Week 3 Endocrine Lectures Flashcards
What does prolactin do?
Stimulates lactation
Where is prolactin secreted?
Lactotrophs in the anterior pituitary
What does Hyperprolactinemia lead to?
hypogonadotropic hypogonadism
What is hypogonadotropic hypogonadism?
a form of hypogonadism that is due to a problem with the pituitary gland or hypothalamus
What can any drug that interferes with dopamine action cause?
Hyperprolactinemia
What drugs can affect dopamine action (and therefor can cause hyperprolactinemia)
- Antipsychotics – typical and atypical
- Antiemetics – metoclopramide, domperidone
- Antidepressants – SSRIs, MOA-I, TCA
- Opiates
- H2 receptor antagonists
What is a prolactinoma?
The commonest functioning pituitary tumour
- Microprolactinoma <1cm
- Macroprolactinoma >1cm
What is the medical treatment of a prolactinoma?
Dopamine (D2) agonists
- Cabergoline – long half life, once/twice weekly dosing
• Quinagolide
• Bromocriptine – short half life
What is vasopressin (ADH)?
A peptide hormone secreted from the posterior pituitary
When is vasopressin (ADH) released?
In response to low plasma volume/increased serum osmolality
When does Diabetes insipidus occur?
When ADH no longer secreted (cranial) or kidneys unresponsive (nephrogenic)
What are the effects of vasopressin (ADH)?
V1 receptors - in vascular smooth muscle —> vasoconstriction
V2 receptors - in distal tubule –> aquaporin channels reabsorb water
What is the synthetic analogue of vasopressin (ADH)?
Desmopressin (DDAVP)
What is the effects of desmopressin?
It is a synthetic analogue of vasopressin (ADH) without the vasoconstrictor effects and has a longer half life
What is desmopressin used for?
Maintenance therapy for cranial diabetes insipidus.
When is desmopressin usually prescribed for?
It is usually prescribed for morning and evening so people aren’t up through the night for the toilet
What causes acromegaly?
Excess secretion of growth hormones stimulating IGF-1 due to pituitary adenoma
What are the different manifestations of a pituitary adenoma?
If the long bones have fused then acromegaly
If long bones have not fused gigantism
What is acromegaly?
Lots of soft tissue growth
What are the treatment options for a pituitary adenoma?
surgery, medical and radiotherapy (if surgery hasn’t been successful radiotherapy on pituitary gland)
What are medical therapies for acromegaly?
Treatment aims to normalise IGF-1 (combination therapy may be required)
- Somatostatin analogues
- Dopamine agonist
- GH receptor antagonist
How are somatostatin analogues used?
- short or long acting (short needs to be given multiple times a day, long just once a month)
- Injection - subcut, IM or IV
What are potential side effects of somatostatin analogues?
- Gallstones
What do GH receptor antagonists do?
Block GH action at the receptor but do not decrease GH secretion
When would GH replacement therapy be required in paediatrics?
- Short stature
- Isolated GH deficiency
- Panhypopituitarism
What is Panhypopituitarism
a condition of inadequate or absent production of the anterior pituitary hormones
When would GH replacement therapy be required in adults?
- GH deficiency following pituitary insult
- Late effects of cancer treatment
- Performance enhancing effects
Describe the negative feedback loop of the thyroid gland?
Hypothalamus releases TRH –> acts on the pituitary causing it to release TSH –> acts on the thyroid causing the release of T3 (triiodothyronine) and T4 (thyroxine)
What is levothyroxine metabolised to?
triiodothyronine (T3)
What do Thionamides do?
Cause reduced thyroid hormone synthesis:
- Inhibit iodide oxidation
- Inhibit iodination of tyrosine
- Inhibit coupling of iodotyrosines
What are examples of Thionamides?
Carbimazole and propylthiouracil (PTU)
What are other treatments (not Thionamides) for hyperthyroidism?
- Betablockers - propranolol
- Potassium iodide
- Radioactive iodine
Why are betablockers used to treat hyperthyroidism?
Reduce symptoms if sympathetic overactivity, do not affect hormone levels
Why is potassium iodide used to treat hyperthyroidism?
Reduces thyroid hormone release acutely, used in thyroid storm and pre-operatively
How do Sulphonylureas work?
Bind to receptor on beta cells, inhibit KATP channels and permit increased insulin secretion
How do Thiazolidinediones work?
pioglitazone, rosiglitazone
- PPARγ agonists – increase transcription of insulin senstising genes
- PPARγ is a nuclear receptor expressed in adipose tissue, muscle, liver
What are the actions of insulin on the liver?
- Decrease gluconeogenesis
2. Increase glycogen synthesis
What are the actions of insulin on skeletal muscle?
- Increased glucose transport via GLUT 4
2. Increase glycogen synthesis
What are the effects of insulin on adipose tissue?
- Increased glucose transport via GLUT 4
2. Increase lipogenesis and decrease lipolysis
How are glucocorticoid and mineralocorticoid release controlled?
The hypothalamus releases CRH —> acts on the pituitary causing it to release ACTH —> acts on the adrenal gland causing it to release cortisol
How do steroid hormones travel through the body?
Bound to proteins in circulation (cortisol binding globulin)
What are the systemic effects of glucocorticoids?
- anti-inflammatory by inhibiting transcription of genes for pro-inflammatory cytokines
- Reduced T-lymphocytes
- Counter-regulatory metabolic effects – gluconeogenesis, increase adiposity
- Improve alertness (circadian rhythm)
- Mineralocorticoid effect
What is aldosterone?
A mineralocorticoid that is stimulated by angiotensin II, ACTH and potassium
What is the main action of aldosterone?
on Na/K pump—>sodium and water reabsorption, loss of potassium
Why can aldosterone not be given orally?
It is metabolised in the liver
What can mineralocorticoid receptor antagonists be used for?
Primary aldosteronism, heart failure, hypertension
What are bisphosphonates used to treat?
Osteoporosis, Paget’s disease, metastatic bone disease
What is the effect of bisphosphonates?
Reduce bone resorption. They bind to bone and inhibit osteoclast activity
What are examples of bisphosphonates?
Alendronate, pamidronate, zolendronate, risedronate
What are examples of other (not bisphosphonates) treatments of osteoporosis?
- Calcium + vit. D - Essential for bone formation
- Denosumab
- Teriparatide
- Strontium ranelate
- HRT
- SERMS
How does denosumab treat osteoporosis?
monoclonal antibody that inhibits RANK ligand which signals to osteoclasts, therefore reduces resorption
How does teriparatide treat osteoporosis?
recombinant parathyroid hormone, binds to osteoblasts to increase bone formation
How does Strontium ranelate treat osteoporosis?
stimulates osteoblasts and inhibits osteoclasts
Why is HRT used in osteoporosis?
used for menopause related bone loss
How do SERMs treat osteoporosis?
bind to oestrogen receptor and decreases bone resorption
What hormones does the hypothalamus release?
GHRH, GnRH, CRH, TRH and dopamine
What senses GH and IGF-1 for negative feedback?
Anterior pituitary and hypothalamus
What is the pattern of GH secretion like?
Pulsatile, mainly overnight
How does GH have its effects?
Either direct effects through surface receptor which is a tyrosine kinase receptor or via production of insulin-like growth factor-1 (IGF-1) from the liver
What are the actions of GH on long bones?
promote cartilage growth (chondrocyte replications) also leads to local release of IGF-1 and IGF-1 receptor
What are the actions of GH on liver?
generates IGF-1
What are the actions of GH on muscle?
trophic hormone, promotes incorporation of amino acids and protein synthesis
What are the actions of GH on adipose tissue?
promotes lipolysis and FFA release
What is inhibin?
a peptide hormone produced by the ovary which exerts negative feedback on FSH secretion (produced in the late follicular phase).
What two hormones does the posterior pituitary produce?
ADH and oxytocin
When is oxytocin important?
Labour and breast feeding
What does oxytocin do during labour?
Stimulates cervical dilatation and uterine contractions
What does oxytocin do during breastfeeding?
‘let down’ reflex in mammary glands; suckling by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.
What can functioning pituitary tumours cause?
Excess production of:
- Prolactin
- GH
- ACTH
- TSH
Where does AVPR2 act?
The basolateral membrane of the kidney collecting ducts
What is the function of AVPR2?
Inserts aquaporin channels to increase renal water absorption
What does the binding of AVP (arginine vasopressin) to the V2 vasopressin receptor do?
stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A (PKA)
This pathway increases the exocytosis of aquaporin water channel–containing vesicles (AQMCV) and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin 2 (AQ2) channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct (CD).
What are the clinical features of Diabetes Insipidus?
Polyuria, polydipsia, nocturia
this must exclude hyperglycaemia and hypercalcaemia
What are the cranial causes of Diabetes insipidus?
o Deficiency of ADH
o Can be idiopathic or genetic (mutation in ADH gene)
o Trauma, tumours, infections, inflammatory conditions of the posterior pituitary
What are the nephrogenic causes of Diabetes insipidus?
o Resistance to ADH
o Genetic (AVPR2 mutation)
o Or secondary to drugs (e.g. lithium), metabolic upset, renal disease
What is the water deprivation test used for?
To test for diabetes insipidus
What happens in the water deprivation test?
- Deprive patients of fluid for 8h
- Measure plasma and urine osmolality every 2-4h
- Then give synthetic ADH (ddAVP) and reassess urine osmolality
What is the treatment of cranial diabetes insipidus?
- Desmopressin (vasopressin/ADH analogue)
- Can be given orally/nasal spray/injection
- Monitor plasma sodium and osmolality
What is the treatment of nephrogenic diabetes insipidus?
- Treat underlying cause
- High doses of desmopressin
What is an incidentaloma?
A non-functioning pituitary adenoma that is asymptomatic and only picked up by accident or post-mortem.
What is it important to check in non-functioning pituitary adenomas?
- Hormone excess
- Hypopituitarism
- effect on visual fields
How can pituitary tumours affect visual fields?
(Pituitary located just below optic chiasm and the tumour can expand upwards and push on chiasm causing loss of peripheral vision (‘bitemporal hemianopia’)
What are the different types of secretory pituitary adenomas?
- Prolactin- ‘Prolactinomas’
• Commonest; 30%
- ACTH- ‘Cushing’s Disease’
• 20%
- Growth hormone - ‘Acromegaly’
• 15%
- TSH – ‘TSHomas’
• Very rare, < 1%What are the clinical features of a prolactinoma?
- Galactorrhoea
- Menstrual disturbance and subfertility in women (more common in women)
- Reduced libido/erectile dysfunction in men
How is a prolactinoma managed?
- Dopamine agonists (cabergoline)
- surgery if large tumour with visual field effects or if medication is not effective
What causes acromegaly?
Excessive production of GH (and IGF-1) usually due to pituitary adenoma (often large)
What are the signs and symptoms of acromegaly?
Sweats, headache, tiredness, increase in ring or shoe size, joint pains
Coarse facial appearance, Enlarged tongue, Enlarged hands and feet, Visual field loss
What is acromegaly called in children?
Gigantism
What are potential complications of acromegaly?
Hypertension, diabetes or impaired glucose tolerance, increased risk of bowel cancer, heart failure
How is acromegaly diagnosed?
- Glucose tolerance test - Glucose load fails to suppress GH and may reveal underlying DM or IGT
- IGF-1 levels - long half-life and protein bound
- Pituitary MRI - tumour usually large (macroadenoma, > 1 cm) and often extends into surrounding structures
How is acromegaly managed surgically?
By trans sphenoidal route – up through the nose
Often not curative
How is acromegaly managed medically?
- Before and after surgery
* Somatostatin analogues to inhibit GH secretion
How is pituitary radiotherapy used in acromegaly?
- To treat residual tumour
* Risk of hypopituitarism and long-term problems
What is hypopituitarism?
Failure of (anterior) pituitary function
What affect does hypopituitarism have?
can affect single hormonal axis (FSH/LH most commonly) or all hormones (panhypopituitarism)
Leads to secondary gonadal/thyroid/adrenal failure – the issue is not with the gonad it isn’t being stimulated appropriately
How is hypopituitarism treated?
Need multiple hormone replacement but cortisol can be given first if all axes are affected
What can cause hypopituitarism?
- Tumours
- Radiotherapy
- Infarction (apoplexy)
• if post-partum then called Sheehan’s syndrome - Infiltrations (e.g. sarcoid)
• Can affect posterior pituitary too - Trauma
- Congenital
What regulates anterior pituitary function?
The hypothalamus via the hypophyseal portal system
How much does the thyroid concentrate iodine by?
20-50x
What is the structure of the thyroid gland?
Two lobes on either side of the trachea
What are the follicles of the thyroid gland made up of?
single layer of cells surrounding a lumen containing colloid (largely thyroglobulin)
What happens when thyroid follicular cells are stimulated?
They become columnar and the lumen is depleted of colloid
What happens when thyroid follicular cells are suppressed?
The cells become flat and colloid accumulates in the lumen
What is necessary for thyroid hormone synthesis?
Iodine
Where is iodine found in the diet and how much is required?
Fruit and vegetables - require 150-300µg daily
Where is iodine deficiency more common?
Mainly in inland areas at high altitude
What does iodine deficiency lead to?
endemic goitre (big neck – enlarged thyroid)
What happens to oral iodine in the GI tract?
It is reduced to iodide and absorbed
How has iodine deficiency been reduced?
By the iodine supplementation of salt
How is iodide transported into follicular cells?
Actively against a chemical gradient by the sodium iodide transporter on the basolateral membrane
what happens after iodide has been transported into the follicular cell?
It diffuses to apex of the cell and is transported into vesicles fused with the apical cell membrane
What happens to iodide in the vesicles of the follicular cell?
It is oxidised to iodine and binds to tyrosine residues in thyroglobulin
What catalyses the organification that takes place in the follicular cell?
Thyroid peroxidase
How are T3/T4 formed after organification has just taken place?
Diodinated/monoiodinated tyrosine’s are formed which then combine to either make T3 or T4
How are T3 and T4 released?
after droplets fuse with lysosome, thyroglobulin is hydrolysed and thyroid hormones reach the circulation
Which is more active T3 or T4?
T3
Which hormone is greater in quantity T3 or T4?
T4
Where is T4 converted to T3?
The periphery
How is the action of Thyroid hormones mediated?
By nuclear receptors
How is production of thyroid hormones mediated?
- TSH from anterior pituitary stimulates synthesis and secretion of T4 and secretion of T4 and T3
- TSH secretion is inhibited by T4 and T3 (negative feedback)
- TRH from HPS stimulates TSH secretion
What are the clinical findings of primary hypothyroid?
High TSH low T4
What are the clinical findings of secondary hypothyroid?
Low TSH and Low T4
What are the clinical findings of primary hyperthyroid?
Low TSH high T4
What is hyperthyroidism?
Excess of thyroid hormone
What causes Hyperthyroidism?
• Auto-immune
o Graves’ disease
• Toxic adenoma
• Multinodular goitre
• Thyroiditis
• Excess administration of thyroxineWhat are the symptoms of thyrotoxicosis?
- Weight loss
- Tachycardia
- Tremor
- Hypertension
- Tremor
- Hypertension
- Heat intolerance
- Palpitations
- Diarrhoea
- Sweating
What happens in Ophthalmopathy
- Lid retraction / lag and periorbital oedema
- Proptosis (30%)
- Diplopia (10%)
- Nerve compression rare
What are the treatment options for graves disease?
- Antithyroid drugs
- Surgery
- Radio iodine
What are the medication options for hyperthyroidism?
- Carbimazole
- Propylthiouracil
What are the potential complications from surgery to correct hyperthyroidism?
- Haemorrhage 0-1.3% - Rec laryngeal palsy 0-4.5% - Permanent hypocalcaemia 0.6% - Hypothyroidism
What are causes of hypothyroidism?
- Autoimmune thyroid disease (Hashimotos)
• Destruction of the thyroid gland (anti TPO antibody)
• May be positive family history, more common in females
- Thyroiditis
• Viral and often painful
- Thyroidectomy
- Following radio iodine therapy
- Drug-induced
• Amiodarone, lithium, sunitinib
- Pituitary disease
• Secondary hypothyroidism
- Severe iodine deficiencyWhat are the signs and symptoms of hypothyroidism?
- Symptoms of hypothyroidism
• Weight gain
• Depression
• Lethargy
• Constipation
• Cold intolerance
• Poor concentration
• Hoarseness
• Menorrhagia
- Signs of hypothyroidism
• Weight gain
• Bradycardia
• Dry skin
• Coarse, thin hair
• Anaemia
• Slow relaxing reflexes
• May have goitre
What investigations are done for hypothyroidism?
Free T4 and TSH
What are the T4 and TSH levels like in primary hypothyroidism?
High TSH and low T4
What are the T4 and TSH levels like in secondary hypothyroidism?
Low TSH and low T4
How is hypothyroidism treated?
The main treatment is levothyroxine
• Generally, need 1.7-2.0 micrograms / kg / day
• Best taken on an empty stomach
• Avoid taking with proton pump inhibitors, ferrous sulphate or calcium
What are the long term treatment goals for hypothyroidism?
To make the patient euthyroid - resolve symptoms and normalise TSH
What are the different types of Differentiated thyroid cancer?
- Differentiated (good prognosis)
• Papillary 17%
• Follicular 13-20%
• Mixed 50%
• Medullary Carcinoma of Thyroid 6%What are the different types of undifferentiated thyroid cancer?
- Undifferentiated 15% (poorer prognosis)
• Anaplastic
• Small cell
