Endocrinology Flashcards
What is the difference between primary and secondary disease in regards to the hypothalamus and pituitary
Primary- gland itself fails e.g thyroid, adrenal cortex, gonad
Secondary- no signal from hypothalamus or anterior pituitary
What are two types of hypothyroidism and how it impacts T3/4 and TSH levels
Primary hypothyroidism- autoimmune destruction of thyroid gland itself so T3 and T4 Fall but TSH is high (don’t measure TRH as too low in the blood) TSH is high as trying to make the gland work and there’s no negative feedback as gland isn’t able to produce T3 and T4
Secondary Hypothyroidism- pituitary tumour damaging thyrotrophs so not a problem with the gland- problem with hypothalamus or pituitary, TSH will fall and T3/4 will also fall as no TSH
What are the disorders associated with the anterior pituitary and adrenal gland
Primary Hypoadrenalism- destruction of adrenal cortex. Cortisol will fall but ACTH increases as is trying to make the gland work (Dont easure CRH but would also be high)
Secondary Hypoadrenalism- pituitary tumour damaging corticotrophs so can’t make ACTH, ACTH and cortisol low
Why is aldosterone not affected if there’s a problem with ACTH
Cortisol is regulated by ACTH but aldosterone is not as its regulated by renin angiotensin
What are the disorders associated with the anterior pituitary and the gonads
Primary hypogonadism- destruction of testes (from mumps) or ovaries (chemotherapy). Testosterone in men and oestrogen in women both fall but LH and FSH increase trying to get gonads to produce
Secondary Hypogonadism- pituitary tumour damaging gonadotrophs cant make LH or FSH so low LH FSH and oestrogen or testosterone
What are the causes of hypopituitarism
CONGENITAL- mutation of transcription factors needed for anterior pituitary development, deficient in GH and at least one other Anterior Pituitary hormone. Will have a short stature and hypoplastic (underdeveloped) anterior pituitary gland
ACQUIRED- tumours, radiation, infection, trauma, pituitary surgery, inflammatory, pituitary apoplexy (haemorrhage or infarction), peri-partum infarction (sheehans)
What is the name for loss of all anterior and posterior pituitary function
Panhypopituitarism
If there is loss of some of the anterior pituitary function and some of the posterior pituitary but not complete loss, what is the diagnosis
hypophytis
How does radiotherapy cause acquired hypopituitarism and what cells in the pituitary are most sensitive
Pituitary and hypothalamus both sensitive to radiation, can be radiotherapy to pituitary or indirect to a tumour nearby, higher the radiotherapy dose the higher the risk of HPA axis damage
GH (somatotrophins) and gonadotrophins most sensitive
Must monitor for 10 years as risk persists that long
What are the different presentations of hypopituitarism
LOW FSH/LH (secondary hypogonadism-pituitary failing) low libido, secondary amenorrhea, erectyle dysfunction, reduced pubic hair
ACTH: (secondary hypoadrenalism-pituitary failing) fatigue as cortisol about energy, (won’t affect salt loss as still have aldosterone as its under the renin angiotensin system not cortisol)
TSH: fatigue maybe weight gain
GH: reduced quality of life, short stature but only in children as adults has finished growing
PROLACTIN: can’t breastfeed
What is post-partum hypopituitarism secondary to hypotension called
Sheehans syndrome- is post partum haemorrhage
Describe Sheehan’s syndrome
In pregnancy the anterior pituitary gets larger due to the lactotrophs enlarging to prepare for breastfeeding (lactotroph hyperplasia)
Postpartum haemorrhage means that blood pressure drops massively and without fast transfusion (hypotension) thus the pituitary does not get enough blood especially due to its size so causes pituitary infarction and the pituitary stops working.
Presentation- tried, anorexic, weight loss, TSH/ACTH/GH deficiency, CANT lactate, secondary amenorrhea, posterior pituitary okay
in short- lactotrophs increase for breastfeeding, AP gets bigger, preganancy causes haemorrhage, AP not supplied with blood= infarction= doesnt work
What is it called when there is bleeding into the pituitary or infarction of the pituitary
Pituitary apoplexy
Describe pituitary apoplexy
Haemorrage of pituitary (fills with blood) or infarction of pituitary (not enough blood), have excruciating headache if patient has pre-existing pituitary tumours (which is normal)
Pituitary gland is much bigger in both cases, either due to blood filling or infarction will cause inflammation, this squashes the pituitary gland against optic chiasm so bitemporal hemianopia
Blood thinners can cause
Presentation- sudden severe headache, bitemporal hemianopia (optic chiasm compressed), double vision- Diplopia or CANT open eyes- ptosis (cavernous sinus problem)
What is the issue in trying to diagnose hypopituitarism and what is done instead
Lots of the hormones depend on other factors like
Cortisol is affected by time of day
T4 circulates for 5-7 days so a drop may not be detected
FSH and LH is cyclical in women
GH and ACTH is pulsatile
Instead dynamic pituitary function tests are used. This involves inducing hypoglycaemia (give insulin) which cause stress to the body and GH and ACTH release (cortisol measured for this)
TRH given to stimulate TSH
GnRH given to stimulate FSH and LH
What scan is needed to check for pituitary tumours
MRI as CT has a low resolution
How is hypopituitarism treated
Prolactin doesn’t need treatment
Growth Hormone- confirm deficiency with pituitary function test, assess the quality of life. Then do a daily injection and measure response by improvement in plasma IGF-1 and change in quality of life
Thyroid Stimulating Hormone- levothyroxine once daily, can’t use TSH to adjust dose as their TSH will stay low as it’s a pituitary problem not primary hypothyroidism, need fT4 above middle of reference range
LH/FSH-
men- replace testosterone, this doesn’t restore sperm production as this is dependent on FSH. If fertility is needed then spermatogenesis can be inducted through gonadotrophin injections (best response if it’s secondary hypogonadism after puberty). Then measure testosterone and analyse semen
women- replace oestrogen and progesterone (prog if uterus intact), if fertility required then carefully timed gonadotrophin injections
ACTH- replace cortisol , prednisolone once daily or hydrocortisone three times per day
Describe the posterior pituitary gland, its anatomy, what neurons it has and what hormones it produces
is anatomically continuous with hypothalamus
has magnocellular neurons that contain either AVP if the neurons originate in the supraoptic hypothalamic nuclei and oxytocin if they originate in the paraventricular hypothalamic nuclei
How does vasopressin work, through what receptors
vasopressin acts to stimulate water reabsorption by acting on V2 receptors in the kidneys collecting duct. (V2 is a g protein receptor so when bound, triggers adenyl cyclase, which turns ATP to cAMP which phosphorrylates protein kinase A, PKA phosphorylates aquaporins which fuse with apical/uminal membrane making it water permeable)
At high levels acts on V1 receptor to cause vasoconstriction, and stimulates ACTH release from anterior pituitary
What is osmolality
Relates to amount of particles in the blood. Is increased when there are more particles aka dehydrated, is decreased when less particles aka overhydration
What is the stimuli for vasopressin release and give examples of when these may occur
1)OSMOTIC- rise in plasma osmolality (blood that flows in) sensed by osmoreceptors in the posterior hypothalamus which stimulate magnocellular neurons (in the supraoptic hypothalamic nuclei) to secrete ADH. High osmolality means more particles in the blood so triggers ADH to absorb water from the urine to lower this, e.g. dehydration
2) NON-OSMOTIC- decrease in atrial pressure sensed by atrial stretch receptors, e.g. lots of blood/volume loss so less blood back to the atria and the lack of filling decreases the pressure, secrete ADH to build this volume back up
Describe osmotic stimulation of vasopressin release
two nuclei named the organum vasculosum (closer to pituitary) and the subfornical organ are circumventricular (sit around the 3rd ventricle) , theres no blood brain barrier so neurons can respond to changes in SYSTEMIC circulation, are highly vascularised nuclei. The neurons project to the supraoptic nucleus.
Osmotic pressure is dependent on the plasma osmolality. Plasma osmolality is in turn affected by the total body plasma volume. Following a fall in plasma volume there is an increase in the plasma sodium (Na+) concentration, and therefore the osmolarity is increased. Subsequently water exits cells, and moves down its concentration gradient into the plasma. This stimulates the osmoreceptors cells to contract/shrink, which results in increased osmoreceptor firing so more afferent signals being sent from the hypothalamus to the posterior pituitary gland to increase the release of ADH
Alternatively, if there is an increase in the total body volume then the osmolality of the plasma will reduce. In this situation, water will move down its concentration gradient from the plasma, into osmoreceptor cells, causing them to expand. As a result, afferent signals are sent from the hypothalamus to the posterior pituitary gland to decrease the release of ADH.
Describe non-osmotic stimulation of vasopressin release and why it occurs
ADH secretion also occurs during states of hypovolemia. Baroreceptors in the left atrium, carotid artery and aortic arch detect changes in arterial blood volume.
The stretch receptors inhibit vasopressin release via the vagus nerve communicating with the hypothalamus. AVP works throught the V2 receptor to restore the circulating volume and it also causes vasoconstriction through V1 receptors
If blood pressure reduces for example due to a haemorrhage there is less stretch of atrial receptors, baroreceptors relay this to the vagus nerve, which sends afferent signals that directly stimulates the release of ADH from the posterior pituitary, less stretch= less inhibition. Conversely, in a hypervolemic state, the release of ADH will be reduced.
Vasopressin results in higher water reabosrption in the kidney via V2 receptors and vasconstriction via V1 so it is needed following a haemorrhage to increase blood volume and pressure
What is the result of dehydration
higher plasma osmolality (less water more particles)
osmoreceptors shrink and are stimulated
thirst is experienced and AVP is released
Vp acts on V2 to cause water reabsorption from renal collecting ducts. Less water in urine means less urine volume, increase in urine osmolality but decrease in plasma osmolality
what are the symptoms of diabetes mellitus and insipidus and what are the symptoms due to
polyuria
nocturia
thirst
polydispia
Diabetes mellitus- symptoms due to osmotic diuresis. the concentration of glucose exceeds the maximum re-absorption capacity of the kidney, glucose remains in the filtrate. This causes an increase in osmotic pressure causing water and potassium to move out and into the urine.
diabetes insipidus- symptoms due to a problem with arginine vasopressin
MELLITUS= GLUCOSE IN PEE
INSIPIDUS= AVP NOT WORKING
What are the types of diabetes insipidus
1) CRANIAL(central)- problem with hypothalamus and or posterior pituitary, cant make argenine vasopressin. VASOPRESSIN INSUFFICIENCY
2) NEPHROGENIC- can make ADH but the kidneys renal collecting duct is unable to respond to vasopressin. VASOPRESSIN RESISTANCE
What are the acquired and congenital causes of the two types of diabetes insipidus
CRANIAL
ACQUIRED- traumatic brain injury, pituitary tumour, pituitary syrgery, metastasis of cancers to the pituitary gland, granulomatous infliltration of pituitary stalk, autoimmune
CONGENITAL
NEPHROGENIC- much less common than cranial
ACQUIRED- drugs like lithium
CONGENITAL-rare mutation in V2 receptor, aquaporin 2 receptor
Presentation of a patient with diabetes insipidus and an explanation of why these symptoms occur
polyuria, polydipsia, polynoctuira, thirst
Urine- dilute (hypoosmolar), and large volumes (AVP is either not there or kidney resistant to it, so cantstimulate water reabsorption)
Plasma- increased concentration hyperosmolar as patient is dehydrated, increased sodium, normal glucose
WHY? argenine vasopressin problem either cranial diabetes insipidus where there is a insufficiency of vasopressin or nephrogenic where there is resistance to vasopressin, this causes impaired concentration of urine in the collecting duct- so cant concentrate urine, leads to large volumes of hypotonic urine and an increase in plasma osmolality and sodium as no water is reabsorbed. This higher osmolality stimulates osmoreceptors and causes the feeling of polydipsia aka thirst.
if the patient has access to water the circulating volume/plasma is maintained however, without water it can lead to dehydration and death
What is psychogenic polydipsia
polydipsia, polyuria, nocturia, but No problem with vasopressi. problem is that the patient drinks all the time.
patient drinks more water, plasma osmolality falls, less AVP secreted, large volumes of hypotonic urine to increase plasma osmolality
How do we distinguish between diabetes insipidus and psychogenic polydipsia
water deprivation test. dont give anythig to drink and measure urine volumes, urine concentration-osmolality and plasma concentration
psychogenic polydipsia will be slight lower than normal in regards to urine osmolality and diabetes insipidus will have 0
stop the test if the patient loses more than 3% of bodyweight
plasma osmolality between the two will also be different. diabetes insipidus have a slightly higher plasma osmolality than normal and psychogenic polydipsia have a lower one than normal
Diabetes insipidus will have a high sodium (high plamsa osmolality), psychogenic polydipsia will have a low sodium
How do we distinguish between the two types of diabetes insipidus
give ddAVP/desmopressin which works like vasopressin, cranial will respond but nephrogenic wont
what is the treatment of diabetes insipidus
CRANIAL- Desmopressin which is selective for V2 receptor, it replaces vasopressin
NEPHROGENIC- rare and difficult to treat, thiazide diuretics like bendofluazide
What is SIADH, the different osmololities you would find, the causes and management
Syndrome of Inappropriate Anti Diuretic Hormone
too much ADH, reduces urine output and leads to urine retention
have high urine osmolality, low plasma osmolality as absorb too much water, dilutional hyponatraemia - less sodium due to the dilution
CAUSES-
CNS- head injury, stroke or tumour
Pulmonary disease- pneumonia or bronchiectasis
Malignancy- Lung cancer
Drug-related- SSRI’s
Idiopathic
MANAGEMENT- fluid restrict or use VAPTAN a vasopressin antagonist which binds to the V2 receptors in the kidney but is very expensive
What is the treatment for someone with primary hypothyroidism
T4 Levi-something
Increase the dose until TSH falls to normal
What is Graves’ disease, symptoms and
Autoimmune, antibodies bind to and stimulate the TSH receptor in the thyroid, causes HYPERTHYROIDISM and a smooth goitre
Symptoms : sweating, facial flushing, muscle wasting , breathlessness, exophthalmos, goitre, increased appetite with no weight gain, tachycardia, palpitation, loss of periods, pretibial myxoedema (growth of soft tissue no pitting)
In the conditions Graves, plummers and viral thyroditis what would be the difference between thyroid scans in terms of radioiodine uptake
Really dark on radioiodine scans means over activity as more is taken up
In Graves’ disease there is an enlarged goitre due to antibodies stimulating the thyroid so there will be a moderate size thyroid with uniform radioiodine uptake. Dark in scan
In plummers disease it’s a toxic nodular goitre so a small region is overactive so only one half of the thyroid will be dark and the other half light grey and usually smaller
In viral thyroditis the virus attacks the thyroid and stops it working completely so there would be no colour on the scan at all
What is plummers disease
Toxic nodules goitre, not autoimmune, a benign tumour is small and comes from thyroid cells that grow and become overactive. Will feel lumps and bumps
As it’s not autoimmune there will be no exophthalmos, no pretibial myxoedema
There will be enlargement in one side of the thyroid as it’s a nodule that overactive
What are the effects of thyroxine on the sympathetic nervous system
Sensitises beta adrenocorticotrophic to ambient(normal/resting) levels of adrenaline and noradrenaline. Means that there will be a larger response to stimuli considered normal like being nervous for an interview, it would result in palpitations, tachycardia, lid lag and tremor - WILL BE APPARENT SYMPATHETIC ACTIVATION
What is thyroid storm
Untreated hyperthyroidism
Hyperprexia- temperature over 41
Tachycardia and arrhythmia
Cardiac failure
Delirium
Hepatocellular dysfunction (stops clearing billirubin)
ANY TWO MEANS THYROID STORM
Is an emergency needs treatment
Give propanalol (beta blocker) and then give thionamides
What are the treatment options for hyperthyroidism
- Surgery
- Radioiodine
- Drugs
- thionamides the anti thyroid drugs includes propyltiouracil and carbimazole
- potassium iodide- large doses of iodine causes negative feedback which blocks TSH and thus reduces T4, only works for a short time after 10 days will make more thyroxine from the iodine (done before operation)
- beta blockers - to reduce tachycardia
Radioiodine, potassium iodide and thionamides reduce thyroid hormone synthesis whereas beta blockers are for symptoms
What are the treatments and follow up for hyperthyroidism
Thionamides like propylthiouracil and carbimazole used daily
Propranolol (a non selective beta blocker as all receptors are sensitised so all need to be blocked) for tremors as anti thyroid drugs take several weeks to have effects on tremor,anxiety and heart rate
Aim to stop anti thyroid drugs after 18 months,
How do thionamides work, what are the possible side effects
Thyroid hormone is synthesised by oxidising iodide to make iodine, this then bonds to thyroglobulin by the thyroidperoxidase enzyme and hydrogen peroxide to make thyroxine
Thionamides block thyroidperoxidase so T3/4 synthesis is decreased
Side effects- rashes and aganulocytosis (reduction of neutrophils) problem as no immunity so will tend to get streptococcus throat sores.
How does potassium iodide work
Directly inhibits thyroglobulin with some effect on thyroperoxidase
Causes the
Wolff-Chaikoff effect is an autoregulatory phenomenon, whereby a large amount of ingested iodine acutely inhibits thyroid hormone synthesis within the follicular cells, irrespective of the serum level of thyroid-stimulating hormone (TSH)
Symptoms reduce within 1-2 days
Vascularity and size of gland reduce within 10-14 days
What are the risks of thyroid surgery
Risk of voice change due to recurrent laryngeal nerve
Risk of losing parathyroid glands- can become hypocalcaemic
Scar
Anaesthetic
How does the radioiodine treatment work
Swallow a capsule
Can’t use when pregnant and bead to avoid children and pregnant mums for a few days
What is the condition where a virus attack the thyroid, what are the symptoms and what’s the treatment
Viral thyroditis
Virus attacks the thyroid gland causing pain and tenderness, causes thyroid gland to stop making thyroxine and makes viruses instead so no iodine uptake if tested, instead will release all thyroxine, eventually will become hypothyroid as cant produce thyroid hormone and has exhausted its stores .
Painful dysphasia, hyperthyroidism, prexia and thyroid inflammation, tender pretracheal lymph nodes, pain radiating to ear, neck painful, free T4 rises as thyroxine stores are released, TSH drops, no new thyroxine
fT4 drops after a month (hyperthyroid for a month) then become hypothyroid
Treatment- none as will resolve by itself in two months
How are pituitary tumours classified
Microadenoma or macroadenoma
Sellar or suprasellar
Compress optic chiasm or not
Invade cavernous sinus or not
Excess secretion of a specific pituitary neurone or no excess e.g prolactinoma or non functioning adenoma
Benign or malignant , pituitary adenomas can have benign histology but display malignant behaviour
Describe the pituitary tumours and which ‘troph’ cells they come from in the anterior pituitary
Acromegaly - somatotrophic cells
Prolactinoma- lactotrophs
TSHoma- thyrotrophs
Gonadotrophinoma- gonadotrophs
Cushings/ corticotrophadenoma- corticotrophs
Describe the cells in the anterior pituitary and the hormones they produce
Somatotroph- produce growth hormone/somatotrophin
Lactotrophs- Prolactin
Gonadotrophs- LH and FSH
Thyrotrophs- TSH
Corticotrophs- ACTH
How are pituitary tumours classified
Radiological- Microadenoma is less than 1cm, macroadenoma if over. can be sellar or suprasellar. whether it compresses the optic chiasm or invades the cavernous sinus.
Can be a hormone secreting tumour or a non functioning one.
Ki-67 index used to see how many cells are dividing.
even if have a benign histology can have malignant behaviour.
How does prolactin affect the hypothalamic pituitary axis
Prolactin binds to prolactin receptors on kisspeptin neurones in the hypothalamus inhibiting the release of kisspeptin. Kisspeptin stimulates the release of GnRH, so without this GnRH decreases which stops the anterior pituitary gonadotrophs releasing LH, FSH and thus Testosterone and Oestrogen
How does hyperprolactinaemia/a prolactinoma affect a patient
GnRH needs to be pulsatile to for puberty, GnRH is also needed to stimulate release of LH and FSH. Too much prolactin inhibits this.
Thus high prolactin will cause oligo-amenorrhea, low libido, erectile dysfunction, galactorrhoea, sub/infertility (infertility if happens before puberty) or osteoporosis
What are some causes of elevated prolactin
pregnancy
stress- venepuncture, exercise, seizures
primary hypothyroidism - problem with thyroid so get high TRH which also stimulates lactotrophs to release prolactin
polycystic ovarian syndrome
chronic renal failure- reduces the clearance and brakdown of prolactin
Antipsychotics, SSRI, high doses of oestrogen, opiates
If serum prolactin in a patient is elevated, what should you do next
Pituitary MRI
if a prolactinoma is confirmed, how would you treat it?
Dopamine receptor agonist - cabergoline
is safe in pregnancy and dosage relates to how big the prolactinoma is
How does cabergoline work ?
Lactotrophs in the anterior pitutary have D2 dopamine receptors, Dopamine binds to the D2 receptor and inhibits the secretion of prolactin. Cabergoline is a dopamine receptor agonist so will bind to the D2 receptor and also inhibit prolactin secretion
Pituitary tumours that secrete excess GH cause what conditions
Gigantism (in children)
Acromegaly (in adults)
How does acromegaly present
Slow presentation
Sweatiness
Headache
Coarsening of facial features- Macroglossia and a prominent nose, a large jaw
increased hand and feet size
anoring and obstructive sleep apnoea
hypertension
Impaired glucose tolerance- diabetes mellitus
What is the mechanism of growth hormone
Anterior pituitary when stimulated secretes growth hormone (somatotrophin) which acts on body tissues to cause growth and development.
At the same time GH also acts on the liver to secrete Insulin-like Growth Factor (somatomedin) to act on IGF-1 receptors on body tissues to increase growth and development. IGF-2 is predominantly in children.
How is acromegaly diagnosed
Since GH is pulsatile, cant easily measure it so:
- Elevated serum IGF-1
- Rise of GH when given an oral glucose load, normal peoples GH will lower
Ho is acromegaly treated
Surgical because acromegaly increases cardiovascular risk
trans-sphenoidal pituitary surgery.
Prior to surgery somatostatin analogues such as octreotide or dopamine agonists like cabergoline (pituitary tumours usually have D2 receptors) can be used to shrink the tumour.
Radiotherapy not recommended as will lose all pituitary tumours.
A patient has:
red cheeks
high blood pressure
proximal myopathy (muscle weakness)
Purple striae
Easy bruising
Moon face
Buffalo hump
fat deposition on abdomen
amenorrhea/hirtuism in women and erectile dysfunction in men
What is the condition?
Cushings disease
What is cushings syndrome and what are the causes
Excess of cortisol or other glucocorticoid
Causes are ACTH dependent like : pituitary/corticotroph adenoma which is Cushings disease , ectopic ACTH, adrenal adenoma or carcinoma
What is cushings disease and what are the causes
Excess of cortisol or other glucocorticoid
Causes can be ACTH dependent: pituitary/corticotroph adenoma which is Cushings disease
Or ACTh independent : ectopic ACTH- lung cancer can cause, adrenal adenoma or carcinoma or taking too many steroids
What is the difference between Cushings syndrome and Cushings disease?
syndrome= excess cortisol
disease= a corticotropph adenoma/ pituitary tumour that secretes ACTH
How is Cushings disease diagnosed/investigated
24 hour urine test which measures free cortisol secretion
Cortisol has a diurnal rhythm, in Cushings cortisol remains high throughout the day (elevation of late night cortisol)
Or, the patient is given oral dexamethasone an exogenous glucocorticoid, if there is increase cortisol after then there must be a corticotroph adenoma because giving a glucocorticoid should switch off cortisol. If cortisol not 0 by end of test then have.
Is Cushings disease ACTH independent or dependent
Dependent, so should measure ACTH once find that there is high levels of cortisol, then a pituitary MRI
How would a non functioning pituitary adenoma present and how would it be treated
Bitemporal hemianopia - visual disturbance
Serum prolactin may be raised since dopamine cant travel down the pituitary stalk
can preset with hypopituitarism
trans-sphenoidal surgery needed
Describe the hypothalamo pituitary axis
Hypothalamus and anterior pituitary both recognises low thyroid hormones (low T4 and T3), low adrenal hormone levels (cortisol) and sex hormone levels and there is negative feedback- increasing stimulation.
GRH/TRH/CRH/GnRH is therefore secreted from the hypothalamic paraventricular nucleus to the thyrotrophs/corticotrophs/gonadotrophs in the pituitary.
The anterior pituitary thus secretes GH/TSH/ACTH/LH/FSH.
GH acts on tissues
TSH acts on the thyroid to secrete T3 and T4
ACTH acts on the adrenal glands zona fasciculata to secrete the glucocorticoid cortisol
LH/FSH acts on the sex glands to make testosterone or oestrogen
What is Graves disease and how would it present
An autoimmune condition, antibodies made bind to and stimulate the TSH receptor in the thyroid, this causes the thyroid to enlarge making a smooth goitre and results in hyperthyroidism.
Symptoms: facial flushing, goitre, tachycardic, palpatations, increased appetite but loose weight, shortness of breath (these symptoms happen because patient is sensitised to beta adrenergic receptors so adrenaline is much higher). The antibodies may also bind to other areas causing exophthalamos, pretibial myxoedema (non-pitting swelling on shins due to soft tissue growth),
If radioactive iodine was given to patients with Graves disease, Plummers and Viral Thyroiditis how would the thyroid scans differ
Graves disease: uniform radioiodine uptake
Plummers disease: uptake of iodine on one side- one hot nodule
Viral Thyroiditis: wont see thyroid on scan
What is plummers disease, and how would it present
A toxic nodular goitre- a small benign adenoma that s overactive making too much thyroxine, is not autoimmune.
Will see enlargement on one side of goitre
How does thyroxine affect the sympathetic nervous system
Sensitises beta adrenoceptors to normal/ambient adrenaline and noradrenaline levels which causes sympathetic activation.
This means there is an exaggerated reaction of tachycardia, hand tremor and lid lag to normal stimuli
Describe symptoms of Hyperthyroidism and name three diseases it causes
Graves Disease, Plummers Disease, Viral Thyroiditis
Weight loss despite increased appetite
breathlessness
palpatations, tachy, sweat
heat intolerance
diarrhoea
lid lag
What is a thyroid storm and how is it classified
Hyperthyroidism
Medical emergency
Any two of the following:
Hyperpyrexia- temp over 41
Tachycardia HR is high
Cardiac failure
Delirium
Jaundice as hepatocytes dysfunction
How is hyperthyroidism treated
Thionamides- Propylthiouracil and carbimazole: inhibit thyroid peroxidase which stops thyroglobulin being oxidised and stops T3/4 being made
Potassium Iodide - large amounts of iodine negatively feedback on pituitary by directly blocking thyroglobulin by stopping iodination, it also inhibits H2O2 generation so TPO cant react with it- Wolff-Chaikoff effect
Non-selective B-blockers- such as propranolol reduces tremor and tachycardia, Needed since anti-thyroid drugs take so long to work, needs to be non-selective as all receptors are sensitised due to high thyroxine
Aim to end anti-thyroid drug after 1.5 yrs
How is thyroid hormone synthesised
ANterior pituitary secretes TSH (thyrotrophin) which binds to the TSH-R on the basolateral membrane of follicular cells
When TSH binds to its receptors three things happen:
- Sodium-iodide transporter on basolateral membrane is activated, sodium and iodide is thus transported into follicular cells. The iodide moves further into the colloid where it undergoes iodination to make iodine
- Thyroglobulin a prohormone is made and transported into the follicular cells colloid
- TPO (thyroperoxidase) enzyme is activated, moves into colloid. TPO + H2O2 catalyse the reactions of Iodine and tyrosine residues in thyroglobulin. When TPO iodinates thyroglobulin it makes 3-monoiodotyrosine and 3,5 diiodotyrosine
these combine to make T3 which is 3,5,3 triiodothyronine or T4 3,5,3,5, tetraiodothyronine
What are the side effects of thionamides
Agranulocytosis- reduction in neutrophils, may get streptococcus and a sore throat since immune system is weak
rashes
Why is surgery not the best option in hyperthyroidism
Could have a thyroidectomy
Can damage recurrent laryngeal nerve which may cause a voice change
May lose parathyroid gland and become hypocalcaemic
Scars
How is radioiodine used and if taken what do they need to be careful of
For scans only
Shouldnt use in pregnancy
Need to avoid children and pregnant women
What is Viral thyroiditis (de Quervain’s) and how will it present
A virus attacks the thyroid gland and causes pain and tenderness, thyroid stops working and makes viruses instead, this means no iodine uptake so thyroid wont show on a scan
Painful dysphagia
Painful neck for a month
Hyperthryoidism (high T4, low TSH) : as causes all thyroxine that is stored in colloid will be released, after four weeks will be hypothyroid until the follicular cells regenerate
Pyrexia
Thyroid inflammation
What is postpartum thyroiditis
same as viral thyroiditis but no pain, happens after pregnancy
Which hormones increase and decrease serum calcium and how
INCREASE:
Vitamin D
Parathyroid Hormone (PTH)
regulate calcium and phosphate homeostasis via actions on kidney, bone and gut
DECREASE:
Calcitonin
Describe Vitamin D metabolism
UVB stimulates skin cells to make Vitamin D3 (cholecalciferol), or Vitamin D2 (ergocalciferol) is taken from the diet.
These go to the liver where 25-hydroxylase hydroxylates vitamin D into 25(OH)cholecalciferol which is an inactive form of Vitamin . It then moves to the kidney and is hydroxylated a second time by 1-alpha-hydroxylase to the active 1,25(OH)2 cholecalciferol (same as calcitriol).
After making certain amounts of calcitriol theres negative feedback to stop 1-alpha-hydroxylase, which stops more active vitamin D being formed
How does calcitriol/active vitamin D work
Promotes Ca2+ reabsorption from the bone
Stimulates Ca2+ and PO4^3- absorption from gut
Stimulates Ca2+ and PO4^3 reabsorption in kidney, so less in urine
Where is parathyroid hormone secreted from and how does it work
Chief cells in parathyroid glands detect change in serum calcium through the G-protein coupled calcium receptor. PTH secretion is inversely proportional to serum calcium (more calcium binding to parathyroid cells, the less PTH made, less calcium binding the more PTH) so when calcium is low, it secretes pre-pro-PTH a large protein precursor and cleaved to PTH.
What are the actions of PTH
Promotes Ca2+ reabsorption from the bone
Stimulates Ca2+ reabsorption and PO4^3 excretion in kidney.
Increases 1-alpha-hydroxylase activity of kidney which increases 1,25(OH)2cholecalciferol aka calcitriol synthesis. And active vitamin D works on the gut to increase Ca2+ and PO4^3- absorption
How does PTH and calcitriol affect the bone, whats the difference?
PTH binds to PTH receptor on osteoblasts, stimulates them to release osteoclast activating factors like RANKL to become osteoblast and results in bone reabsorption. Results in phosphate excretion
Calcitriol does the same, if serum calcium is low then calcitriol increases reabsorption from bone as well as promoting osteoblast formation. results in phosphate absorption
How is PTH regulated
Fall in plasma Ca2+ is sensed by receptors on parathyroidgland and stimulates an increase in PTH.
PTH works on bone stimulating osteoclast formation, works on kidney to increase calcium reabsorption, works indirectly on gut by increasing 1-alpha-hydroxylase activity of kidney which increases 1,25(OH)2cholecalciferol which increases calcium absorption from the gut.
As calcium is restored to normal, it negatively feedsback on the thyroid gland to switch PTH off
What is calcitonin and how does it affect calcium
Parafollicular cells of thyroid secrete calcitonin which decreases osteoclast activity, increases kidney Ca2+ excretion and results in lower plasma Ca2+
What does FGF23 regulate and how?
FGF23 reduces phosphate in two ways
1) inhibits the sodium/phosphate co transporter in the proximal convoluted tubule , this means phosphate and sodium can’t be reabsorbed so more is excreted
2) inhibits calcitriol (1,25(OH)2D3), active Vitamin D Causes PO4^3- absorption from the gut, by blocking it then less is absorbed.
What are the symptoms of hypocalcaemia
Calcium sensitises excitable tissues so get muscle cramps, tetany, tingling
Paraesthesia of hands mouth feet and lips
Convulsions
Arrhythmias
Tetany- involuntary contractions
Signs:
Chvosteks’ sign- facial paresthesia
Trousseau’s sign- carpopedal spasm
What are the causes of hypocalcaemia
Low PTH level/hypoparathyroidism: can be from autoimmunity,surgical, magnesium deficiency, congenital
Low Vitamin D levels: poor diet/malabsorption, lack of UV, renal failure (cant make 1-alpha hydroxylase)
what are the symptoms of hypercalcaemia
Stones- Nephrocalcinosis which can lead to renal colic
GI effects- anorexia, dyspepsia, constipation, pancreatitis
CNS effects- fatigue, depression, impaired concentration, coma is very low
What are the causes of hypercalcaemia, how to differentiate between them
Primary hyperparathyroidism: too much PTH even if calcium high, usually parathyroid gland adenoma. High PTH and high calcium
Malignancy- bony metastases produce factors that activate osteoclasts, certain cancers secrete PTH-related peptide that acts on PTH receptors. would have low PTH and high calcium
Vitamin D excess
Describe the different types of hyperparathyroidism
Primary hyperparathyroidism- occurs when a parathyroid adenoma produces too much PTH which results in calcium increasing, loss of regulation due to autonomous PTH secretion = HIGH Ca2+, HIGH PTH, LOw PO4^3- because PTH inhibits Na+/PO4^3-
Secondary hyperparathyroidism- Normal pysiological response to hypocalcaemia. LOW Ca2+, HIGH PTH. Vitamin D deficiency from lack of diet, lack of sunlight or renal failure is the most common cause as calcitriol stimulates Ca2+ reabsorption
Tertiary hyperparathyroidism- Chronic Renal failure means calcitriol (1,25(OH) cholecalciferol) cant be made, No vitamin D to regulate serum calcium so PTH increase and the parathyroid glands enlarge. HIGH PTH, LOW Ca2+. But eventually PTH is secreted autonomously since the glands are so large so HIGH Ca2+
PRIMARY- cancer, hypercalcaemia
SECONDARY- normal response to low calcium, hypocalcaemia
TERTIARY- Renal failure/Chronic VitD deficiency, hypo at first then hypercalcaemia
What are the treatments of the different hyperparathyroidism
Primary hyperparathyroidism- Parathyroidectomy because untreated it can cause osteoporosis, renal stones, affect mental function and mood.
Secondary hyperparathyroidism- Vitamin D replacement- give 25 hydroxy vitamin D if renal function normal : ergocalciferol (25 hydroxy D2) or cholecalciferol (25 hydroxyD3)
If have abnormal renal function (high creatinine, low albumin, low gfr, high U&E etc) they have inadequate 1-alpha-hydroxylase so give alfacalcidol (1 alpha hydroxycholecalciferol)
Tertiary hyperparathyroidism- Parathyroidectomy
If there is low PTH and high Ca2+ what could be the cause
Is a normal response to high calcium
Could also be bony metastases leaking calcium
How to differentiate between primary and tertiary hyperparathyroidism
Primary is a cancer of the parathyroid glands- too much PTH secreted and therefore hypercalcaemia.
Tertiary is chronic renal failure which causes prolonged calcitriol deficiency, Low calcium will cause lots of PTH secretion, eventually all four parathyroid glands enlarge so too much PTH and hypercalcaemia
What are the different symptoms associated with primary, secondary and tertiary hyperparathyroidism
PRIMARY- high calcium so nephrocalcinosis can cause loin pain, anorexia, nausea , constipation , fatigue, depression, cant concentrate
SECONDARY - muscle crmaps/convulsions, arrythmias, tetany, numbness/paraesthesis
TERTIRY- high calcium so nephrocalcinosis can cause loin pain, anorexia, nausea , constipation , fatigue, depression, cant concentrate
compare hypoparathyroidism and secondary hyperparathyroidism
Hypoparathyroidism is Low PTH and low Ca2+
Secondary hyperparathyroidism is High PTH and low Ca2+
Describe how the adrenal glands make each of the corticosteroids roughly including where
All steroids come from cholesterol and first step is to turn cholaesterone into pregnenolone through side chain cleavage then progesterone through 3 hydroxysteroid dehydrogenase
Mineralocorticoids- Zona glomerulosa- Aldosterone : 3,21,11,18 hydroxylases
Glucocorticoids- Zona fasciculata - Cortisol: 3, 17,21,11
Sex steroids- zona reticularis- androgens and oestrogens: after 17
How does angiotensin II affect the adrenals
activates hydroxylases 3,21,11,18 to make aldosterone and aldosterone increases sodium uptake, decreases potassium to control blood pressure
Where in the adrenal gland are the catecholamines secreted from
Adrenal medulla secretes adrenaline, noradrenaline and dopamine
How does ACTH affect the adrenals
Causes 3,17,21,11 hydroxylase activation to make cortisol
Describe Addisons disease and the symptoms
Adrenal failure (primary).
Autoimmune destroys adrenal cortex. Therefore, cant make cortisol or aldostorone so BP is low, ACTH increases to try to stimulate.
BP is low, weakness
hyperpigmentation of skin, nipples and gums, dark hair ad freckles
No aldosterone so Na+ is low (lost in urine) but K+ is high
No cortisol so low glucose
nausea, diarrhoea, vomiting, abdom pain, constipation
Why are patients tanned in Addisons disease
Pituitary makes POMC (pro opio melanocortin) as a precursor to ACTH and MSH. so cleaving more ACTH also cleaves MSH (melanocyte stimulating hormone) so tanned appearance.
What are the causes of adrenocortico failure
Adrenal glands destroyed- TB common or autoimmune
Enzymes in the steroid synthetic pathway not working : congenital adrenal hyperplasia
How do you diagnose Addisons Disease
Measure cortisol and ACTH early in the morning, High ACTH and low cortisol suggests
synACTHen test: give ACTH and measure cortisol changes, if cortisol doesnt change is addisons as adrenal glands dont function
Treatment of Addisons
Fludrocortisone 50-100mcg
Prednisolone 3mg x1 - OR - hydrocortisone x3 (10mg,5mg and 2.5mg)
Why is fludrocortione better than aldosterone replacement
Aldosterone has a short half life
FLuorine is not in natural steroids so slows metabolism = longer half life and effects seen for 18h so can be given once daily. Binds to both receptors so can stimulate cortisol and aldosterone
Compare prednisolone and hydrocortiosone
Hydrocortisone has short half life so have to take three times a day
Prednisolone has a double bond so a longer half life, is more potent so given once a day
What is congenital adrenal hyperplasia
Deficiency of one of the hydroxylase enzymes needed to make an adrenal hormone from birth
Compare complete vs partial 21hydroxylase deficiency
Complete:
21 hydroxylase needed for aldosterone and cortisol, will have excess of 17-OH progesterone which will be converted to testosterone, less than 24h survival
Partial:
some cortisol and aldosterone, still deficient
excess sex steroids and testosterone
will survive but later in life hirtuism and virilisation in girls, in boys precocious puberty. Get acne, clitoral enlargement, male pubic hair pattern,
How would 11 hydroxylase deficiency affect someone
usually due to consanguinous marriage as its recessive
Low cortisol and aldosterone but build up of 11 deoxy corticosterone which behaves like aldosterone.
So have excess sex steroids, testosterone and 11 deoxycorticosterone
Will have the effects of high aldosterone which is high Na+, and low K+. Will also get virilisation
How would 17-hydroxylase deficiency affect someone
17 hydroxylase needed to convert progesterone to 17 OH progesterone which then makes the sex steroids and cortisol.
So deficient in cortisol and sex steroids but excess aldosterone so hypertension, high Na+, low K+, low glucose
What is Cushing’s disease, it’s causes, symptoms etc
Too much cortisol, usually pituitary tumour that makes too much ACTH
Taking too many steroids, Pituitary adenoma, ectopic ACTH from lung cancer, adrenal adenoma
Symptoms: centripetal obesity, moon face, buffalo hump, proximal myopathy, hypertension and low K+, red striae, thin skin and bruising, osteoporosis
What drugs are used for Cushings syndrome and how do they work
Metyrapone: 11-beta-hydroxylase inhibitor, 11 hydroxylase needed to make aldosterone and cortisol. 11 deoxycorticosterone can act as aldosterone and 11 deoxycortisol doesn’t feedback on the pituitary gland or hypothalamus so reduces cortisol well.
Adjust dose until serum cortisol is 150-300.
Use prior to surgery and after radiotherapy as can cause hypertension in long term due to the inc in 11 deoxycorticosterone and hirtuism
Ketoconazole: 17-alpha hydroxylase inhibitor. Stops cortisol production as well as sex steroids.
Used prior to surgery and to control symptoms.
Can cause liver damage
Osilidrostat: blocks 11-beta-hydroxylase and 17-alpha-hydroxylase so buildup of 11-deoxycorticosterone blocks cortisol and sex steroids
What is Conn’s syndrome and how is it diagnosed
Benign adrenal cortical tumour in zona glomerulosa: Primary hyperaldosteronism
aldosterone increases causing hypertension and low K+.
Diagnosed by finding a tumour in adrenal gland (primary hyperaldosteronism). Check renin levels to exclude secondary hyperaldosteronism, renin and angiotensin should be suppressed as BP is high already
How is Conns syndrome treated, how do they work and what are the unwanted side effects
Spironolactone: orally active, converted to active metabolites such as CANRENONE which is a competitive antagonist of the mineralcorticoid receptor to stop aldosterone production, also acts on kidney tubules to block Na+ reabsorption and K+ excretion (potassium sparing diuretic)
Can cause: is a androgen receptor antagonist - menstrual irregularities as more progesterone and gynaecomastia in men
Epleronone: mineralocorticoid receptor antagonist but binds less to androgen and progesterone receptors compared to spirinolactone
What is the name of tumours of the adrenal medulla which secrete catecholamines
Phaeochromocytomas
What would the symptoms of a phaeochromocytoma be
Cathecholamines are secreted so
Sudden hypertension in young people (may lead to MI) , severehypertension when palpate abdomen too, High adrenaline (may lead to atrial fib)
High BP, High Cardiac Output, Hyperglycaemia
Headache, Sweating, Vomiting, Palpatations, Dizziness
What is the management of phaeochromocytoma
Alpha blockade, to prevent crisis, this decreases BP so may need to give fluids too.
Beta blockade to reduce tachycardia
Surgery, with careful prep
What is the definition of infertility
Failure to achieve pregnancy after 1 year of regular unprotected sex
Primary Infertility- no birth before
Secondary Infertility- have had a birth more than a year ago
List the potential causes of male infertility
Pre testicular: congenital and aquired endocrinopathies like Klinefelters, prolactin issues, testosterone problems
Testicular: Cryptorchidism, Infection, Antisperm antibodies, trauma, toxins- drugs and smoking
Post-Testicular : no vas deferens, erectile dysfunction, vasectomy
Describe cryptorchidism
undescended testes, in abdomen instead of through inguinal canal
List some potential causes of infertility in females
Infection/Inflam of cervix
Antisperm antibody
Tubopathy due to endometriosis, surgery or infection
Endometrium malformed, infected or inflamed, fibroids
Anovulation, Corpus luteum insufficiency
Describe endometriosis
Oestrogen responsive tissue outside of the endometrium, causes higher menstrual pain and irregularities, pain during sex, infertility
Describe fibroids
Benign tumours of the myometrium, responds to oestrogen.
Usually asymptomatic but can increase menstrual pain, cause irregularities, infertility and pain during sex
How does prolactin affect LH, FSH and Testosterone
Decrease all as prolactin binds to kisspeptin neurones to inhibit the release of GnRH
What is Kallmann Syndrome
GnRh neurones dont migrate to hypothalamus with the olfactory neurones: get no smell (anosmia), no puberty and infertility
Low GnRh, low LH, low FSH, low Testosterone
Define oligomenorrhea and amenorrhoea
Oligo- more than 35 days between periods, 4-9 periods per year
Amenorrhea- no periods for 3-6 months
What is Klinefelters Syndrome
Trisomy of the sex chromosomes XXY
Will have high LH and FSH but low Testosterone
Symptoms: tall stature, lack of facial hair, breast development , low bone density, wide hips, narrow shoulders, less chest hair, female pubic hair pattern, small penis and testes, infertility
What examinations and investigations are needed for male infertility
BMI
Sexual Characteristics
Testicular VOlume
Anosmia
Semen Analysis, Blood Tests (LH, FSH, Prolactin, testosterone when fasted, Karotyping), Imaging- Scrotal Ultrasound and MRi Pituitary
How is male infertility treated
BMI, stop smoking, reduce alcohol
Dopamine agonist for hyperprolactin
Gonadotrophin treatment for fertility
Testosterone for symptoms
Surgery
What is Premature Ovarian Infusfficiency and the causes
Early Menopause: have High FSH, High LH and low oestradiol (not enough oestrogen to turn off LH and FSH)
CAuses: autoimmune, genetic cause or cancer therapy
What is Polycystic Ovarian Syndrome and how is it diagnosed
An imbalance of androgens- LH and FSH too high but oestradiol is low
two of the following:
- Oligomennorhea (less than 8-9 cycles) or Anovulation/Amenorrhea
- Clinical or Biochemical Hyperandrogenism
clinical- acne hirtuism or alopecia
biochem- raised androgens
-Polycystic ovaries o ultrasound
How is PCOS treated
Oral contraceptive pill to fix the periods
Ovulation induction for the infertility
Diet , Lifestyle and Metformin to improve insulin resistance and help glucose homeostasis
Hirtuism- anti-androgens or hair removal methods
Progesterone courses and Metformin to shed endometrium layer and reduce risk of endometrial cancer
What is Turners Syndrome and the symptoms
Only one X sex chromosome
Symptoms:
Short stature, low hairline, Shield chest, coarctation of aorta, poor breast development, elbow deformity, amenorrhea, short fourth metacarpal, webbed neck
What are the key examination and investigations of female infertility
Examinations- hyperandrogenism signs, anosmia
Investigations- Pregnancy test, Imaging (ultrasounds, MRI pituitary,), Blood test (LH, FSH, Oestradiol, ANdrogens, Mid Luteal progesterone (high would mean ovulation occured)
What treatment should be given to a man low in testosterone who doesnt desire fertility
Confirm low testosterone, 2 low fasting morning T, investigate cause
Give testosterone replacement to treat eraly morning erections, libido, decreased energy.
Monitor hamatocrit and prostate size
What treatment should be given to a man with hypogonadism who doesnt desire fertility
Gonadotrophins to stimulate spermatogenesis so hCG injections (acts on LH receptors) if no response add FSH injections after 6 months
DO NOT GIVE Testosterone because it will neg feedback and worsen sperm count by reducing LH and FSH
Lh needed to stim leydig cells to increase intratesticular testosterone
FSH needed to stim the seminiferouse tubule development and spermatogenesis
What is hypothalamic Amenorrhoea
Insufficient energy left for fertility causing amenorrhoea or oligomennorhoea.
Due to low body eight, excessive exercise, stress or genetic susceptibility. Will have low everything
What is the aim of ovulation induction
Develop one ovarian follicle by increasing FSH by a small amount
How is ovulation restored in PCOS
PCOS- weight loss, metformin (helps with insulin resistance bcs insulin increases androgen production which inhibits ovulation, decrease insulin= ovulation more likely), Letrozole (aromatase inhibitor- aromatase converts androgens to oestrogen which feeds back on HPG axis to inhibit LH and FSH), Clomiphene (oestradiol receptor modulator, blocks so doesnt feedback), FSH stimulation
How is ovulation restored in Hypothalamic Amenorrhoea
weight gain, less exercise
pulsatile GnRH pump
FSH stimulation
letrozole and clomiphene not as effective as oestradiol usually low anyway
How does IVF work
FSH stimulates ovaries to make egg
Oocyte retrieval
Fertilise in vitro
Embryo incubation
Embryo transfer
What are the pros and cons of condoms
+ protect against STI, easy to obtain, no contra-indications
- interrupt sex, some skill to use, reduce sensation
How does the oral contraceptive pill work
High oestrogen and progesterone, negatively feeds back o the pituitary gland to decrease LH and FSh and on the hypothalamus to decrease GnRH. This causes
-anovulation
-thickening of cervical mucus
thinning of endometrial lining to reduce implantation
What are the pros and cons of the combined oral contraceptive pill
+ easy to take, doesnt interrupt sex, reduces endometrial and ovarian cancer, weight neutral, can avoid withdrawal bleeds and take packets back to back
- difficult to remember, no STI protection, nausea, soe breasts, mood changes, hungrier , blood clots in legs, Dont use in breastfeeding, P450 enzyme inhibitors reduce efficacy
What may the oral contraceptive pill be used for
contraception
To make periods lighter and less painful: endometriosis, menorrhagia
To have regular withdrawal bleeds or no bleeds
In PCOS can reduce LH and hyperandrogenism so helps with acne/hirtuism
What are the positives and negatives of Progesterone Only Pill
+ suitable if cant take oestrogen e.g. histories of breast or womb cancer or chance of clotting
easy to take, doesnt interrupt, helps painful or heavy periods, can be used when breastfeeding
- difficult to remember, STI, shorter acting- same time each day, irregular bleeding, headaches, sore breasts, mood change.
What are the long-acting reversible contraceptives
1) Coil: prevent implantation, can be used as emergency contraception
-IUD (copper coil): mechanically prevents implantation, causes heavy periods, 5-10 year survival
-IUS (mirena coil):secretes progesterone which thins the lining of the womb and thickens cervical mucus, 5 years
2) Progesterone-only injectable contraceptives or subdermal implants: long lasting
What are the three emergency contraceptives
1) IUD: up to 5 days after unprotected sex
2) Ulipristal acetate: stops progesterone working normally ad prevents ovulation, take within 5 days
3)Levonorgestrel: synthetic progesterone prevents ovulation, take within 3 days
The pills can cause nausea, headache and abdominal pain, Liver P450 enzymes reduce efficacy, if vomit need to take again
When should you avoid the oral contraceptive pill
If have migraine with aura as may cause stroke
Smoking more than 15 a day over 35 years
Stroke history
Breast cancer
Breastfeeding
P450 inhibitors
When should more effective methods of contraception be used
If taking teratogenic drugs which can cause defects, so look at progesterone only implant, or IUD/IUS
What is Hormone Replacement Therapy used for
Menopause symptom relief due to low oestrogen (stops flushing, sweating, disturbed sleep, low libido and low mood)
reduces osteoporosis related fractures
What are the risks of Hormone Replacement Therapy
1) Deep Vein Thrombosis or Pulmonary Embolism risk- oral oestrogens inactivated by first pass liver metabolism, and they also increase clotting factors. Transdermal oestrogens are safer than oral especially if BMI over 30
2) Hormone sensitive cancers- in breast cancer affects duration of treatment, continuous use worse than sequential. Ovarian cancer inc risk after long term. Endometrial cancer at higher risk so must prescribe progestogens
3)Cardiovascular Disease- risk if started HRT late after menopause, but benefit those with POI
4) stroke risk- oral higher risk than transdermal oestrogens and combined more risky than oestrogen only
Compare the risk between oestrogen only HRT and combined Oestrogen and progesterone HRT
Oestrogen only : higher risk of endometrial cancer
Combined: no risk of endometrial cancer but, sequential and continuous use increase risk of breast cancer, increased risk of venous thrombotic embolisms
same risk of ovarian cancer and stroke
What are the benefits and risks of HRT
+ symptom control, skeletal benefit, decreased CHD,
(if transdermal E2 only- less risk of venous thrombotic embolisms and stroke)
- venous thrombosis, stroke, breast cancer, gallstones
How are transgender patients treated
Prepubertal: GnRH agonist to delay puberty
Transgender men: testosterone and progesterone (P stops menstruation)
Transgender women:
- reduce testosterone through GnRH agonists, anti-androgen medications
- Estrogen
Describe Type 1 and Type 2 diabetes
TYPE 1 - Autoimmune condition where pancreatic beta-cells are attacked and destroyed by the immune system, impairs insulin production leading to hyperglycaemia- ABSOLUTE INSULIN DEFICIENCY. usually childhood but also develop later
TYPE 2 - Obesity or genetic risk causing insulin resistance and beta cell failure leading to RELATIVE INSULIN DEFICIENCY. also leads to hyperglycaemia. usually later but can present any time.
What other type of diabetes can there be
Monogenic diabetes/Mitochondrial diabetes- Mutation in one gene causing 50% likelihood of getting diabetes.
Can lead to either T1 or T2
How does type 1 diabetes develop
Usually have a genetic predisposition and a precipitating event. How fast diabetes develops depends on how many beta cells are in tact. Start with immunological abnormalities (activation and then response) but normal insulin release, the progressively lose insulin as beta cells are attacked. When diabetes is overt most beta cells will be dead and C peptide will be present (as still trying to produce enough insulin to control hyperglycaemia), end stage there will be no c peptide as all beta cells have been lost
What is C peptide
proinsulin, cleaved into C-peptide and insulin. Best to measure as if diabetic will be on insulin medication and insulin has a short half life so C peptide measured first
Why does insulin have a short half life
First pass mechanism of the liver
On a histology slide, if there is Type 1 diabetes what will be seen
Immune system kills the cells so the islet wont be dense
Why is it important to know if there is an immune base to diabetes
inc prevalence of other autoimmune
complete destruction of beta cells
auto antibodies can be useful to measure
How does the immune destruction of beta cells occur
auto-antigen presented to autoreactive CD4+ T cells, these cells activate CD8+ T cells which lyse the beta cells with the self antigen. Pro inflammatory cytokines make it worse
What allele is most significant in diabetes
HLA-DR allele
DR3 and 4 pose significant risk, 1 ad 5 slight, 2 is protective
What environmental factors may trigger the destruction of beta cells
enteroviral infections- seasonal variation (reduction in summer)
cows milk protein
microbiota changes
What autobodies can be detected in T1D
Insulin antibodies (IAA)
Glutamic acid decarboxylase (GADA)
Insulinoma-associated-2 autoantibodies (IA-2A)
zinc transported 8 (ZnT8)
How does T1D present
polyuria, polydipsia, nocturia, vision blurring, recurrent infections, weight loss, fatigue, dehydration, glycosuria, cachexia/thinning
How is diabetes diagnosed
Based on clinical features and HbA1c or two HbA1c if asymptomatic
Type 1- presence of ketones, C peptide or AABs can be considered
Type 2- fewer osmotic complications, renal failure
What effect does insulin deficiency have
reduction of insulin induces a catabolic state
1) Proteinolysis: break down muscle into amino acids for fuel
2) Hepatic Glucose Output: increases to make more glucose (insulin would suppress HGO)
3) Lipolysis: fats broken down to glycerin and non-esterified fatty acids
Describe ketone body formation, why it occurs and name the three
Lack of insulin leads to lipolysis which results in NEFA and glycerin.
NEFA taken into the liver, undergo beta oxidation and become
- Acetyl CoA
- Acetoacetate
- Acetone + 3 hydroxy butyrate
Insulin turns off this process because enough sugar taken into cells, glucagon stimulates this process so when no insulin glucagon is secreted causing hyperglycaemia as well as ketones
Ketone bodies fuel when starved, when accumulate get keto-acidosis
What is the counter regulatory response of hypoglycaemia
Glucagon, Growth Hormone, Catecholamines, will all help to bump up glucose levels
What are the complications of diabetes
acutely : causes diabetic ketoacidosis, uncontrolled hyperglycaemia, Hypoglycaemia (of insulin treatment)
chronically: microvascular (retinopathy, neuropathy, nephropathy), macrovascularly (ischaemic heart disease, cerebrovascular disease, peripheral vascular disease)
How is Type 1 diabetes managed
Insulin treatment: basal (long acting) and bolus (with meals) given
education about diet- adjust dose to carbs, sub refines carbs (high GI or sugary) with complex carbs (starch, low GI).
technology: Use self monitoring of blood glucose and the Hb1Ac results to adjust- is self managed
transplantation
What are the types of insulin
Bolus: Actrapid (human insulin replicate) or Insulin analogue.
Take three times a day, with meals
Basal: Bound to zinc or protamine like Neutral Protamine Hagedorn. Insulin analogues also used. Once or twice a day
Other than insulin injections what other treatment options are there ?
Insulin pump therapy: continually delivers short acting analogue in subcutaneous space so achieve a flat basal profile, user programmes the bolus dose
Closed-loop/Artificial pancreas: automated insulin delivery by detecting glucose levels (automatically adjusts)
Transplantation: Islet cell transplant OR pancreas with kidney transplant (both require life long immunosuppression)
What is HbA1c
Glycated haemoglobin, reflects last 3 months of glycaemia
N-terminal valine residue of HbA’s beta chain binds with glucose to make a schiff base, results in amadori product
Describe the acute complications of T1D in detail
1) Diabetic Ketoacidosis: Can be what T1D initially presents with, an acute complication/missed or inadequate insulin dose in T1D patients. Usually T1D but can occur in T2, pH lower than 7.3 in urine or capillary, HCO3- less than 15, and glucose over 11
2) Hypoglycaemia: is less than 3.6 glucose level, get adrenergic symtpoms like tremor, palpatations, sweating and hunger , can get neurological symptoms like confusion etc. If get it frequently may get no symptoms so impaired awareness, may happen at night too : can result in seizure, coma, impact emotions, driving, daily function and cognition
What puts T1D patients at risk of a hypo and how can they be supported
Exercise, missing meals, inappropriate insulin, alcohol, low HbA1c, lack of training/education
support: different insulin analogue, insulin-pump therapy, carb counting education, transplant
How is an acute onset of hypoglycaemia managed
If alert and orientated: eat carbs, juice/sweets are rapid, sandwich takes longer
If drowsy but can swallow: buccal glucose like glucogel
Unconscious: IV glucose
If deteriorating, insulin induces or IV is difficult then give IM (intramuscular) glucose
What are the stages of developing T2D
Intermediate: High insulin production and rising insulin resistance (beta cells working harder to try to keep up). Fasting glycaemia (6-7), oral glucose test (7.7-11), Hb1Ac (42-48)
T2D: beta cells fail and insulin resistance peaks, all levels will be above
What presents sooner T1D or T2D
T2D presents before all the beta cells die, presents due to increasing resistance rather than the cells dying
If a T2D patient is in a hyperglycaemic state what will happen
Hyperglycaemia will NOT USUALLY cause ketosis as there is still insulin to suppress lipolysis and ketogenesis. This stops the formation of NEFA and the formation of ketone bodies which stops ketoacidosis.
Instead T2D patients will release catecholamines, GH , glucagon all the stress hormones. This will make them even more insulin resistant tho so might eventually lead to DKA
What factors affect insulin secretion and action
Body weight : visceral fat affects glucose uptake in adipose and skeletal muscle
Exercise
Smoking
Alcohol
Genetics
Gene-environment
How would impaired glucose tolerance vs T2D respond to insulin
Impaired: slight increase in insulin
T2D- no inuslin production : loses the first phase insulin release which is the large spike of insulin that normally get after eating
Describe the relationship between insulin sensitivity and insulin secretion, where do T2D patients fall on this?
Inverse relationship, if insulin sensitivity is low/resistance is high then insulin secretion will rise to try to make up for it. When very insulin sensitive/low resistance then dont need to secrete much insulin to achieve result
T2D patients secrete less insulin at an sensitivity
What is the consequence of insulin resistance
1) increased HGO (NEFAs trigger)
2) Skeletal muscle cells dont take up glucose efficiently
3) Lipolysis of adipocytes which make NEFA and glycerin, adipokines made from fat cells drives proinflam state (e.g. leptin, TNF-alpha, IL-6, glucocorticoid, fatty acids)
How does obesity contribute to development of T2D
Inc in adipocytokines which drive the pro inflam state and NEFA which can be made into ketones
What are the risk factors for T2D
Changes in gut microbiota:obesity causing insulin resistance, inflammation, bacterial lipopolysaccharides fermented to short chain fatty acids
Age
PCOS (increases insulin resistance)
If intra-uternine growth is retarded
How does T2D present
Hyperglycaemia
Overweight
High cholesterol
Diabetic retinopathy
fewer osmotic issues
Renal failure usual
If give fluids to someone too fast what issue can occur
central pontine myelinolysis
How does the management of Diabetes mellitus differ
T1-Exogenous insulin, self monitoring
T2- diet (lower calories, lower fat or refined carbs, inc complex carbs, inc fibre, less sodium, oral medication, may need insulin later, education
In a type 2 diabetes consultation what occurs
check HbA1c
Weight
blood pressure
Cholesterol profile
Foot check (for diabetic foot) and retinal screening
What drugs are used for T2D and what do they do
Metformin: reduced hepatic glucose production, improves insulin sensitivity, increases glucose disposal.
Sulphonylureas: boost insulin secretion, bind to the ATP sensitive potassium channel and close it which is needed for insulin secretion
Pioglitazone: insulin sensitiser, works on peripheral cells may gain weight peripherally instead of centrally. Works on peroxisome proliferator-activated receptors, improves glycaemia and lipids
What is the name for a drug that reduces hepatic glucose production, reduces insulin resistance and reduces amount of glucose absorbed by the intestines
biguanide
What channel do sulphonylureas binds to
ATP sensitive potassium chnels
What are the side effects of metformin and when should you not use
GI side effects
shouldnt use if severe liver failure, severe cardiac failure, or moderate renal failure
What hormone is secreted in response to nutrients being in the gut and what does it do
Glucagon like peptide-1 (GLP-1)
From L cells, stimulate insulin and suppress glucagon, makes feel satiated, short half life as rapidly degraded
(incretin).
Increases satiety, Increases insulin, Increases sodium excretion, inc endothelial function
What enzyme degrades GLP-1
by the enzyme: dipeptidyl peptidase-4 (DPP4)
How can the effect of GLP-1 be utilised in treatment of diabetes mellitus
GLP-1 suppresses appetite, has short half life so by using a dipeptidyl peptidase 4 inhibitor or a GLP-1 agonist the satiety feeling can be prolonged as GLP-1 wont be released
What are the two GLP-1 agonists
Liraglutide/Saxenda and Semaglutide
are daily injections, decrease glucagon and glucose (high GLP-1 levels helping insulin production), cause weight loss
Name a DPPG-4 inhibitor
Gliptins
increases half life of exogenous GLP-1, Increases GLP-1, decreases glucagon and glucose (high GLP-1 levels helping insulin production), no weight changes
What are the names of SGLT-2 inhibitors an what do they do
Empagliflozin, Dapafliflozin, Canafliflozin
Inhibit the Na-Glu transporter in the proximal renal tubule to increase glycosuria. This owers HbA1c as more glucose is excreted in urine, helps with CKD
What treatments can be used to induce T2D remission
Gastric bypass surgery
800 cal a day for 3-6m
Other than glucose what needs to be managed in T2D
Blood pressure- hypertension common so use ACE inhibitor
Lipid management- red cholesterol and triglycerides,
What is obesity
Abnormal or excessive fat accumulation in adipose tissue which impairs health
Not many obese individuals die from obesity itself, so whats the issue
Die from comorbidities : sleep apnoea, bowel cancer, hypertension, MI, stroke, T2D, CVD,
How is obesity assessed and managed?
Determine degree
Assess lifestyle and comorbidities
consider referring to specialist care OR manage through lifestyle changes or drug treatment
What hormone may be the reason for someones obesity
Leptin deficient people
leptin (from adipose tissue) tells the brain about energy stores and food intake, if dont have then can cause obesity, infertility (as leptin affects the thyroids gonadal axid), stunted linear growth (affects thyroid GH), low body temp, low energy expenditure and lower immune function
How can leptin be used for women with amenorrhea and leptin deficient children
Restore LH pulsatility so in women that are very thin tricks brain to think there is adipose tissue
What treatment can be used for leptin deficiency, how does it work and what are the side effects
Orlistat : gastric and pancreatic lipase inhibitor, reduces dietary fat absorption
Side effects: fatty and oily stool, faecal urgency, oily spotting
If all measures to reduce weight loss have failed for 6 months what treatment is next
If all measures to reduce weight loss have failed for 6 months and over 40 BMI, 35-40 BMI with comorbidity or BMI of 30-34.9 with T2D then bariatric surgery:
Gastric bypass: Top of stomach joined to small intestine, dont absorb as many calories
Gastric band : band around stomach
Sleeve gastrectomy: remove some of stomach
What is the name of the medication that is a GLP-1 receptor and a GIP receptor agonist.
Tirzepatide
GIP (glucose dependent insulinotropic polypeptide) receptor: if glucose is high then stimulates insulin, if glucose low then stims glucagon
What are the microvascular and macrovascular complications of diabetes
MICRO: retinopathy, nephropathy, neuropathy
MACRO- cerebrovascular disease, ischaemic heart disease, peripheral vascular disease
What increases risk of microvascular complications
Hyperglycaemia extent- HbA1c
Systolic BP
Duration of Diabetes
Smoking
Genetic factors
Hyperlipidaemia
Bad glucose control early on can affect later (hyperglycaemic memory)
How does hyperglycaemia cause damage, describe the mechanism
Hyperglycaemia and hyperlipidaemia increase the formation of mitochondrial superoxide free radicals in the endothelium.
Hyperglycaemia also increasesgeneration of glycated plasma proteins to form advanced glycation end products (AGEs).
The oxidatove stress, hypoxia and AGEs activate inflammatory pathways. Damage to endothelium results in leaky capillaries and ischaemia
Why is diabetic retinopathy screened annually and what do you look for
Early stages are asymptomatic so screened.
Background retinopathy :earliest stage see hard exudates (brighter yellow spots on the retina, see microaneurysms (tiny dots) and blot haemorrhages.
Pre-proliferative retinopathy: see cotton wool spots/ soft exudates which means retinal ischaemia, still see haemorrhage
Proliferative retinopathy: see new vessels on optic disk, forms in response to ischaemia
Maculopathy: hard exudate/oedema around macula, same as background retinopathy but background doesnt occur on macula
How is retinopathy and maculopathy treated
background retinopathy is just surveilled
pr-proliferative retinopathy and proliferative retinopathy : panretinal photocoagulation (will see green burns from laser, reduces peripheral vision but stops new blood vessels forming)
Diabetic maculopathy: if oedema then Anti-VEGF(vascular endothelial growth factor) injections to the eye and grid photocoagulation
How is diabetic nephropathy diagnosed
Annual screen, look for albumin in the urine.
urine albumin increases- get high ACR, see frothy urine.
check BP
eGFR will be abnormal
peripheral oedema potentially
How does diabetic nephropathy occur
Hyperglycaemia and Hypertension cause pressure to build in the glomerulus (glomerular hypertension), this damages it and forces protein out (proteinuria) which causes glmoerular and interstitial fibrosis which causes GFR decline and renal failure
Describe the renin-angiotensin system
Liver produces angiotensinogen
Kidney makes renin which converts angiotensinogen to angiotensin I. ACE in the lung converts angiotensin I to II and AGII acts on the kidneys zona glomerulosa to secrete aldosterone
What is used to block the renin angiotensin system
ACE inhibitors (-pril) or angiotensin 2 receptor blocker (ARB -sartan). Reduces blood pressure and nephropathy progression.
How is diabetic nephropathy managed?
ACE inhibitors (-pril) or angiotensin 2 receptor blocker (ARB -sartan) given as soon as patient has microalbuminuria.
start SGLT-2 inhibitor for T2D
What is diabetic neuropathy
Vasa nervorum are small vessels supplying nerves, if blocked results in diabetic neuropathy. More common in feet as nerves are longest, can be painful
What are the risk factors of diabetic neuropathy
age, diabetic duration, poor glycaemic control, height (longer nerves in taller people), smoking, diabetic retinopathy
Why do diabetic patients have their feet checked and who are at risk
Diabetic foot ulceration- look for deformity or ulcers, assess sensation and foot pulses.
Peripheral neuropathy and peripheral vascular disease are more likely to get ulcers as cant feel legs
How is diabetic foot disease managed
Peripheral neuropathy- inspect regularly, footwear, avoid barefoot
PN with ulceration- offloading, revascularisation, AB’s if infected, orthotic footwear, amputation
What other type of neuropathy is common in diabetic patients
Mononeuropathy: sudden motor loss like foot or wrist drop, cranial nerve palsy double vision if oculomotor affected (3rd nerve palsy is where one eye looks down and out)
Autonomic neuropathy: symp and parasymp nerves to GI tract, bladder and cardiovasc system damaged. get delated gastric emptying, nausea and vomiting (makes bolus insulin difficult), constipation. postural hypotension- collapse on standing, sudden cardiac death if autonomic supply to heart is cut
Risk factors for macrovascular disease
Age, sex, birth weight, fam history
lipid levels, hypertension, smoking, diabetes, centripedal obesity
How is cardiovascular risk managed in diabetes
Smoking cessation
BP - ACEi, ARB
Lipids: cholesterol low and LDL low: orlistat
Weight: SGLT-2i, GLP-1agonist, DPPG-4i
Annual microalbuminuria screen
