Where is the pituitary gland located?
Located at the base of the brain, just below the hypothalamus. The sphenoidal sinus is posterior to the pituitary gland, and it is in close proximity to the optic chiasm
What parts make up the pituitary gland?
Anterior and posterior parts
What hormones are secreted by the anterior pituitary, and what hypothalamic hormones stimulate their secretion?
Growth hormone (GHRH), FSH and LH (GnRH), adrenocorticotrophic hormone (CRH), TSH (TRH) and prolactin (dopamine)
What hormones are secreted by the posterior pituitary?
ADH and oxytocin
What system allows transport of hormones from the pituitary lobes into the blood?
Hypophyseal portal system
What is the posterior pituitary an extension of?
The central nervous system (neurohypophysis is a storage area for hypothalamic hormones)
What cells make hormones in the anterior pituitary?
Somatotrophs (GH), gonadotrophs (FSH/LH), corticotrophs (ACTH), thyrotrophs (TSH) and lactotrophes (prolactin)
What stimulates release of GHRH from the hypothalamus?
Stress, exercise, sleep and hypoglycaemia
What organs does GH affect?
Liver, directly, to produce IGF-1, and bone, adipose tissue and metabolism, either directly or through the action of IGF-1
How is GH production inhibited?
By negative feedback- GH inhibits GHRH secretion, and IGF-1 inhibits GH and GHRH secretion. Somatostatin released from the hypothalamus also inhibits anterior pituitary production of GH
Describe the HPA axis:
Time of day, illness and stress stimulate hypothalamus to release CRH, which stimulates anterior pituitary to secrete ACTH, stimulating cortisol and androgen production by adrenal cortex. Cortisol and androgens negatively affect production and secretion of CRH and ACTH
Describe the lactotroph axis:
Hypothalamus produces dopamine (decreases with stress), which acts on the anterior pituitary to inhibit secretion of prolactin. Oestrogen stimulates anterior pituitary production of prolactin
What is the action of prolactin?
Development of the mammary gland, and stimulation of lactation
Where are ADH and oxytocin produced?
Hypothalamic nuclei
What is oxytocin important for?
Labour and breast feeding- stimulates cervical dilatation and uterine contractions, as well as ‘let down’ reflex in mammary glands
What are the clinical disorders of the posterior pituitary?
Diabetes insipidus, and syndrome of inappropriate anti-diuretic hormone (SIADH)
What are the clinical disorders of the anterior pituitary?
Tumours (functioning or non-functioning), excess hormones (prolactin, GH, ACTH, TSH) and hypopituitarism
What does ADH action on the AVPR2 receptor cause?
Increased exocytosis of aquaporin channels (AQ2), and decreased endocytosis of AQ2, causing increased water uptake from the collecting duct
What are the clinical features of DI?
Polyuria- passage of >3 L/day of dilute urine, polydipsia, nocturia. Low urine osmolality and high plasma osmolality
What must be excluded before DI is tested for?
Hyperglycaemia and hypercalcaemia
What are the two classifications of DI aetiology?
Cranial and nephrogenic
Describe cranial DI:
Deficiency of ADH; can be idiopathic or genetic (mutation in ADH gene); more commonly caused by trauma, tumours, infections, inflammatory conditions of the posterior pituitary
Describe nephrogenic DI:
Resistance to ADH. Genetic (AVPR2 mutation), or secondary to drugs (lithium), metabolic upset, renal disease
How does the water deprivation test work?
Patients are deprived of fluid for 8 hours. Urea and electrolytes are taken every hour, and plasma and urine osmolality are measured every 2-4 hours. Synthetic ADH is then given, and urine osmolality reassessed
How is cranial DI treated?
Desmopression (ADH analogue), can be given orally/nasal spray/injection. Monitor plasma sodium and osmolality
How is nephrogenic DI treated?
Underlying cause treated, high doses of ddAVP given. Very difficult to treat
What can non-functioning pituitary adenomas effect?
Visual field- presses on optic chiasm, causing loss of peripheral vision (bitemporal hemianopia)
What are the different secretory pituitary adenomas, and how common are they?
Prolactinomas, 30%; cushing’s disease (ACTH), 20%; acromegaly (GH), 15%; TSHomas <1%
What are the clinical features of prolactinomas?
Galactorrhoea (milky discharge from breasts), menstrual disturbance and sub-fertility in women, and reduced libido/erectile dysfunction in men (gonadotrophins are switched off)
How are prolactinomas managed?
Mostly medical management- dopamine agonists. Surgery if large tumour with visual field effects
What causes acromegaly (or gigantism in children)?
Excessive production of GH (and IGF-1), due to pituitary adenoma (often macroadenoma)
What are the symptoms of acromegaly?
Sweating, headache, tiredness, increasing in ring or shoe size, joint pains (cartilage, muscle and tendons grow)
What are the signs of acromegaly?
Coarse facial appearance, enlarged tongue, enlarged hands and feet, visual field loss
What are the 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, may reveal underlying DM or IGT
IGF-1 level: produced by liver in response to GH, long half-life, protein bound, more useful than plasma GH
Pituitary MRI- tumour usually large and often extends into surrounding structures
How is acromegaly managed?
Surgery: by transsphenoidal or transcranial route, often not curative
Medical: before and after surgery, somatostatin analogues to inhibit GH secretion
Pituitary radiotherapy: treat residual tumour, risk of hypopituitarism and long-term problems
What is hypopituitarism?
Failure of anterior pituitary function; can affect single hormonal axis or all hormones (pan-hypopituitarism). Leads to secondary gonadal/thyroid/adrenal failure- need multiple hormone replacement (give cortisol first if all axes affected)
What causes hypopituitarism?
Tumours, radiotherapy, infarction (apoplexy) (if post-partum called Sheehan’s syndrome), infiltrations (e.g. sarcoid, can affect posterior pituitary too), trauma, congenital
What does hyperprolactinaemia lead to?
Hypogonadotrophic hypogonadism
What drugs affect prolactin?
Any drug interfering with dopamine action can cause hyperprolactinaemia:
- antipsychotics
- antiemetics
- antidepressants
- opiates
- H2 receptor antagonists
What size is microprolactinoma?
<1cm
What size is macroprolactinoma?
> 1cm
What the first line medical treatments of prolactinomas?
Dopamine (D2) agonists (cabergoline, quinagolide, bromocriptine)
What are high levels of dopamine associated with?
Cardiac fibrosis and valvopathy
What receptors does ADH act on?
V1 receptors in vascular smooth muscle (vasoconstriction)
V2 receptors in distal tubule- aquaporin channels recruited to reabsorb water
What is desmopressin?
Synthetic analogue of vasopressin with no vasoconstrictor effects and a longer half life
When should levothyroxine be taken?
In the morning on an empty stomach with a glass of water. It has a long 1/2 life
What are some antithyroid drugs?
Thionamides:
- carbimazole
- drug of choice
- absorbed well from gut and converted to methimazole via 1st pass metabolism
- PTU
- less active and shorter half life so higher doses twice daily are required
- usually second line (pregnancy)
What is the mechanism of action of thionamides?
Reduced thyroid hormone synthesis: inhibit iodide oxidation, inhibit iodination of tyrosine, inhibit coupling of iodotyrosines, takes weeks to reduce circulating hormones
PTU also reduced conversion of T4 to T3 peripherally, giving some more acute effects
What are other treatments for hyperthyroidism?
Beta-blockers
- reduce symptoms if sympathetic overactivity, do not affect hormone levels
Potassium iodide
- reduces thyroid hormone release acutely, used in thyroid storm and pre-operatively
Radioactive iodine
What are the classes of type 2 diabetes medication?
Insulin sensitisers, increasing insulin and increasing glucose in urine
What are the actions of glucocorticoids?
Steroid hormones are protein bound in circulation (cortisol binding globulin) and intracellular receptors before entering the nucleus. Glucocorticoids have many systemic effects:
- 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 the closest preparation to cortisol?
Hydrocortisone (most physiological)
What are some common preparations of gluococortiocoid?
Hydrocortisone, prednisolone, dexamethasone, betamethasone
What is aldosterone?
Mineralocorticoid- stimulated by angiotensin II, ACTH and potassium. Main action on Na/K pump to stimulate sodium and water reabsorption and loss of potassium.
What are some mineralocorticoid receptor antagonists?
Sprionolactone (competitive antagonist at MR, androgen and progesterone receptors, unwanted side effects include gynaecomastia and hyperkalaemia), eplerenone (selective MR antagonist)
What are bisphophonates used to treat?
Osteoporosis, paget’s disease, metastatic bone disease (reduce bone resorption)
What are common bisphosphonates?
Alendronate, pamidronate, zolendronate and risendronate
What is the thyroid gland composed of?
Two highly vascular lobes either side of trachea, containing follicles made up of single layer of cells surrounding a lumen containing colloid (largely thyroglobulin)
How is iodine transported into follicular cells?
Via the sodium-iodide transporter
What happens to iodine within follicular cells?
Iodide then diffuses to apex of cell and is transported by prendrin into vesicles fused with the apical cell membrane
How are T3 and T4 formed?
Oxidation of iodide to iodine occurs in the vesicles and binds to tyrosine residues on thyroglobulin. Formation of DIT/MIT, then T3/T4 and endocytosis of thyroglobulin into the cell.
When are T3 and T4 released?
Release of T3/4 after droplets fuse with lysosome- thyroglobulin is hydrolysed and thyroid hormones reach circulation
How does T4 become T3?
In the periphery, T4 becomes T3 by 5’deiodination of T4
How much thyroid hormone is bound/free?
0.5% free, 99.5% bound. Free component is active and regulated, bound to thyroid binding globulin, transthyretin and albumin
What is thyroid hormone required for?
Development of the brain and somatic development- important in pregnancy
What is seen in 1ry hypothyroid?
High TSH and low T4
What is seen in 2ry hypothyroidism?
Low TSH and T4
What is seen in 1ry hyperthyroid?
Low TSH and high T4
What is seen in sick euthyroid?
Low TSH and low T4
What causes hyperthyroidism?
Grave's disease Toxic adenoma Multi-nodular goitre Thyroiditis Excess administration of thyroxine
What are the clinical manifestations of hyperthyroidism?
Weight loss, tremor, heat intolerance, diarrhoea, tachycardia, hypertension, palpitations, sweating
What signs are specific to Grave’s disease?
Dysthyroid eye disease and dermopathy
What is the treatment for Grave’s disease?
Antithyroid drugs, surgery and radioactive iodine
What is the medical treatment for antithyroid drugs?
Carbimazole (works on thyroid peroxidase) and propylthiouracil
How does radio iodine therapy treat Grave’s disease?
Destroys thyroid tissue by beta emission- causes hypothyroidism
What causes hypothyroidism?
Hashimoto’s (destruction by anti TPO antibody), thyroiditis, thyroidectomy, radio-iodine therapy, drug induced (amiodarone, lithium, sunitinib), pituitary disease, severe iodine deficiency
What are the symptoms of hypothyroidism?
Weight gain, depression, lethargy, constipation, cold intolerance, poor concentration, hoarseness, menorrhagia
What are the signs of hypothyroidism?
Weight gain, bradycardia, dry skin, coarse, thin hair, anaemia, slow relaxing replies, may have goitre
How is thyroid disease investigated?
Measure: free T4 and TSH
How is hypothyroidism treated?
Thyroxine (levothyroxine), started at low dose and built up over time
Where does the pituitary develop from?
The anterior pituitary develops from the adenohypophysis, and the posterior pituitary develops from the neurohypophysis
What is the neurohypophysis?
A ventrally orientated down-growth from the diencephalon
Where does the adenohypophysis develop from?
A dorsal outgrowth from the wall of the embryonic pharynx
What is the pituitary surrounded by, and where does this develop from?
A thin fibro-elastic capsule, which develops from meninges, continuous with the dura
Which anterior pituitary cells are acidophils?
Somatotrophs and lactotrophs
Which anterior pituitary cells are basophils?
Thryotrophs, gonadotrophs and corticotrophs
What are chromopbobes?
Exhausted secretory cells (in the pituitary)
Where does the thyroid develop from?
As an endodermal down-growth from the floor of the developing pharynx. The foramen caecum at the back of the tongue marks the site of the down-growth
What does the thyroid descend as embryologically?
Thyroglossal duct via the hyoid bone
Where do parafollicular cells come from?
4th and 5th branchial pouches
What is the abnormal thyroid lobe, and what structure is associated with it?
Pyramidal lobe, levator glandulae thyroidae muscle
Where are parafollicular C cells found?
Both between and within follicles
What do parafollicular C cells secrete?
Calcitonin
What is the action of calcitonin?
Lowers serum calcium by inhibiting osteoclast resorption of bone, and reduces calcium reabsorption at the renal tubule
Which enzyme, synthesised by the follicular cell, enables iodine to be converted into iodine?
Thyroid peroxidase
What is the epithelium of the follicles of the thyroid?
Simple low cuboidal, or squamous in inactive follicles. but cells become columnar when they are actively secreting
What are the different aetiologies of hypothyroidism?
Primary (high TSH), secondary (low TSH), and tertiary (hypothalamic TRH deficiency)
What are the clinical features of hypothyroidism in infancy?
Cretinism- developmental delay and severe mental retardation
What are the clinical features of hypothyroidism in children and adults?
Slowed physical and mental activity, fatigue, cold intolerance, periorbital oedema, coarsening of skin and facial features, cardiomegaly, effusions and hair loss
What is Hashimoto’s thyroiditis?
Autoimmune condition in which there is a reaction against thyroid antigens
- anti-TSH receptor antibodies
- antithyroglobulin
- antithyroid peroxidase
What happens to the thyroid in Hashimoto’s?
The thyroid is usually diffusely, but asymmetrically enlarged. Paler, and may resemble lymph nodes on section- there are lymphocytes, plasma cells, macrophages and germinal centre formation. There is oncocytic change in epithelium (Hurthle cells) and fibrosis
Where do the parathyroid glands develop?
The upper pair develop in the 4th branchial cleft, and the lower pair with the 3rd branchial cleft
What do the parathyroid glands descend with?
Upper with thyroid, and lower with thymus
What are the two types of secretory cell within the parathyroid gland?
Chief cells (contain PTH granules) and oxyphil cells
What does PTH cause?
Increased renal phosphate loss, renal and intestinal calcium reabsorption and osteoclast activation (via receptors on osteoclasts)
