses than normal of glucocorticoid replacement for 24-48 hours
- Then reduce to maintenance
86
How are hormones control in the Adrenal Cortex?
* There is only indirect control
* NO direct control
* Control is through the pituitary gland and hypothalamus axis
87
What are the different layers of the adrenal gland and what does each layer produce?
What is its target?
What are the hormonal effects?
What is the regulatory control?
Zona Glomerulosa
Produces:
• Mineralo corticoids - mainly aldosterone
Targets:
• Kidneys
Hormone effects:
• Increase renal absorption of Na and water especially in presence of ADH.
• Accelerates urinary loss of K
Regulatory control:
• Stimulated by Angiotensin II.
• Inhibited by Natriuretic peptides ANP and BNP
Zona Fasciculata:
Produces:
• Glucocorticoids such as cortisol and corticosterone
Targets:
• Most Cells
Hormonal Effects:
• Release amino acids from skeletal muscles and lipids fro adipose tissues
• Promote liver formation of glucose and glycogen
• Promote peripheral utilisation of lipids
• Anti-inflammatory effects
Regulatory control
• Stimulated by ACTH from anterior lobe of pituitary gland
Zona Reticularis:
Produces:
• Androgens
Hormonal effects:
• Uncertain significance under normal conditions
Regulatory control:
• Stimulated by ACTH
• Significance uncertain
88
What does the Adrenal Medulla secrete?
What is its target?
What are the hormonal effects?
What is the regulatory control?
The adrenal Medulla
Hormones:
• Epinephrine
• Norepinephrine
Targets:
• Most cells
```
Hormonal Effects
• Increases:
○ Cardiac activity
○ Respiratory rate
○ Blood pressure
○ Glycogen breakdown
○ Blood glucose levels
• Releases lipids by adipose tissue
```
Regulation:
• Stimulated during sympathetic activation by sympathetic preganglionic fibres
89
What is the normal short term response to stress?
* Increase in Catacholamines
* Fight or flight response
* Mobilisation of glucose reserves
* Changes in circulation (increased BP)
* Increase Respiratory rate
* Increased energy use by all cells
90
What is the long term/chronic response to stress?
| Aka Resistance phase
• Increase in ACTH
• Increase in Glucocorticoids
○ Mobilisation of remaining energy reserves
§ Lipids are released by adipose tissue
§ Amino acids are released by skeletal muscle
○ Conservation of glucose
§ Peripheral tissue breaks down lipids to get energy
○ Elevation of blood glucose concentrations
§ Liver synthesizes glucose from other carbs, amino acids and glycerol
• Increase in Growth hormone
• Increase in glucagon from the pancreas
• Increase in renin/angiotensin
○ Increase in mineralocorticoids with ADH
○ Leads to conservation of salts and water
○ Loss of K and H ions
91
What is the exhaustion phase of the normal stress response?
* Caused by exhaustion of lipid reserves or cumulative structural or functional damage to vital organs
* Inability to produce glucocorticoids
* Failure of electrolyte balance
92
How is ACTH synthesis and release regulated?
* Stress and circadian rhythms stimulate the Hypothalamus to release CRH
* CRH acts on the anterior pituitary corticotroph cells via GCPR receptors
* Activation of CAMP which targets protein kinase A
* Increased POMC (precursor of ACTH)
* Cleavage to make ACTH
* Packaged into secretory Granules
* Release of ACTH
* ACTH then acts peripherally to stimulate the secretion of Cortisol from the Adrenal glands
93
Are CRH and ACTH water or lipid soluble?
• Both are water soluble and therefore act on extracellular receptors
94
Cortisol
What type of hormone is it?
Where is it synthesised?
Is it bound or unbound?
• Lipid soluble steroid hormone
• Diffuses out of the cell
• Synthesised in the adrenal cortex zona fasciculate Via an enzymatic reaction
• Cholesterol required for synthesised
• Rate limiting step is cholesterol cleavage into pregnenolone- converts to other hormones in other Zonas which use different enzymes
• Bound to:
○ Most is : cortisol binding globulin or transcortin (80%)
○ Albumin (15%)
• Unbound:
○ Only about 5% is unbound and active
95
How does cortisol act on the cell?
* The steroid hormone diffuses through the plasma membrane and binds to an intracellular receptor
* The receptor hormone complex enters the nucleus
* The receptor hormone complex binds a hormone response element- such as a specific DNA sequence
* Binding initiates transcription of the gene to mRNA
* The mRNA directs protein synthesis
96
What is the feedback mechanism for the Hypothalamus-pituitary-adrenal axis/
• Rising cortisol levels feedback to the pituitary and the hypothalamus to inhibit secretion of ACTH and CRH respectively
97
What things increase the hypothalamus release of CRH?
* Physical stress
* Emotional stress
* Hypoglycaemia-basis of the insulin challenge
* Cold exposure
* Pain
* Circadian rhythm
98
What are the implications of HPA axis for disease?
• People who have cushings disease
○ Too much ACTH production due to tumour and therefore too much Cortisol is produced
○ Feedback does not work and ACTH can be normal inappropriately or high if tumour large
○ ACTH should be low
• Adrenal tumour
○ Adrenal cells will make too much cortisol
○ ACTH should be low in response to the feedback loop.
• Ectopic ACTH tumour
○ Cortisol will be high due to stimulation by ACTH
○ ACTH will be inappropriately high due to ectopic production
○ Ie small cell lung carcinoma
• Addisons disease
○ Adrenal damage leads to low cortisol in the presence of high ACTH
• Hypopituitarism
○ Low cortisol due to low ACTH
○ Inappropriately low ACTH
99
What are the actions of ACTH?
• Activation of CAMP/PKA signalling
• Acute immediate response
○ Increases cholesterol uptake (LDL endocytosis)
○ Increases mobilisation (inhibits cholesterol esterification and storage)
○ Increases the availability of free intracellular cholesterol
○ Increases the adrenal steroid synthesis
• Slower response:
○ Increased expression of P450 enzymes that promote conversion of cholesterol to pregnenolone and cortisol
• Trophic action
○ Increases gland volume
100
What is the circadian rhythm of cortisol and ACTH
* Pulsatile stimulation by CRH
* ACTH secretion = 12-18 pulses per 24 hours
* ACTH highest pulse is during the early morning
* This leads to a pulsatile secretion of cortisol 6am - 10am
101
How can results of the Dexamethasone suppression test be interpreted?
Normal:
• Low doses of DEX should cause a negative feedback loop on CRH and ACTH release
• There will be an inhibition of cortisol release
Cushings Syndrome:
• HIGH doses of DEX supress the cortisol release
Ectopic ACTH syndrome or Adrenal neoplasm:
• Failure to suppress cortisol on high doses of DEX
102
What are the anabolic/catabolic , direct/indirect effects of Cortisol?
Anabolic
• Liver - causes gluconeogenesis
Catabolic
• Muscle - protein catabolism
• Adipose Tissue- lipolysis
Direct effects:
• Action on intracellular receptors - induction of enzymes
Indirect Effects:
• Permissive modulatory effects on other hormones
○ Glucagon, adrenaline, insulin
103
Is Cortisol Slow or fast acting?
* SLOW
* Induction of production takes several minutes
* Full effect of the hormone takes several hours
104
What are the effects of cortisol on glucose metabolism and urea cycle?
• Has an anti-insulin effect but is SLOW acting
• Decreases the insulin dependent peripheral glucose uptake in adipose tissue and skeletal muscle
• Interferes with insulin signalling and modulates protein/lipid metabolism indirectly
• Inhibits insulin release by B-pancreatic cells at HIGH levels
• Increases gluconeogenesis in the liver from amino acids
• Increases breakdown of muscle and fat to provide substrates for hepatic glucose production
• Increases liver glycogen synthesis - due to excess glucose
• Enhances action of glucagon
• Increases rate limiting enzymes of gluconeogenesis pathway
• INCREASES BLOOD GLUCOSE net effect
○ Link to development of T2DM- insulin resistance
• Urea cycle:
○ Cortisol activates enzymes involved in amino acid metabolism - converted to glucose
○ Increased rate of metabolism leads to the increase of urea cycle enzymes to dispose of generated Nitrogen
○ Leads to increased urinary nitrogen excretion
105
How does Cortisol promote protein catabolism in muscle?
* Inhibits insulin dependent amino acid uptake and protein synthesis
* Promotes proteolysis and influx of glucogenic amino acids which will be used in the liver for gluconeogenesis
* Alanine is a major precursor and nitrogen carrier
* Glucose alanine cycle is stimulated
106
How does Cortisol effect lipid metabolism?
* Excess cortisol results in preferential expansion of central visceral fat deposits
* At the same time peripheral subcutaneous deposits are depleted
* Mechanism is poorly understood- possibly due to high glucocorticoid receptor expression
* Promotes HSL dependent fat mobilisation and stimulate LPL expression activity in adipocytes to increase FFA
* Excess uptake and storage as TG in visceral tissue and liver - can develop steatosis
107
How is cortisol anti inflammatory?
• Increases expression of anti-inflammatory genes
• Decreases expression of inflammatory and immunomodulatory genes
○ Cytokines
○ Inflammatory enzymes
• In small quantities can be very helpful
○ Speeds tissue repair
○ Controls excess immune cell production
• In large quantities
○ Depresses immune function too much
108
What is the Normal impact of increased cortisol?
* Increased energy to deal with stress
* Increased cognitive performance
* Decreased inflammation
109
What is the impact of chronic increased Cortisol?
```
• Anabolic/catabolic imbalance
• Hyperglycaemia
○ Prolonged exposure can be maladaptive with adverse consequences such as insulin resistance and T2DM
• Visceral obesity
○ Dislipidaemia- insulin resistance and metabolic syndrome
• Muscle wasting
○ Increased protein catabolism
• Osteoporosis
○ Increased bone resorption
• Mood swings and memory impairment
○ Shrinking synapses in prefrontal cortex, decreased neurogenesis and increased oligodendrogenesis
• Increased risk of infection
○ Suppresses immune system
• Slow wound healing
○ Suppressed immune system
○ Increased glucose - hyperglycaemia
```
110
Summary of Cortisol action during hypoglycaemia or stress
Adipose tissue
• Promotes FFA release via lipolysis from peripheral fat deposits
• Preferential accumulation of fat in visceral deposits
Muscle
• Decreased Protein Synthesis
• Decreased Glucose uptake - inhibition of insulin dependent receptors
• Increased Amino acid release - specifically alanine (glucogenic)
Liver
• Increased Conversion of amino acid to glucose
• Increased gluconeogenesis and release
• Increased Glycogen synthesis due to excess glucose
All slow effects
Increased prolonged plasma glucose and FFA may lead to insulin resistant diabetes
111
What are the 6 Posterior Pituitary hormones and their general function?
```
TSH
Target : Thyroid gland
Action: Stimulate production of T3 and T4
Excess: Central Hyperthhyroidism
Deficiency: central hypothyroidism
Tests: TSH and Free T4/T3
```
```
ACTH
Target: Adrenal Cortex
Action: Produce Cortisol
Excess: Cushings disease
Deficiency: Secondary adrenal insufficiency
Tests: ACTH and Cortisol
```
```
FSH and LH
Target: Gonads
Action: Sex steroids, gamete production, reproduction and sex characteristics
Deficiency: Swx hormone deficiency
Tests: Oestradiol and testosterone
```
Prolactin
Target: Breasts
Action: Stimulate growth of mammillary glands and lactation
Excess: Hypogonadotrophic hypogonadism glactorrhoea
Deficiency: failure to breast feed
Tests: Prolactin
```
Growth Hormone
Target: Liver
Action: produce IGF 1 then act on bones and soft tissues to stimulate growth
Excess: Acromegaly or gigantism
Deficiency: short stature
Test: GH and IGF-1
```
112
What are the signs of mass effect in the pituitary?
* Diabetes insipidus (If it occurs in the posterior pituitary- loss of Vasopressin )
* Headache
* CSF
* Bitemporal hemianopia
113
What kind of visual defect would someone with a pituitary tumour causing mass effect have?
How is it tested?
* Bitemporal hemianopia
* Lack of pupillary reflex if compressing the cavernous sinus
* Visual Field Test
114
What are some genetic mutations that can cause pituitary adenomas- what other implications do they have?
```
MEN1
○ Causes loss of function of menin gene (tumour suppressor)p
○ Autosomal Dominant
• Causes:
○ Parathyroid adenomas
○ Pituitary adenomas
○ Pancreatic islet cell tumours
```
Gs Alpha mutations
○ 40% of Somatotroph adenomas
○ It is a component of the GPCR- causes hypersecretion
115
What approach do you follow if you suspect Hormone insufficiency?
What tests do you order?
• Try to stimulate the hormone production
• Tests:
○ Short synacthen test
§ See if the cells are able to manufacture cortisol in response to ACTH
§ Testing the adrenal function - primary
§ Does not give information about pituitary function
○ Insulin tolerance test
§ Pt becomes hypoglycaemic
§ Should cause CRH release in response to the stress
§ Gives information about the function of the pituitary
○ Metyrapone suppression test
§ Drug inhibits the production of cortisol in the adrenal gland- can see if the feedback works correctly to stimulate more CRH and ACTH
• Test when supposed to be high
○ 9am cortisol and ACTH
116
What approach do you follow if you suspect Hormone excess?
| What tests do you order?
• Try to physiologically suppress the hormone
• Exclude Exogenous steroid use causing cushings syndrome
• Test:
○ Dexamethasone suppression test
§ Long acting synthetic glucocorticoid- doesn’t interfere with assay
§ Measure ACTH and cortisol the next day
§ If low then the system is suppressed
§ If doesn’t suppress there may be an autonomous secretion/adenoma hypersecreting- location is not pointed at.
• Test when supposed to be low
○ Midnight salivary cortisol
○ 24 hour urine free cortisol
§ Would be high if there was an autonomous population of cells producing the hormone
• Any abnormal result = determine if it is ACTH independent or ACTH dependent
a. Check ACTH- If it is high then it is Cushings disease or an ectopic ACTH
b. If low then it's an adrenal secreting tumour
117
What are some causes of deficiency of a hormone?
• Compression from mass lesion
○ Within pituitary - non functioning adenoma
○ External to pituitary: craniopharyngioma, meningioma
• Destruction
○ Immune : eg hypophysitis
○ Haemorrhage: sheehans syndrome, apoplexy
○ Radiation (previous radiotherapy)
○ Inflammation eg sarcoidosis
○ Malignant: metastases
○ Post pituitary surgery
118
What is the cause of excessive hormone secretion?
• Hormone secreting adenoma
| ○ Most common is a prolactinoma
119
How much should cortisol be suppressed after a dexamethasone test?
* Should be suppressed to < 50nmol/L
| * If it is not suppressed this points towards a ACTH dependent cause
120
Why do you need to check the K level when someone has an EXCESS of cortisol?
• Excess cortisol can overflow and stimulate the mineralocorticoid receptor
• This increases the amount of Aldosterone which stimulates urinary K loss
• This would then cause increased K losses through the kidney
Resulting in hypokalaemia
121
What is the most common cause of ACTH dependent Cushings syndrome?
* Cushings Disease = 85%
* Ectopic ACTH 15%- ie small cell lung cancer
* Ectopic CRH = 1%
122
What happens to Potassium in Addisons disease? ie primary adrenal INSUFFICIENCY
• There is diminished Aldosterone therefore decreased urinary excretion of Potassium
Leading to hyperkalaemia
123
What happens to salt levels in primary adrenal insufficiency?
* Low levels of cortisol leads to an increase in CRH stimulating ADH
* Cortisol is also usually a direct inhibitor of ADH- when it is deficient the inhibition is lifted
* Also the low levels of aldosterone encourage secretion of ADH
* ADH has the purpose of lowering osmolarity- ie reducing sodium concentration by increasing water resorption from the kidneys
* The Patient would become Hyponatraemic (reduced concentration of salt)
124
What is the most common cause of ACTH independent Cushings syndrome?
• Adrenal benign adenoma 51%
• Adrenal malignant carcinoma 41%
Micro and macro nodular hyperplasia are less common
125
What is more common? ACTH dependent or Independent causes of Cushings syndrome?
80% of cases are ACTH dependent
126
What is the normal reference range of cortisol?
200-500
127
What is the most common cause of Addisons disease/ Primary adrenal insufficiency?
Autoimmune adrenitis
128
Why do you get skin pigmentation changes in Addisons disease?
· The Pre hormone - POMC (pro-opropmelanocortin) is cleaved to form ACTH
· There is an excess of ACTH - because it is trying to stimulate the non responding adrenal gland
· This is then converted into alpha melanocyte stimulating hormone (a-MSH)
· This cross reacts with the MSH receptor and causes proliferation of the melanocytes
Seen in gums, scars and palmar creases
129
What are the different neurosecretory neurones in the hypothalamus?
Where do they project to?
There are two different Nuclei that have their cell bodies in the hypothalamus
They project long axons into the posterior pituitary to stimulate the release of different hormones.
• Supra optic Nucleus
○ Secretes ADH (vasopressin)
• Paraventricular Nucleus
○ Releases Oxytocin
130
How is the posterior Pituitary controlled?
```
• Direct Neural control
• ADH is controlled largely by the osmolarity of the plasma and CSF
• Oxytocin has a reflex control
○ Receptors in the nipples stimulated
○ Impulses propagated to spinal cord
○ Stimulation of hypothalamic nuclei
○ Oxytocin release
```
131
How is the Anterior Pituitary controlled?
• Sub types of Hypothalamic neurons that have short axons
• They secrete releasing and inhibiting peptide hormones into the base of the Hypothalamus into a capillary bed
• Taken up by the blood and transported by a portal system
• Taken to a second capillary bed in the anterior pituitary
Affect specific endocrine populations of cells to stimulate secretion of hormones.
132
What are the populations of cells in the anterior pituitary?
What hormone do they release?
What Hormone controls them?
Corticotrophs:
Controlled by: corticotrophin releasing hormone
CRH is stimulated by: Diurnal rhythm and stress
Secretes: Adrenocorticotrophic hormone (ACTH)
Targets: Adrenal Cortex
Hormone from target organ: Glucocorticoids
Feedback: Cortisol feeds MOSTLY back to the hypothalamus to inhibit CRH but also feeds back to the anterior pituitary to inhibit release of ACTH
Thyrotrophs:
Controlled by: Thyrotropin releasing hormone
Secretes: Thyroid Stimulating hormone
Targets: Thyroid Gland
Hormone from second organ: Thyroid hormones (T3 and T4)
Feedback: Thyroid hormones feed back to the hypothalamus to inhibit release of TRH AND as to the anterior pituitary to inhibit release of TSH
Gonadotrophs
Controlled by : Gonadotropin releasing hormone
Secretes: Luteinising hormone and Follicle stimulating hormone
Targets: Ovaries and Testes
Hormone from second organ:
LH and ovaries = Progestin's and Oestrogen's
LH and Testes = Androgens
FSH and Ovaries = Inhibin and Oestrogens
FSH and Testes = Inhibin
Lactotrophs
Controlled by: Prolactin releasing hormone and Prolactin inhibiting hormone
Secretes: Prolactin
Somatotrophs:
Controlled by: Growth hormone releasing hormone and Growth hormone inhibiting hormone
Secretes: Growth Hormone
133
What hormones are secreted by the Zona Reticularis?
What is the Target?
What is the function at the target?
What is the control?
```
• Androgens
• DHEA- precursor for testosterone
• Target
○ Normally not significant
• Hormonal control
○ ACTH
```
134
```
What hormone does the Zona Fasciculata produce?
How long does it take?
What is the Target?
What is the function at the target?
What is the control?
```
```
• Glucocorticoids
• At least a few hours
• Target
○ Most cells
• Control
○ ACTH hormonal
```
135
What hormones are produced by the Zona Glomerulosa?
What is the Target?
What is the function at the target?
What is the control?
```
• Mineralocorticoids
○ Aldosterone
• Target
○ Kidneys
• Target function
○ Na retention and K excretion
• Control
○ Hormonal and local
○ Na and K levels
○ Angiotensin
```
136
What is the difference in speed of production of adrenalin and steroid hormones?
• Adrenalin is produced fast because it has neural input
| Steroid hormones take hours
137
When the adrenal is overstimulated and there is increased cortisol- what other hormone becomes elevated?
- Androgens can also be over secreted
- This is not important in males due to a high level of testosterone
- In post-menopausal women- this can have an important effect where there is androgen like effects- hirsutism etc
138
What happens during the Hypothalamic- pituitary- adrenocortical axis activation during stress?
- Attempts to mobilise energy stores
- Hormonal pathway
○ CRH
○ ACTH
○ Adrenal cortex
○ Glucocorticoids
- Glucocorticoids action
○ Increase gluconeogenesis in the liver
○ Decrease cell glucose intake peripherally
○ Increase lipolysis
○ Increase effect of catecholamines on blood vessels- BP rises
Decreases inflammation and antibody production
139
What is cortisol?
What kind of receptor does it act on?
What effects does it have on inflammation?
What drugs are used as synthetic cortisol?
○ Endogenous hormone released from the adrenal cortex
○ Binds to a glucocorticoid receptor
○ DRUGS
○ Prednisolone
○ Betamethasone
○ Effects:
○ Down regulation of inflammatory mediators- cytokines
Used in treatment of chronic inflammatory and autoimmune disease ie rheumatoid arthritis, asthma and transplant rejection
140
What are the two types of Pituitary adenomas? What effect do they have?
1) Non secretory
○ Cause damage to gland cells
○ Cause hypOpituitarism
○ Can be large
2) Secretory adenoma
○ Causes hypERpituitarism
○ Disorder will be related to the type of cell type that is involved
Prolactinoma is the most common
141
What is the difference in outcome for people who have GH abnormalities before and after epiphyseal closure?
Somatotrophs are effected
Before closure:
• Hypersecretion causes gigantism
• Hyposecretion causes short stature
After closure:
• Acromegaly
142
What can happen if steroids are abruptly ceased?
Acute adrenal insufficiency
143
What side effects can occur with excessive or long term steroid use?
```
• Diabetes
• Reduced resistance to infection
• Osteoporosis
• Cataracts
• Increased appetite
• Central weight gain
• Hypertension
• Fluid retention
○ Aldosterone causes resorption of water and NA and causes excretion of K and H
```
144
What are some complications of a trans-sphenoidal removal of a pituitary adenoma?
* Damage to the posterior pituitary causing Diabetes insipidus (inability to concentrate urine)
* Damage to the working cells of the anterior pituitary requiring replacement therapy for deficiency
145
What can you use to treat low Adrenal secretion if surgery not available?
* Exogenous ACTH and analogues
| * Glucocorticoids
146
What is the mechanism of action of Metyrapone?
| When would it be used?
* Used in hypersecretion of cortisol
| * Acts on the adrenal cortex as an inhibitor of cortisone synthesis
147
What is the difference in classification between primary, secondary or tertiary problems with the hormonal axis?
```
Primary = problem within the target organ
Secondary = Problem with the Pituitary
Tertiary = Problem with the hypothalamus
```
