Endocrine Flashcards
MEN1 typically has tumours where?
95% parathyroid, 70% pituitary, pancreas 50% and adrenal 40% (but normally non-functional adenoma).
3x Ps and adrenal
MEN2a has what features? And what about MEN2b?
Pheochromocytoma, medullary thyroid carcinoma, parathyroid (70%). MEN2b is the same as MEN2a PLUS Marfinoid features and visceral gangliomas.
Which hormones are classically carried by carrier proteins?
Thyroxine (t4), triiodothyronin (T3), the steroid hormones (aldosterone, cortisol, oestrodiol, progesterone, and testosterone, growth hormone and insulin like growth factors 1 and 2.
Where are ADH/AVP and oxytocin synthesised?
The supraoptic nuclei and the paraventricular nucleus of the hypothalamus.
Where are ADH/AVP and oxytocin synthesised?
The supraoptic nuclei and the paraventricular nucleus of the hypothalamus.
What are the zones of the adrenal cortex? What’s the acronym to remember is order?
From superficial to deep glomerulosa, fasciculata, reticularis. Acronym GFR.
What are the final hormones output each of the zones of tghe adrenal cortex?
The way or remembering is salt, sugar, sex. Glomerulosa produces aldosterone, fasciuclaris produces cortisone, and reticularis produces the sex hormones.
What are the hormones produced by the anterior pituatary gland?
FLAT PEG. FSH, LH, ACTH, TSH, Prolactin, endorphins, GH.
The FLAT hormones are those that act on other endocrine tissue, which produce another hormone to act on other tissue, and are named the tropic hormone. The PEG hormones are direct acting on non-endocrine tissues.
In what order are pituatary hormones typically lost in the presence of pituatary adenoma?
Go look for the adenoma please. GH, LH, FSH, TSH, ATCH, Prolactin.
What is the most common type of hormone produced by a pituatary adenoma?
Prolactinomas make up at least 30% of all pituatary adenomas
Which part of the pituatary gland receives an arterial blood supply?
The posterior pituatary (neurohypophysis) recieves arterial supply from the superior hypohyseal artery (direct branch from the carotid artery) and the inferior hypohyseal artery (branch off the meningiohypophyseal branch which comes off the internal cariotid artery). The anterior pituitary however only receives blood from the pituitary portal system.
What is the name of the cells in the anterior pituatary that produce growth hormone?
Somatotrophs.
What is the name of the cells in the anterior pituitary that produce TSH?
Thyrotrophs
What is the name of the cells in the anterior pituitary that produce FSH and LH?
Gonadotrophs
What is the name of the cells in the anterior pituitary that produce prolactin?
Lactotrophs
What is the neuotransmitter that inhibits the activity of lacotrophs and suppresses the production of prolactin?!
Dopamine. This is the issue with taking dopamine receptor antagonists - they end up causing hyperprolactinaemia which can cause inadvertant lactaion.
Waht is the effect of growth hormone release?
It stimulates the production of IGF-1 by multiple somatic tissues - especially the liver.
What is the effect of TSH?
It acts on thyroid follicular cells to make thyroid hormone.
What is the effect of ACTH?
It acts at the fasciculata and reicularis cells of the adrenal cortex to produce corticosteroids
What is the effect of FSH?
It acts at ovarian follicular cells to make oestrogens and progestns. It also acts at sertoli cells in testicles to initiate spermatogenesis
What is the target of LH in men?
Leydig cells to make testosterone
What is the target of prolacitn?
Mammary glands to initiate and maintain milk production
What is the only anterior pituitary gland hormone that has not been shown to have a negative feedback loop?
Prolactin. It’s production is suppressed by dopamine, however there is no clear mechanism by which increased prolactin leads to increased dopamine.
What is the purpose of the ‘small diameter’ neurons in the hypothalamus?
They produce the ‘releasing hormones’ that travel via the pituitary portal system to act on the ‘troph’ cells of the anterior pituitary.
What is the purpose of the ‘large diameter’ neurons of the hypothalamus?
These neurons, with bodies in the supraoptic nuclei and the paraventircular nuclei, have axons that project into the neurohyphophysis and release oxytocin and ADH for them to be released.
What is neurophysin?
Neurophsyin is co-secreted with ADH from the neurohypophysis as part of its processing. Failure for the neurophysin to properly cleave from the ADH can cause issues with both elements secreting properly. This can lead to partial or complete diabetes insipidus.
What causes pseudohypoparathyroidism?
Theses patietns have a defect in their PTH G protein coupled receptor - this leads a PTH that doesn’t do anything. These patients end up with high PTH levels, low serum calcium and high serum phosphate.
What is made by the adrenal medulla?
Adrenaline (mostly) and noradrenaline. Both are derived from the maino acid tyrosine and are considered ‘amine’ hormones.
What is the the hormone that is in excess in carcinoid syndrome that causes the symptoms?
Serotonin
Outside the CNS, where is serotonin typically produced?
It’s produced in the neuroendocinre cells that are found in GI and respiratory tracts.
What are the symptoms of carcinoid syndrome?
Spontaneous and intense flushing ina typical pattern involving the head and necke, associatedd with diarrhoea, bronch9ospasm, and occasionally righded valvular disease. Typically the tumours responsible are in the intestines or are in the bronchial trees.
What type receptors are the adrenoreceptors?
They are all G protein-coupled receptors.
What is the precursor molecule for all steroid hormones?
Cholesterol (mostly from LDL) -> pregnenolone (happens in the adrenal glands, testes or ovaries)
What are the only two organs in the body with tissue capable of forming hormones out of cholesterol?
1) the adrenal glands and 2) the gonads
How are steroid hormones transported around the body?
They are hydrophobic, so they usually bind to binding protein to move around the body.
Which of T3 and T4 has higher affinity for intracellular thyroid hormone receptors?
T3
Where does T3 come from?
It’s manufactured in two places. 1) along with thyroglobulin and T4 in the follicular cells of thyroid. T3 and T4 are secreted in there free forms, wresteled from thyroglobulin during secretion. 2) in peripheral tissues, particularly the liver, T4 is cconverted into T3 and secreted into the plasma
How is GH secreted?
It is stored in vesicles, as with all amine peptide hormones (cf with steroid hormones), and then released in a highly variable, pulsatile, minute - minute, manner. This makes it difficult to measure. Instead, IGF-1 should be measured.
When is GH usually secreted?
~70% of growth hormone is thought to be secreted during slow wave sleep.
What are the steroid hormones?
Cortisol, aldosterone, oestridiol, progesterone and testosterone.
What pituitary hormone increases in response to Ghrelin?
Produced by the stomach and also by the arcuate nucleus of the hypothalamus - ghrelin leads to increased secretion of growth hormone. Ghrelin also stimulates appetite.
What impacted does hypothalamic somatostatin have on growth hormone production?
Somatostatin is produced in the hypothalamus and transported by the portal venous system where it inhibits the production of growth hormone from the somatotrophs (thus ‘somato’ ‘statin’). Note that somatostaint is also produced by pancreatic islet cells (delta cells) and D cells in the GI tract - although the types outside the CNS have slightly different structure.
How does insulin-like growth factor negatively feedback to reduce the production of growth hormone?
3 ways. It stimulates the production of hypothalamic somatostatin, which inhibits the anterior pituitary somatotrophs from making GH. IGF-1 also directly acts on the anteior pituitary directly, downregulating GH production. IGF-1 also acts on the hypothalamus, down regulating the production of GHRH (growth hormone releaseing hormone)
What type of receptor does growth hormone bind to?
Tyrosine kinase associated receptor - within the JAK2 family
What is the impact of growth hormone on blood sugar regulation? What does this mean for patients with acromegaly?
Growth hormone (not IGF-1/2), which has wildly fluctating and pulsatile release mainly at night, is said to act like an anti-insulin - increases lipolysis, increases gluconeogenesis, decreases muscle uptake of glucose. As such patients with acromegaly often end up with glocuse intolerance or frank diabetes.
What are the actions of IGF-1?
Unlike GH which acts like an ‘anti-insulin’ IGF-1 acts very much like insulin. It increases the uptage of glucose by muscle and fat, encourages lipogenesis, stimulates amino acid uptage, stimulates protein synthesis. Noteably however, IGF-1 has a lower effect on circulating blood sugar than insulin, and continues to promote growth whilst having a small impact on circulating blood sugar.
What are the actions of IGF-2?
Very similar to IGF-1, which is very similar to insulin (e.g. glycolysis, lipogenesis, glycogenolysis, protein synthesis etc. The main difference between IGF1/2 is that IGF 2 is not as dependent on GH for its production.
Apart from growth hormone, and the hormones it stimulates production of (IGF1/2), what other hormones are important for growth?
T3/4, insulin, glucocorticoids, and sex hormones
What cancer is associated with abuse of androgenic anabolic steroids?
Hepatocellular carcinoma
Where is the satiety centre located?
Ventromeial nucleus of the hypothalamus
Where is the hunger centre located?
Lateral hypothalamus. If this area is ablated, animals completely lose the will to eat.
What is leptin?
It’s a hormone produced by adipocytes that influences the hypothalamic satiety and hunger centres to reduce appeptite.
What is the action of POMC and neuropeptide Y?
These are produced in the arcutate nucleau of the hypothalamus in respons to stimulation from insulin and leptin. They act on hunger and satiety centres to reduce appetite and increase sympathetic activity to consume more energy.
Where is synthesised, but not circulating, thyroid hormone stored?
It’s stored in proteinacious material as an extracellular pool, but surrounded by and stuck to the thyroid, called thyroid colloid. The protein that makes up the thyroid colloid for the most part is thyroglobulin.
What is the hormone made by the thyroid gland that is not T3/T4? What is the name of the cell that makes it?
Calcitonin, but by the C cells.
How is idodide (iodine anion) taken into follicular thyroid cells?
By the NIS! (the sodium/iodide cotransporter)
How does thryoid hormone make its way out of the thyroid colloid pools?
When demand for thyroid hormone is detected (TSH receptor activity) the follicular cells take up iodinated thyroglobulin, hydrolyze it, and realese T4 and T3 intoth the blood for binding to thyroid binding globulin and other proteins.
What percentage of free thyroid hormone released from the thyroid is T4?
~90%. The remaining 10% is T3.
What percentage of T3 comes frome the thyroid and what comes from peripheral conversion from T4?
25% is from the thyroid, the remainder comes from T4->T3 conversion.
What are the most common clinical scenarios that lead to elevations in thyroid binding globulin?
Pregnancy, oral oestrogen therapy, hepatitis, chronic heroin use.
What can lead to reduced thyroid binding globulnin concentrations?
Nephrotic syndrome, chronic steroid use, liver failure.
If thyroid binding globulin levels change, do free T4/T3 levels also change?
No. The protein bound thyroid acts a buffer to enable a near constant level of free T4 and T3 to have their actions on peripheral tissues.
What tissues can deidonate T4 -> T3?
Type 1 deiodinases work in the liver, kidneys and thyroid (peripheral) and type 2 deiodinases work in the pituitary and central nervous system (slighly different enzymes between periphreal and central conversion).
Sick euthyroid syndrome is the result of what?
Stress causes reduction in Type 1 deiodinases causing a reduction in circulating T3. However, the type 2 deiodinases that work in the pituitary gland are not impacted by this, and so the TSH producing thyrotrophs continue to receive the same T3 concentration and the same amount of TSH is produced. This leads to sick euthyroid patients having low T3 with normal T4 and low/normal TSH.
What hormones do hypothalamic neurons
and thyrotrophs of the anterior pituatary respond to limit the creation of TSH?
T3 - converted from T4 in the thyrotrophs and arcuate nucleus cells of the hypothalamus by type 2 deiodinase. This sends a negative feedback signal. In the the hypothalamus this leads to reduced producdtion of thyroid releasing hormone. In the pituitary this leads to reduced TSH production.
Which hormone is, as a percentage, more likely bound to Thyroid bidning globulin in plasma? (T4 or T3)
T4. T3 is more likely to be free. This contributes to somewhat to why it is more biologically significant - it has a 25x higher free to bound ratio. Furhter, once intracellulur, a proprotion of T4 is convereted to T3, which means that the cytoplasmic concentration of each ends up being about the same. Then, the nuclear receptors for thyroid hormone are 10x more likely to bind to t3 than t4. This means that at the end of theday, T3 is primarily responsible for the biological impacts of thyroid hormone.
By what mechanism does hyperthyroidism lead to tremor, sweathing, increased temporature and tachycardia?
Likely increased expression of beta adrenergic receptors
What is the target of abs in patients with Graves’ disease?
The TSH receptor on the follicular cells of the thyroid. They activate the TSH receptor and sitmulate the unregulate production of T4/T3
What protein is typically targetted by autoantibodies in patients with hypothyroidism secondary to hashimotos’s thryoiditis?
Anti-follicular cells, anti-microsomes, and inhibitory (rather than activating) binding to the TSH receptor. However, the most useful are the anti thyroglobulin and anti-TPO (thyroperoxidase) abs. Note that these abs are quite common in the well population - they can be found in low levels at least in up to 20
What protein is typically targetted by autoantibodies in patients with hypothyroidism secondary to hashimotos’s thryoiditis?
Anti-follicular cells, anti-microsomes, and inhibitory (rather than activating) binding to the TSH receptor. However, the most useful are the anti thyroglobulin and anti-TPO (thyroperoxidase) abs. Note that these abs are quite common in the well population - they can be found in low levels at least in up to 20% of the population, despite clnically significant hypothyroidism only impacting 1-2% of the population.
What is thought to initiate damage in hashimotos hypothyroidism - B-cells or T cells?
T-cells. This is because the abs found in hashimotos hypothyroidism are polyclonal and rise after damage begins in the thyroid. Although autoantiboides in this condition are likely a secondary phenomena, they are typically IgG1/3, and so they are able to fix complement and likely contribute to damage later in the disease.
When does the fetal thyroid gland start producing thyroid hormone?
2nd trimester. In 1st trimester, it is critical that the mother is providing the right amount of thyroid hormone. It is controlversial how much T3/T4 traverses the placenta. Some argue that the placenta produces T3 from T4.
What things trigger the secretion of aldosterone from the glomerulosa?
Angiotensin II, ACH, plasma potassium.
What dynamic test is performed to establish a diagnosis of acromegaly if there is ambiguity about the diagnosis?
Oral glucose tolerance test. In patients without an unregulated source of GH, GH levels will reduce reliably 2hrs after the administration of 75mg of oral glucose. If the GH level does not reduce, it is likely the patient has acromegaly.
What are the common physical features associated with a diagnosis of acromegaly?
Coarsening of facial features (frontal bossing, large nose, jaw enlargement, separation of teeth and macroglossia), skin thickening and hypertrophy, carpal tunnel syndrome, arthropathy (due to cartilage overgrowth), OSA, sexual dysfunction.
Why does pituitary stalk compression lead to increased secretion of prolactin?
Because dopamine, that is produced in the hypothalamus, is delivered to the lactotrophs of the anterior pituitary via the stalk and causes prolactin inhibition. Stalk compression reduces the amount of dopamine making it to the anterior pituitary, and prolactin secreion is free to increase.
Other than changes to physicial appearence, what other coniditions are likley to result from acromegaly?
Hypertension and arrythmias are thought to occur more frequently as a result of hypertrophic cardiomyopathy. Goitre and prostate enlargement are not uncommon. Increased appetite, polyuria and polydipisa are seen due to glucose intolerence.
Other than changes to physicial appearence, what other coniditions are likley to result from acromegaly?
Hypertension and arrythmias are thought to occur more frequently as a result of hypertrophic cardiomyopathy. Goitre and prostate enlargement are not uncommon. Increased appetite, polyuria and polydipisa are seen due to glucose intolerence. Headaches secondary to the pitutary mass are common.
Acromegaly is sometimes the presenting problem associated with one of the MEN (multiple endocrine neoplasia) syndromes. Which one?
MEN1. Pituitary adenomas are present in 10-40% of patients with this condition. MEN1 is due to germline mutations in the MEN-1 gene, which encodes for a protein called menin. The other tumours seen in this condition are parathyroid adenomas leading to hyperparathyroidism, and pancreatic neuroendocrine tumours.
What is the definition of acromegaly remission?
Normal IGF-1 levels, and nadir GH after oral glucose testing.
What cancers are associated with acromegaly?
Colon and thyroid. Colonoscopy is recommended for all patietns with acromegaly, and thyroid US should be performed if there is a nodular thyroid gland.
What is the definition of a microadenoma?
<10mm in diameter
What is the first line treatment for acromegaly secondary to a growth hormone producing pituitary adenoma?
Transphenoidal debulking surgery. 70-90% remission is achieved with microadenomas, and 30-60% for macroadenomas.
On histopathology of a growth hormone producing adenoma, what do you expect to see if it was growing agressively?
Sparsely granulated adenomas are more aggressive than densely granulated ones.
If sugery fails to induce remission for a patient with a growth hormone producing adneoma, what is the next line of therapy?
Somatostain analogues. Recall that somatostatin is a negative regulatory of growth hormone production. First generation options - octreotide and lanreotide - are available and work by binding to SST-2/5 receptors. However, more effective second generation psireotide (high SST-5 affinity) is more effective.
What are the adverse effects of somatostatin analogue therapy used for acromegaly?
Octrotide and lanreotide cause gall stones or biliary sludge in up to 25% of patients. They, as well as the second generation pasireotide, also cause hyperglycaemia and can cause frank diabetes.
After surgery and somatostatin analogues, what other oral treatment options are available for acromegaly?
Dopamine agonists - particualalry cabergaline - can reduce the concentration of GH and IGF-1 in about 1/3 of patietns. However cabergoline carries a lot of potential side effects. Of great concern - valvular heart disease, and fibrotic disease of the pericardium, lungs, pleura or retroperiotoneal. Other general concerning adverse effects common to dopamine agonists: nausea, vomiting, abdominal pain, constipation, headaches, dizziness, orthostatic hypotension, wekaness, fatigue, nasal congetsion, peripheral oedema, digital vasospasm, dyskinesias, impulse control disorders, drowsiness.
What is pegvisomant?
It’s a recombinant growth hormone analogue that competes with GH for receptor binding used to treat acromegaly. It’s highly effective at normalising IGF-1 levels, but is very expensive. It doesn’t shrink pituitary somatotroph adenomas though, as it doesn’t target GH production.
