Endocrinology Flashcards
How is hypothalamus connected to pituitary?
Pituitary stalk
Where is the pituitary located?
Between internal carotid arteries, above sphenoid sinus
On top of pituitary is optic chiasm
What structure surrounds the pituitary at the base of the skull?
Sella turcica
What structure allows the hypothalamus and pituitary to communicate?
Portal vessels
Describe the pituitary gland structure
Two lobes (bilobed gland) -lies below the brain in the Sella Turcica.
The anterior lobe (adenohypophysis) is derived from an invagination of the roof of the embryonic oropharynx = Rathke’s pouch.
The posterior is formed from a notochordal projection which forms the pituitary stalk, which connects the gland to the brain and also the posterior lobe of the pituitary (neurohypophysis).
Why is the posterior pituitary known as neurohypophysis?
Axons from hypothalamus project down towards pituitary and then synapse onto blood vessels rather than nerves, so posterior pituitary releases hormones into bloodstream = neurohypophysis
Where are the cell bodies for the posterior pituitary?
In brain (no hormonal production in brain, just released there
What are the cells in the anterior pituitary?
Glandular, nuclei within anterior pituitary
What is the pituitary gland’s blood supply?
The pituitary gland has a dual blood supply.
– The first is via the long and short pituitary arteries (bring oxygenated blood)
–The second is from the hypophyseal portal circulation (hypothalamus to pituitary). This begins as a capillary plexus around the Arc
How were pituitary cell types originally classified?
Staining characteristics- acidic (orange G) and basic (aldehyde fusion) dyes
What hormones are produced by cell types: Gonadotroph Lactotroph Somatotroph Corticotroph Thyrotroph
LH + FSH
Prolactin
GH
ACTH
TSH
What are the anterior pituitary hormones and what do they regulate?
ACTH- regulates adrenal cortex
TSH- thyroid hormone regulation
GH- growth increase
LH/FSH- reproductive control
PRL- breast milk production
What are the posterior pituitary hormones and what do they regulate?
ADH- governs water release from kidney and fluid balance
Oxytocin- breast milk expression and parturition (contractions to expel foetus)
Describe the endocrine system and what happens in the three layers
Primary layer- end organ
Secondary layer- pituitary
Tertiary layer- hypothalamus
Hypothalamus role = takes input from brainstem (HR, BP etc) and senses (surroundings) and makes sense of these neural electrical signals into hormones to give the right state for the situation
Eg, stress response = increase in cortisol, GH, PRL, NA, adrenaline and thyroid hormone + repro function inhibited
What is the hypothalamus’s hormonal output?
Hypophyseal portal blood vessel (goes from hypothalamus to pituitary)
When hormones are sent to pituitary from hypothalamus what is its role now?
Amplification of signal
What is negative feedback?
Hormone production and release are primarily controlled by negative feedback. In negative feedback systems, a stimulus elicits the release of a substance; once the substance reaches a certain level, it sends a signal that stops further release of the substance.
Clinical presentation of pituitary tumours
Hormone hypersecretion
Space occupying lesion (can compress structures like pituitary):
- Headaches
- Visual loss (field defect)
- Cavernous Sinus Invasion
Hormone deficiency states:
Interference with surrounding normal pituitary
Excess GH secretion
Acromegaly- adult
Gigantism- child
Excess ACTH secretion
Cushing’s
Excess TSH secretion
Secondary thyrotoxicosis
Excess LH/FSH secretion
no symptoms, seen in non-functional pituitary tumour
Excess prolactin secretion
Prolactinoma
What inhibits growth hormone?
Somatostatin
Action of growth hormone
Growth hormone stimulates liver to produce IGF-1 which acts on chondrocytes of long bones to cause linear growth
Direct act of Growth Hormone is on fat and muscle tissue so glucose trapped in cells so decrease in glucose metabolsim
Systemic affects of GH/IGF-! excess
Acral enlargement
- spade like hands rings too small
- Inc shoe size
- macroglossia
- carpal tunnel syndrome
Increased skin thickness
Increased sweating
Skin tags and acanthosis nigricans
Change appearance
- inter-dental spacing
Visceral enlargement
Metabolic Changes
Impaired fasting glucose
Impaired glucose tolerance
Diabetes mellitus
Insulin resistance
Reduced total cholesterol
Increased triglycerides
Increased nitrogen retention
Subtle changes due to acromegaly in face
Coarsening of facial features (nose, lips, orbital arches increasing in size over time)
Actions of cortisol on glucose
Increases plasma glucose levels
- Inc gluconeogenesis
- Dec glucose utilisation
- Increases glycogenesis
- Inc glycogen storage
Actions of cortisol on lipolysis, proteins
Increases lipolysis
Proteins are catabolised
Releases Amino Acids
Na+ and H2O Retention
- Maintains BP
Anti inflammatory
Increased gastric acid production
Cushing’s syndrome
- Changes in protein and fat metabolism:
Change in body shape Central obesity Moon face Buffalo hump Thin skin, easy bruising Osteoporosis (brittle bones Diabetes
- Changes in sex hormones:
Excess hair growth
Irregular periods
Problems conceiving
Impotence
- Salt and water retention:
High blood pressure
Fluid retention
Prolactin mechanism
Excess prolactin -> prolactinomas (common)
PRL different control to all other anterior pituitary hormones
- -> PRL high intrinsic production of it in pituitary, so Tonic release of dopamine inhibits PRL release
- -> controlled by Positive Feedback
NORMALLY during lactation, mechanical stimulation of nipple sends neural signal to brain to stop production of DA so surge in PRL to produce milk for baby- terminated by removing baby from breast
PRL inhibits LH/FSH so that during lactation another bbay is not produced. bc who wants more of these bitches
What drugs interfere with dopamine and PRL secretion?
Antiemetics
Antipsychotics
OCP/HRT
What are features of PRL excess (hypogonadism)?
Infertility - Oligoamenorrhoea
Amenorrhoea - Galactorrhoea
Reduced libido - Impotence
Treatment of prolactinomas
Dopamine antagonists
bromocriptine,
cabergoline
not surgery
Non-functioning pituitary tumours
30% of all pituitary tumours
No syndrome of hormone excess produced
Cause symptoms due to space occupation
- headache
- visual field defects
- nerve palsies
- interfere with rest of pituitary function - deficiency of hormones
Treatment for non-functioning pituitary tumours
surgery (transsphenoidal approach) ± radiotherapy
no effective medical therapy
Why do pituitary tumours affect vision?
Eyes at front of head so both eyes look at an object at the same time- each eye sees slightly different image, both together gives depth perception
Images joined from nasal and temporal retinas- neurons from nasal side of one retina line up with neurons on temporal side of other retina, cross over and signal sent to brain
Area of crossing over = OPTIC CHIASM sits directly above pituitary, so if tumour compresses this area you get BITEMPORAL HEMIANOPIA (places lesion at optic chiasm exactly)
If a patient with a tumour suffers from bitemporal hemianopia where must the tumour be?
Optic chiasm
In which order are pituitary hormones lost due to expanding tumour?
LH/FSH - sex GH - growth TSH - metabolism ACTH - survival increased PRL - stalk compression
Treatment of pituitary adenomas
SURGERY
Transsphenoidal
(Adrenalectomy - Nelson’s syndrome)
RADIOTHERAPY
Slow
DRUGS
Block hormone production
Stop Hormone Release
Trans sphenoidal surgery
Done with telescope -> enter through side of nose/top of jaw to see pituitary tumour and remove it
Causes of pituitary failure
Tumour
- Benign
- (Malignant)
Trauma
Infection
Inflammation
- Sarcoidosis - general
- Histiocytosis - affects pituitary specifically
Iatrogenic
Low thyroid hormone levels lead to:
Bradycardia Weight gain Cold intolerance Hypothermia Constipation
Low sex steroid hormones lead to:
Oligomenorrhoea
Reduced libido
Hot flushes
Reduced body hair
Low cortisol levels lead to:
Reduced Cortisol:
Tiredness Weakness Anorexia Postural hypotension Myalgia
Low GH levels lead to:
Fatigue + central weight gain
Treatment for low thyroid
Thyroxine
Treatment for low sex steroids
Testosterone
Oestrogen
Treatment for low cortisol
Hydrocortisone
Treatment for low GH
GH
What does Vasopressin (antidiuretic hormone) do and what stimulates its release?
Acts on collecting ducts increasing their permeability to water -> allows water to return to body from urine -> decreases amount of urine produced (antidiuretic)
Causes vasoconstriction and increasing blood pressure - produced in response to dehydration -> plasma osmolality increase leads to increased production of vasopressin
Produced when blood pressure low - sensed by baroreceptors in atria and arch of aorta
Also produced due to low oxygen and high CO2 in bloodstream - signals to brain circulating volume is reduced (cortisol, sex steroids and angiotensin 2 stimulate vasopressin release here)
Syndrome of inappropriate ADH (SIADH)
Too much ADH
Brain injury/infection
Lung cancer/infection asthma IPPV
Metabolic
- Hypothyroidism
- Addison’s
What would determine a diagnosis of SIADH?
- Plasma Na+ (low sodium bc osmolality reduced)
(<130mmol/l) - Plasma osmolality - reduced
(>285mOsm/kg) - Urine osmolality (very concentrated)
(>100mOsm/kg) - Urine Sodium
(>30mmol/l)
Treatment of SIADH
Fluid restriction
Demeclocyline - stops ADH in kidney
ADH Antagonist (Tolvaptan)
Treat underlying cause tho- usually chest infection
Diabetes insipidus
Underproduction ADH
- Cranial issue eg damage to hypothalamus or injection causing Lack of Production
Nephrogenic
- Receptor resistance (ADH is being produced by brain but damage to kidney)
What would confirm a diagnosis of diabetes insipidus?
Too much urine being produced
Polyuria (>3l)
but could be Polydipsia (drinking large amounts of fluid)
- Plasma Na+
- Plasma osmolality increased (> 295 mosmol/kg)
- Urine osmolality - too diluted (< 700 mosmol/kg)
- Urine Na+
How to confirm between diabetes insipidus and polydipsia?
Water deprivation test
Patient not allowed any access to water for 8 hours - body weight measured at start of test and weighed after and look for signs of dehydration
Then given ADH injection
How would a normal person vs diabetes insipidus patient respond to water deprivation test?
Normal person: maintain plasma osmolality and urine concentrated and low volume (osmolality of urine 3x of plasma)
Cranial Diabetes insipidus: continue to pass urine so plasma concentrated, but urine not concentrated and LESS 3x upper limit of normal and ADH injection makes it normal (so DI confirmed because can’t maintain normal plasma osmolality but respond to ADH, so body not making any ADH as they can respond)
Nephrogenic DI: plasma concentrated and urine too dilute, person dehydrated and things do NOT get better after ADH injection because they can’t respond to ADH, telling us its nephrogenic
Treatment for diabetes insipidus
ADH injection/tablet/nasal spray
for CRANIAL- low dose
for NEPHROGENIC - high dose bc receptor resistance
How does the thyroid develop in embryo?
Develops from Tongue root (foramen cecum)
Descends into the neck as the Thyroglossal duct
Formed by 5th-6th week of development
Where are C cells derived from?
Ultimobranchial body (arch V(
What do C cells secrete?
Calcitonin
What happens if thyroid fails to descend?
Lingual thyroid sits at back of tongue, root of thyroid down to hyoid bone
What happens if the thyroglossal duct fills with fluid?
Thyroglossal cyst
Blood supply of thyroid gland
Inferior thyroid artery from SUBCLAVIAN
Superior thyroid artery from CAROTID
Location of thyroid gland
Isthmus sits between 2nd + 3rd tracheal ring just below larynx
Thyroid hormone pathway
TRH release from hypothalamus
Stimulates anterior pituitary to release TSH -> TSH stimulates thyroid
TSH causes release of Triiodothryonine and thyroxine from thyroid gland
Thyroid stimulating hormone TSH (thyrotropin)
Produced by the Thyrotroph cells of the anterior pituitary
Acts on the thyroid follicular cell
Increases iodine uptake
- Increases thyroid colloid production
- Increases thyroid hormone secretion
- Increase thyrotroph growth
Act via G coupled protein receptor
What are the plasma thyroid hormones?
3,5,3,5-tetraiodo L-thyronine (thyroxine T4)
3,5,3`-triiodo L-thyronine (triiodothyronine T3)
T4 and T3 receptor types
Receptor is nuclear (type2) forms heterodimer
What proteins do thyroid hormones bind to in circulation?
- Thyroid Binding Globulin
- Albumin
- Prealbumin
Half life of thyroid hormones
Plasma half life
T3 (1-3 days)
T4 (4-7 days)
Daily iodine requirement
50ug/day
How is thyroglobulin protein produced?
TSH circulates through blood and binds onto receptor outside cell (peptide hormone) activating intracellular pathway to produce thyroglobulin protein:
- G stimulatory protein bound to GDP -> converted to GTP active form
• Activates effector enzyme adenylate cyclase, reacts with G protein
• Converts ATP -> cyclic AMP
• Activates PKA
• PKA phosphorylates transcription factor in nucleus
o Stimulates genes to make a specific protein
o Transcription produces mRNA -> goes to ribosomes on rough ER and produces proteins
o Proteins modified etc
o Sent to golgi and packaged/modified in vesicles
o Protein in vesicle fuses with cell membrane
o Exocytosis
o Releases protein into luminal space (colloid)
What residues are on thyroglobulin?
Thyroglobulin has tyrosine residues which are iodinated by thyroid peroxidase
Thyroid peroxidase
THYROID PEROXIDASE enzyme converts iodide into IODINE (iodide oxidation- loss of electrons) kicks iodide so hard the electrons get knocked off him (I- to I2)
It then ADDS IODINE to tyrosine amino acids on thyroglobulin IODINATION of the protein
(o MIT- monoiodotyrosine (one iodine on tyrosine) T1
o DIT- diiodotyrosine (2 iodine on tyrosine) T2)
How are T3 and T4 produced?
o Iodide circulating in bloodstream
In ion form with negative charge IODIDE
Concentrated in follicular cells, low concentration outside
Sodium high conc outside cell, low in cell so moves passive transport from high to low into cell, co-transporting iodide
• Symporter moves iodide into the cell with sodium SECONDARY ACTIVE TRANSPORT
• PENDRIN protein pumps iodide out from cell into luminal space
• THYROID PEROXIDASE enzyme converts iodide into IODINE (iodide oxidation- loss of electrons) kicks iodide so hard the electrons get knocked off him (I- to I2)
• Iodines then added to tyrosine amino acids on thyroglobulin protein so IODINATION of the protein via thyroid peroxidase
Leads to:
o MIT- monoiodotyrosine (one iodine on tyrosine) T1
o DIT- diiodotyrosine (2 iodine on tyrosine) T2
o MIT and DIT are coupled by TPO
- DIT + DIT = T4 or THYROXINE
- MIT + DIT = T3 or TRIODOTHYRONINE
How do T3 and T4 get into the bloodstream?
So thyroglobulin has T3 and T4 in it post iodination, whole protein brought into cell
- Done via lysosomes
- Endocytosis of protein into cell
T3 and T4 need to be isolated to be secreted
- Lysosomes fuse with vesicle
- Cleavage enzymes enter and cut and isolate T3 and T4
- So only thyroid hormones remain in vesicle
- Vesicle fuses with follicular cell membrane to release T3 and T4 into bloodstream
- Act as steroid hormones (not water soluble) so need to be transported through blood via transport protein produced by liver THYROXINE BINDING GLOBULIN → Transports T3 and T4
Actions of thyroid hormones
Increases Basal Metabolic Rate Increase thermogenesis Increases sympathetic nerve activity Increase protein synthesis Chronotropic
Hyperthyroidism
Over production: Thyrotoxicosis Graves disease Multinodular Goitre Toxic Solitary Nodule Thyroiditis
Tests for hyperthyroidism
Thyroid Function
Autoantibodies
Technesium Scanning
ESR
Thyrotoxicosis symptoms
Sympathetic overactivity
Poor appetite Myopathy Increased Growth Diarrhoea In the elderly Minimal symptoms Anorexia CCF or AF
Grave’s: Pretibial Myxodema Exopthalmos Chemosis Acropachy
Investigation for thyrotoxicosis
- Thyroid Function tests
- Autoantibodies
- Technesium Scanning
- Lack of uptake in thyroiditis and iodine ingestion
- In MNG it serves to define the functional characteristics of the gland
Treatment for hyperthyroidism
Carbimazole (side effects: agranulocytosis eg white cell drops, rash, aplasia cutis) Propylthiouracil Beta Blockers (Lugol’s Iodine) DXT Surgery (Subtotal thyroidectomy)
Complications of thyroidectomy
Bleeding
Hypocalcaemia
Hypothryoidism
Recurrent laryngeal nerve damage
Thyrotoxicosis and pregnancy
Drugs are safe in pregnancy
Possible association of carbimazole with foetal aplasia cutis
Some physicians may substitute PTU for CMZ in pregnancy
No contraindication to breast feeding
PTU is excreted less in breast milk
Patients receiving CMZ in the dose of 20mg or less need not be changed to PTU
Outcome of hyperthyroid treatment
Long term remission can be achieved in 50-60% of cases Large goitre Positive TSH receptor antibodies F/H of thyroid disease Opthalmopathy Smoking Male Gender
Radioactive iodine
Safe and appropriate treatment in nearly all types of hyperthyroidism, especially in elderly
Contraindicated in children, pregnancy and women who are breast feeding
Women of childbearing age should wait for 4 months after 131I before becoming pregnant
Should be used with caution in patients with opthalmopathy
Use prophylactic steroids and avoid hypothyroidism
Clinical signs of thyroiditis
- Inflammatory response and gland is painful
- Investigation High ESR
- Technesium scan no uptake
Treatment for thyroiditis
- beta-blocker is usually sufficient to control the symptoms of hyperthyroidism
- NSAIDS
- steroids
2 types of amiodarone induced thyroiditis
Type 1
- usually affects patients with latent or preexisting thyroid disorders
- more common in areas of low iodine intake.
- Caused iodine-induced excess thyroid hormone synthesis and release (Jod-Basedow phenomenon).
Type 2
- previously normal thyroid gland
- caused by a destructive thyroiditis that leads to the release of preformed thyroid hormones from the damaged thyroid follicular cells.
Mixed forms of AIT may occur
Hypothyroidism
Underproduction:
Congenital
- Pendred’s Syndrome
- Congenital Hypothyroidism
Iodine deficiency
Hashimoto’s thyroiditis
Gland destruction
Tests for hypothyroidism
Thyroid Function
Autoantibodies
Hypothyroidism symptoms
Sympathetic underactivity:
Bradycardia Mental slowness Poor memory Decreased locomotor activity Weight gain Cold intolerance Hypothermia
Poor appetite Myopathy Decreased growth Constipation Dry skin and hair Slow relaxing Reflexes
Hoarse voice
Puffy face
Menstrual Irregularity
Features of hypothyroidism on ECG
Increased amount of electricity needed in machine to produce ECG
So ECG is small volume
Gap between start of P wave and QRS is increased = FIRST DEGREE HEARTBLOCK
Bradycardia
Small uptick in upstroke of R wave = REVERSE TICK PATTERN
Investigations for hypothyroid
Underproduction
Thyroid Function
Autoantibodies Thyroid peroxidase antibody
Ultrasound if goitre present
- Can be associated with
- High CK
- Abnormal lipids
Guthrie Test
Treatment for hypothyroidism
Thyroxine
Investigation for thyroid nodule
NODULES: Thyroid Function Ultrasound FNA (CT/MRI)
GOITRE: Thyroid Function Ultrasound CXR CT/MRI Flow Volume Loop - see how gland is affecting breathing by compressing trachea
U classification of thyroid nodules
U1 + U2 = benign, no biopsy
U3, U4, U5 = biopsy needed, could be malignant
Thy Classification
Biopsy of thyroid lobe done, looking at cells under microscope- classify them as thy
Thy 2 benign
Thy 3 possible cancer
Thy 4 probably cancer
Thy 5 definitely cancer
CASE:
A 39-year-old-woman presents with weight gain, lethargy, headaches and constipation. She is 10 weeks post partum. Examination of the neck is normal but she is found to have papilloedema. Her investigations reveal.
TSH mU/L [0.3-3.2] <0.05 fT4 pmol/l [9-26]4.2 fT3 pmol/l [2.5-5.7]0.8
The most likely diagnosis is:
Secondary hypothyroidism
A 42-year-old-woman presents with weight gain, lethargy, headaches and constipation. Examination of the neck is reveals a smooth goitre.
Her investigations reveal:
TSH mU/L [0.3-3.2] 50 fT4 pmol/l [9-26]6.2 fT3 pmol/l [2.5-5.7]1.8
The most likely diagnosis is:
Primary hypothyroidism
Diurnal rhythms
Most hormones are pulsatile and vary during the day
Insulin tolerance test
Gold standard for assessing adrenal reserve
- Insulin is administered to achieve hypoglycaemia with glucose less than 2.1 mmol/L
- Hypoglycaemia stimulates the stress response which is mediated by the compensatory hormones for hypoglycaemia
- Glucagon, catecholamines, growth hormone, prolactin.
The test is contraindicated in
- Ischemic heart disease.
- Epilepsy.
- Severe panhypopituitarism
- The very old or very young
- Pregnancy
Where the insulin tolerance test is contraindicated, the glucagon test can be used
Radioimmunoassay
Uses radiolabeled molecules in a stepwise formation of immune complexes.
A RIA is a very sensitive in vitro assay technique used to measure concentrations of substances, usually measuring antigen concentrations (for example, hormone levels in blood) by use of antibodies.
What is the problem with total hormone assays?
Dependant on binding protein levels
SO
Not always reflective of the free hormone levels
Free hormone assays pros and cons
PROS:
representative of the active hormone fraction
not binding protein dependant
CONS:
complex and expensive
–> Have a separation step
Can have poor reproducibility
Why do peptide hormones need to be measured using an immunometric assay?
RIA means that useless peptide fragments will also be measured along with biologically active peptide hormone, making it inaccurate for measuring actual amount of peptide hormone in blood
Immunometric assay washes away fragments leaving only antibodies behind
Investigation for thyroid issues
Thyroid function- looking at overproduction and underproduction and thyroiditis
Autoantibodies- looking at overproduction and underproduction
Technesium scanning- overproduction and thyroiditis
ESR- thyroiditis
If there is thyroiditis present what will technesium scanning show?
Quiet and negative bc gland not biologically active
Technesium scanning in Grave’s disease
Technesium uptake HIGH
Technesium scanning in Grave’s disease
Technesium uptake HIGH
bc excess thyroid hormone produced (more hormone = higher uptake)
What is in this technesium scan?
- Diffuse uptake throughout gland = Grave’s disease
- single toxic nodule
- multi nodular goitre
- cold nodule - due to cyst
Thyroid function tests: what results mean primary/secondary hypo/hyperthyroidism?
if T3/T4 high → hyperthyroid
+ TSH detectable
= SECONDARY HYPERTHYROID
if T3/T4 high → hyperthyroid
+ TSH low, suppressed
= PRIMARY HYPERTHYROIDISM
if T3/T4 low → hypothyroid
+ TSH is high
= PRIMARY HYPOTHYROIDISM
if T3/T4 low → hypothyroid
+ TSH low, pituitary not responding normally
= SECONDARY HYPOTHYROIDISM
What is sick euthyroid?
T4/T3 normal but TSH low
due to stress response -> CRH from pituitary can inhibit TSH/TRH production
= SICK EUTHYROID
T3 toxicosis
T4 normal, T3 high and TSH low
= T3 toxicosis
seen with toxic nodule
Screening and confirmation of Cushing’s
- Screening
- Urinary free cortisol
- Diurnal Rhythm
- Overnight dexamethasone suppression test - Confirmation of the Diagnosis
- Low dose Dexamethasone Suppression testing - Differentiation of the Cause
- High dose Dexamethasone Suppression testing
- ACTH
- CRH test
- Localisation
Overnight Low Dose Dexamethasone Suppression Test
Cortisol is measured at 8am
Dexamethasone 1mg is given at 11pm
Cortisol is measured at 8am the next morning
Cortisol suppression to <50nmol/l is normal
Psuedocushing’s syndrome
Depression
Alcoholism
Anorexia Nervosa
Obesity
How to tell between True Cushing’s and Pseudocushing’s?
LOW DOSE DEX SUPPRESSION TEST
0.5 mg Dexamethasone six-hourly, 48 hrs
Result: complete suppression (<50nmol/l) in normal subject
If cortisol detectable then patient has CUSHING’S SYNDROME
Why is the kidney useful for measuring cortisol?
Cortisol: Circadian rhythm
- highest in morning
- undetectable at midnight
- if see cortisol levels high at night and detectable suggests diurnal rhythm disrupted- but difficult so use kidney
- 24 hour urine collection, use kidney to create peaks- so if large amounts of cortisol throughout day can suggest a problem
Why do we use dexamethasone and not cortisol for the suppression test?
Instead of giving cortisol for negative feedback, give dexamethesone to actually be able to measure cortisol levels (if you gave cortisol it would appear in the assay)
Why would someone with depression/anxiety score above 50 on dexamethasone test?
Chronic stress, so cortisol levels higher and seen as pseudocushing’s
How to rule out Cushing’s disease?
High dexamethasone suppression test
HIGH DOSE
2 mg Dexamethasone six-hourly for 48 hrs
If cortisol suppresses to < 50% of baseline then the patient has Pituitary dependent Cushing’s Disease
If the Cortisol does not suppress then the patient has ectopic ACTH production or an adrenal tumour
only pituitary has cortisol receptors
Differential diagnosis if Cushing’s is ruled out
Adrenal tumour (low ACTH)
Ectopic ACTH production (high ACTH)
benign or malignant
What enzyme reduces cortisone to cortisol
11 Beta Hydroxysteroid dehydrogenase type 1 (HSD1)
type 2 does reverse
What test is used to differentiate between pituitary dependant Cushing’s and ectopic ACTH?
CRH TEST
0.1 µg/kg of human CRH is given
Blood is assayed for ACTH and cortisol at time -15, 0, 15, 30, 60, 90, 120.
An exaggerated response indicates pituitary dependant Cushing’s Disease
A flat response indicates ectopic ACTH production
What is the test for adrenal insufficiency?
Synacthen test
Short vs Long Synacthen test
Short Synacthen (250mcg)
Blood taken over 1 hour
Used to diagnose primary adrenal failure
Long Synacthen Test (1mg)
Blood taken over 24 hours
Used to diagnose secondary adrenal failure
Why is cortisol level higher on day 2 of synacthen test in secondary adrenal failure?
Adrenal gland grows due to high dose of synacthen
Short synacthen test
Long synacthen test
What is the test for acromegaly?
Oral glucose tolerance test
Oral Glucose Tolerance test
Take blood sample for GH and IGF-1
75 grams oral glucose
Take blood for GH and glucose at t=30, 60, 90 and 120 minutes
A synacthen test can be carried out at the end of this test
samples for cortisol taken at t=120, 150 and 180. Synacthen 250 mcg is administered at t=120
What suggests acromegaly in oral glucose tolerance test (vs normal) ?
In normal individuals, GH levels fall following oral glucose, and at least one of the samples during the test should have undetectable GH levels.
Failure of suppression or a paradoxical rise in GH suggests acromegaly.
Following treatment safe level of GH < 1.0mU/l (0.4ng/ml)
What hormones are produced in the renal cortex?
Cortisol, aldosterone, sex steroids
Where is 21 hydroxylase expressed?
21 hydroxylase only expressed in adrenals
so only in adrenal is aldosterone and cortisol produced
Oestrogen and dihydrotestosterone production
Enzymes for testosterone production in both ovary and testis
Production of testosterone in ovary but also production of aromatase enzyme so oestrogen produced
In males testosterone produced but active androgen is actually dihydrotestosterone, so testosterone is reduced by 5 alpha reductase to dihydrotestosterone
Why is it important for women that the adrenal cortex produces androgens?
For women, androgen production in circulation is 50% from ovary directly and 50% from adrenal synthesis
What enzyme is downregulated in 2nd half of menstrual cycle?
17 alpha hydroxylase (meaning progesterone reduced)
Defects in this pathway can cause what?
Congenital adrenal hyperplasia
Cushing’s syndrome vs Cushing’s disease
Cushing’s Syndrome
Excess cortisol in the blood
Cushing’s Disease
Excess cortisol in the blood due to an ACTH secreting pituitary tumour
Clinical features of Cushing’s syndrome
Excess hair growth
Irregular periods
Problems conceiving
Impotence
High blood pressure
Fluid retention
(due to salt and water retention)
Depression and anxiety
Genes from POMC
Gene for ACTH part of POMC (pro opiomelanocortin)
alpha MSH strong appetite suppressor
POMC often activated in cancer - but if in a cell where intracellular machinery for making hormones is not present it will do nothing, but will in one that does
Labartpry features of Cushing’s
Hypokalaemia
Metabolic alkalosis
Hyperglycaemia
Mechanism of hypernatremia, hypokalaemia and metabolic alkalosis in Cushing’s
Mineralocorticoid receptor binds aldosterone
Channel retains sodium → need to lose positive charge to bring in sodium so potassium booted out, when potassium runs out H+ used
So when cell overactive = hypernatremia, hypokalaemia and metabolic alkalosis
Cortisol to cortisone mechanism
Cortisol can also bind to mineralocorticoid receptor to equal affinity to aldosterone so 11 Beta hydroxysteroid dehydrogenase 2 protects receptor by DESTROYING CORTISOL and converting it into cortisone
Catalytic site of enzyme has saturation point higher than cortisol level produced daily, but lower than cortisol level produced in extremis
THUS normally when aldosterone controls BP all cortisol daring to near receptor is demolished so only aldosterone remains victorious controlling BP
But if we are busy dying in extremis cortisol much higher presence in bloodstream so catalytic site saturated and now cortisol can acsess receptor and do its job
Treatment for adrenal adenoma
SURGERY
Cortisol Production Blockers
- Metyrapone
- Ketoconazole
Patients need to have steroid replacement tablets at the time of and following surgery
The adrenal tumour suppresses the function of the normal gland
Many will not need the steroid tablets long term
Clinical features of Addison’s disease
Tiredness Weakness Anorexia Weight loss Postural hypotension Myalgia Salt Craving Nausea Vomiting Hyperpigmentation Vitiligo Hyponatraemia Hyperkalaemia Acidosis Hypercalcaemia Hypoglycaemia Increased urea and creatinine Eosinophilia Lymphocytosis
Causes of Addison’s syndrome
Investigations for adrenal insufficiency
9 AM cortisol ACTH Electrolytes FBC Adrenal imaging Adrenal anti-bodies
Investigations for other causes of adrenal failure
Infection screen
Imaging for cancer
Biochemical testing for enzyme deficiency
Dynamic Tests for adrenal insufficiency
Short Synacthen (250mcg)
- Stimulate adrenal directly
- Used to diagnose primary adrenal failure (Addison’s disease)
Long Synacthen Test (1mg)
- Prolonged stimulation of adrenal directly
- Used to diagnose secondary adrenal failure (due to pituitary failure)
Insulin tolerance test
- stimulates the hypothalamus directly
- Gold standard for assessing adrenal axis
Glucagon test
- stimulates the hypothalamus directly
- Performed when insulin tolerance test is contraindicated
Treatment for Addison’s
Hydrocortisone
- 10mg 5mg 5mg
- Mimicks the diurnal rhythm
- Last dose before 6pm
Fludrocortisone
- 50-200mcg o.d.
21-hydroxylase Deficiency (Classical) CAH
Cortisol can’t be produced = no negative feedback = lots of cholesterol bc lots of ACTH
→ build up of 17 hydroxyprogesterone (intermediate product) needs to be destroyed and only way to do this is production of testosterone bc cortisol pathway blocked
In female causes virilisation of genitalia, hirsutism, premature adrenarche, infertility
Bc no aldosterone also salt losing crisis eg hyperkalaemia and hypotension
11β-hydroxylase Deficiency (Non-Classical)
Accounts for approx 5% of reported CAH. Incidence 0.5:100 000 live births Autosomal recessive Increased in Moroccan Jews (1:6000 live births) HLA linked - HLA-B14,DR1
Defect here is lower in pathway than classical-
11β-hydroxylase Deficiency (Non-Classical)
Accounts for approx 5% of reported CAH. Incidence 0.5:100 000 live births Autosomal recessive Increased in Moroccan Jews (1:6000 live births) HLA linked - HLA-B14,DR1
Defect here is lower in pathway than classical- 17 hydroxyprogesterone increases = masculinisation of female via testosterone
Also deoxycorticosterone produced in excess (partial mineralocorticoid receptor agonist) so present with hypertension rather than salt crisis
→ so hypertension and hypokalaemia
Cortisol not produced so lots of cholesterol bc no neg feedback
Investigation for congenital adrenal hyperplasia
Synacthen Test:
- No cortisol rise
- Increased 17OH Progesterone levels
Prednisolone suppression:
-Androgens should fall into normal range
Treatment for congenital adrenal hyperplasia
Both entities comprise a spectrum of disease – partial deficiencies complicate matters.
Rx of 11b- and 21- hydroxylase deficiency lies mainly in the use of glucocorticoid therapy
- To replace cortisol
- To inhibit ACTH production, reducing adrenal testosterone production
Surgery to virilised female genitalia.
Treatment of Mother to prevent foetal Virilisation
Aldosterone
Produced in the zona glomerulosa of the adrenal cortex
Acts on the kidney via receptor binds glucocorticoids with equal affinity
Intranuclear receptor (type 1)
How is aldosterone stimulated?
Stimulation of aldosterone:
- low BP
- low sodium at macula densa (DCT)
- SNS activity
causes renin release from juxtaglomerular cells
renin acts on angiotensinogen in liver to release angiotensin 1 → converted by ACE into angiotensin 2
angiotensin 2 acts on adrenal gland to release aldosterone
aldosterone acts to retain sodium, expanding extracellular fluid and reduced potassium
Aldosterone neg feedback with renin
No aldosterone receptors on kidney but action of it reverses stimuli to renin production = PHYSIOLOGICAL NEGATIVE FEEDBACK
Aldosterone syndromes
What happens in steroid treatable hypertension?
Due to defect in 11 beta hydroxylase dehydrogenase 2 enzyme - enzyme doesn’t work so BP controlled by cortisol not aldosterone
Treated by glucocorticoid eg dexamethasone, causes neg feedback to ACTH so cortisol stops being produced so aldosterone can take over BP again
Dexamethasone replaces cortisol
Conn’s treatment
surgery to remove the gland (tumour)
Spironolactone/Eperelone Amiloride / Triampterine Potassium Supplementation Treatment of the Primary Tumour Sugery
