Week 9 -Endo Flashcards
What are each of these hormones made from:
Peptide?
Steroids?
Amines?
peptides- amino acids
steroids- cholesterol
amines- tyrosine
What are steroid hormones synthesized and secreted by?
- adrenal cortex
- gonads
- corpus luteum
- placenta
What are the steroid hormones?
- cortisol
- aldosterone
- estradiol and estriol
- progesterone
- testosterone
- 1,25-dihydroxycholecalciferol
What are the amine hormones?
- catecholamines (epi, norepi, dopamine)
- thyroid hormones
Define long loop feedback inhibition.
the hormone feeds all the way back to inhibit the hypothalamus
What is the pituitary gland aka?
the hypophysis
What functions does the anterior pituitary carry out?
The posterior pituitary?
- anterior: endocrine function
- posterior: neurologic function
What connects the pituitary gland to the hypothalamus?
the infundibulum
What does the posterior pituitary secrete?
- ADH
2. oxytocin
What does the anterior pituitary secrete?
- TSH (thyroid stimulating hormone)
- FSH (follicle stimulating hormone)
- LH (lutenizing hormone)
- GH (growth hormone)
- prolactin
- ACTH (adrenocorticotropic hormone)
Why is the blood supply to the hypothalamus unique?
most of the blood supply is venous, supplied by long and short hypophysial portal vessels
What cell type secretes TSH?
Where are they located?
- thyrotrophs
- the anterior pituitary
What cell type secretes FSH?
Where are they located?
- gonadotrophs (also makes LH)
- the anterior pituitary
What cell type secretes LH?
Where are they located?
- gonadotrophs (also makes FSH)
- the anterior pituitary
What cell type secretes ACTH?
Where are they located?
- corticotrophs
- the anterior pituitary
What cell type secretes growth hormone?
Where are they located?
- somatotrophs
- the anterior pituitary
What cell type secretes prolactin?
Where are they located?
- lactotrophs
- the anterior pituitary
What is unique about the secretory pattern of growth hormone?
secretion occurs in a pulsatile pattern, especially during sleep
What are potent stimulators for growth hormone secretion?
hypoglycemia and starvation
What molecule stimulates release of growth hormone?
GHRH (growth hormone releasing hormone)
What molecule inhibits release of growth hormone?
What is it released by?
How does it work?
- somatostatin
- the hypothalamus and pancreas delta cells
- acts by blocking the action of GHRH on the somatotroph
Why is prolactin usually inactive in non-lactating individuals?
prolactin secretion is tonically inhibited by dopamine from the hypothalamus, which overrides the stimulatory effect of TRH/PRH
How does prolactin participate in negative feedback?
it inhibits its own secretion by increasing synthesis/secretion of dopamine from the hypothalamus
What is the major hormone concerned with regulation of body fluid osmolarity?
ADH
What is ADH aka?
vasopressin
What stimulates release of ADH?
Where does it act?
What does it do?
- an increase in serum osmolarity sensed by osmoreceptors in the anterior hypothalamus
- distal tubules of the kidney
- increases water absorption
What does the adrenal medulla secrete?
catecholamines epinephrine (80%) and norepinephrine (20%)
What is each zone of the adrenal cortex called?
What does each layer make?
- zona glomerulosa, mineralocorticoids
- zona fasciculata, glucocorticoids
- zona reticularis, sex hormones (androgens)
What is the basis for the specialization of the layers of the adrenal cortex?
the presence or absence of the enzymes that catalyze various modifications of the steroid nucleus
What is the precursor molecule for all things made in the adrenal cortex?
cholesterol
What is a primary endocrine disorder a problem with?
secretion by the target gland
What is a secondary endocrine disorder a problem with?
secretion by the pituitary gland
What is a tertiary endocrine disorder a problem with?
secretion by the hypothalamus
What is the metabolic clearance rate of a hormone?
the volume of plasma cleared of a hormone per minute
How can hormones be removed from plasma?
- metabolism or binding in the tissues
- hepatic excretion
- renal excretion
What is the relative time of onset of action for protein-bound hormones?
What is their relative length of action?
- slower onset
- longer duration of action
Peptide hormones:
Onset fast or slow?
Duration long or short?
Method of action?
- fast
- short
- surface binding to activate second messengers or ion channels
Steroid/thyroid hormones:
Onset fast or slow?
Duration long or short?
Method of action?
- slow
- long
- alter gene transcription or translation
What class of hormones does the anterior pituitary secrete- peptide, steroid, or amine?
peptide
What molecule stimulates the release of TSH?
Any notable negative control?
- TRH (thyrotropin-releasing hormone)
- none
What molecule stimulates the release of ACTH?
Any notable negative control?
- CRH (corticotropin-releasing hormone)
- none
What molecule stimulates the release of FSH?
Any notable negative control?
- GnRH (gonadotropin-releasing hormone)
- none
What molecule stimulates the release of LH?
Any notable negative control?
- GnRH (gonadotropin-releasing hormone)
- none
What molecule stimulates the release of GH?
Any notable negative control?
- GHRH (growth hormone-releasing hormone) (dominant)
- somatostatin
What molecule stimulates the release of prolactin?
Any notable negative control?
- PRH and TSH, but not really
- dopamine/PIF (dominant)
What is dopamine aka?
PIF (prolactin inhibiting factor)
What pattern of release do all hypothalamic-pituitary axis hormones exhibit?
pulsatile release superimposed on a circadian rhythm
What are the effects of GH?
- most important endocrine regulator of final body size by stimulating linear growth through stimulation if IGF-1 secretion
- opposes the effects of insulin by causing lipolysis in adipose, reducing glucose uptake in muscle, and stimulating gluconeogenesis in the liver
When is the largest release of GH?
What are some other triggers for release?
- during the first 2 hours of deep sleep
2. stress, hypoglycemia, starvation
What is the largest source of plasma IGF-1?
the liver
How is GH secretion turned off?
negative feedback from IGF-1
Why is binding hormones to proteins a good thing?
- increases the half life of the hormone
2. provides a stable reservoir in the blood
What is the primary hormone that controls water balance in the body?
ADH
What causes release of ADH?
How much of a change is needed to produce release of ADH?
What receptor does each use?
- changes in body fluid osmolarity, V2 receptors; increase of only 1%
- drops in blood volume, V1 receptors; drop in 15%
How does ADH respond to a drop in blood volume?
V1 receptors caused generalized arteriolar vasoconstriction in vascular smooth muscle
What are the major functions of oxytocin?
- uterine contraction
- milk let-down
- promotion of maternal behavior
What do thyroid follicles contain?
What, then, is that?
What is it produced by?
- thyroid colloid
- a protein-rich extracellular material
- by follicular cells, endocrine cells around each follicle
What is the major protein in thyroid colloid?
What does it contain as part of its primary structure?
- thyroglobulin
- T3 and T4
What must happen before thyroid hormone can be secreted into the blood?
follicular cells must uptake and hydrolyze the thyroglobulin-linked T3 and T4 to free them
What are the steps in thyroid hormone synthesis?
- iodine trapping by follicular cells
- thyroglobulin made in follicular cells and secreted into the colloid, and iodonation
- conjugation of 2 iodinated tyrosyl gropus to make T3/T4 linked to thyroglobulin
- endocytosis back into the follicular cells, hydrolysis of the T3/T4-thyroglobulin to make free T3/4, as well as DIT and MIT (incomplete molecules that are recycled)
- T3/4 secreted
How much of the secreted thyroid hormones is T3?
T4?
10% is T3
90% is T4
Are T3/T4 found free or bound in blood?
Why?
- bound to plasma proteins
- poorly soluble in water
What are the T3/T4 binding proteins?
- thyroid binding globulin
- transthyretin
- albumin
Which has a greater biological activity, T3 or T4?
T3
How do you get more T3 in tissues if so little is secreted?
How does this happen?
- 75% of circulating T3 is derived from deiodination of T4 in tissues
- types one and two 5’-deiodinase (type three makes an inactive version of T3)
What is the difference between types one, two, and three 5’-deiodinase?
type 1- produces T3 in most target tissues (can be regulated)
type 2- expressed in pituitary gland, where locally made T3 augments the negative feedback inhibition of TSH secretion (does not get turned down, really)
type 3- produces reverse T3, which is inactive
What changes in the T4/T3 system during starvation that allows homeostasis?
type 1 5’-deiodinase production is reduced, allowing a low rate of thyroid hormone secretion, decrease in circulating T3, reducing BMR, and conserving energy stores
What are the primary effects of thyroid hormone?
Increasing metabolism
Beta adrenergic drive
GI smooth muscle activity
- increasing BMR
- induce gluconeogenesis
- coordinate normal growth and development
How do thyroid hormones affect BMR?
- stimulates ‘futile cycles’ that generate body heat
- increases heat production in brown adipose (neonates only) by uncoupling ox/phos
- increases expression of B-adrenergic receptors to indirectly increase metabolic rate
Will increase in thyroid hormone cause hyperglycemia?
No. Even though thyroid hormone causes increased gluconeogenesis, this will be balanced by insulin if the pancreas is properly functional
What does TSH do?
it stimulates all of the steps in thyroid hormone synthesis and secretion by thyroid follicular cells
What can a sustained excess of TSH in the blood cause?
Why?
- hyperplasia of the thyroid
- TSH has a trophic effect
How can you tell the difference between primary and secondary hypothyroidism from a blood test?
- primary: low T3/4, high TSH
- secondary: low T3/4 and low TSH
How can you tell the difference between primary and secondary hyperthyroidism from a blood test?
- primary: high T3/4, low TSH
- secondary: high T3/4 and high TSH
What are symptoms commonly associated with hyperthyroidism?
high metabolic rate, weight loss, heat intolerance, sweating, muscle weakness, tachycardia, tremor
What are the most common causes of hypothyroidism?
Hyperthyroidism?
Hypo- dietary iodine deficiency (most common) or Hashimoto’s thyroiditis
Hyper- secretory tumor or Grave’s disease
What type of cells make up the adrenal medulla?
chromaffin cells
What do chromaffin cells mainly (and minorly) secrete?
What is the stimulus for secretion?
- 80% epi, 20% norepi
- acetylcholine from sympathetic stimulation
What do high levels of cortisol in the adrenal glands stimulate?
Why is this important?
- production of epi
- aids in coordination of the stress response
What hormone is a mineralocorticoid?
What does it do?
- aldosterone
- regulates electrolyte balance in several organs, particularly the kidney by conserving Na and secreting K
What hormone is a glucocorticoid?
What does it do?
- cortisol
- increases blood glucose concentration
What is the rate-limiting step in steroid synthesis?
conversion of cholesterol to pregnenolone by 20,22 desmolase
What enzyme is uniquely required for aldosterone synthesis?
aldosterone synthase
What enzyme is uniquely required for cortisol synthesis?
17a-hydroxylase
Which zone of the adrenal cortex is the largest?
the zona fasciculata
What is the function of cortisol?
- mobilizes glucose via gluconeogenesis
- reduces cellular metabolism of glucose
- reduces sensitivity to insulin
- mobilizes amino acids from muscle
- mobilizes fatty acids
- resists the inflammatory/immune responses
What stimulates cortisol release?
CRH stimulates ACTH stimulates cortisol release
How is ACTH made?
What else is made in the process?
- processing of POMC
- MSH (melanin, hunger), Y-lipotropin, and B-endorophin (prior 2 important in reward systems and addiction)
What is aldosterone secretion controlled by?
angiotensin II, some by K, and weakly by ACTH
What does aldosterone do?
it maintains fluid balance by conserving Na and excreting K
Where is renin produced?
Where is angiotensinogen produced?
- renin made in the kidney
- angiotensinogen is made in the liver
What is a secondary stimulus for aldosterone secretion?
How does it work?
- an increase in plasma K
- depolarizes the glomerulosa cell membrane potentials, causing urinary K excretion
What is Addison’s disease?
What are the major signs and symptoms?
- adrenocortical insufficiency
- cortisol deficiency: hypoglycemia, low rates of gluconeogenesis, hypotension (lack of catecholamines), weakness, fatigue, no cortisol in response to stress
- aldosterone deficiency: hypovolemia and hyponatremia (urinary loss of NaCl and water), and hyperkalemia and metabolic acidosis (from reduced urinary excretion of K and H)
- androgen deficiency: reduced libido and thinning of pubic hair in females (no effects in males)
How can you test the hypothalamic-pituitary-adrenal axis if you suspect adrenocortical insufficiency?
using an ACTH stimulation test, where you administer an ACTH analog and see if the serum cortisol levels increase appropriately
What is hypercortisolism aka?
What produces the signs/symptoms?
What are the signs/symptoms?
- Cushing’s syndrome (secondary only)
- excess glucocorticoid
- hyperglycemia (increased gluconeogenesis)
- muscle wasting and weakness (protein catabolism)
- truncal obesity and moon face (redistribution of body fat)
- hypertension (mineralocorticoid effects of excess glucocorticoids)
What is the cause of primary hypercortisolism?
adenoma of the adrenal cortex (secretory tumor)
What is the cause of secondary hypercortisolism?
maybe a pituitary adenoma, or from excess ACTH, or from an ectopic source of ACTH secretion (small cell lung carcinoma)
What is the cause of tertiary hypercortisolism?
excess CRH
What is Conn’s syndrome?
What causes it?
What are the associated symptoms?
- primary hyperaldosteronism
- an aldosterone-producing adrenal adenoma, causing excessive mineralocorticoids
- hypertension (excessive retention of Na and fluids by kidney)
- hypokalemia (increased urinary K excretion)
- metabolic alkalosis (increased urinary H excretion)
Which is more common, primary or secondary hyperaldosteronism?
Why?
- secondary
- conditions that activate the RAS system (renal artery stenosis, cirrhosis, CHF) are more common than an adrenal adenoma (Conn’s)
What is the most common congenital error in adrenal steroid metabolism?
What does it cause?
- 21a-hydroxylase deficiency
- symptoms of primary adrenal insufficiency (can’t make cortisol or aldosterone)
- accumulation of adrenal androgens (pathway shunting)
- adrenal hyperplasia (high levels of ACTH from loss of negative feedback from cortisol)
What are epi and norepi derived from?
What is the rate-limiting step in their synthesis?
Where does the final step occur?
- tyrosine
- conversion of tyrosine to L-dopa by tyrosine hydroxylase
- only in chromaffin cells
What is release of catecholamines controlled by?
CNS via sympathetic neurons releasing acetylcholine
What stimulates the steps for norepi synthesis?
What stimulates the final enzyme to convert norepi to epi?
- ACTH and sympathetic nerve stimulation
- cortisol delivered via portal blood from the adrenal cortex
What is the major product released by the adrenal medulla?
What is the major sympathetic neurotransmitter released?
- epi
- norepi
What type of receptors does epi have a greater affinity for?
B1 and B2 (although still binds to alpha receptors like norepi)
In the stress response, what are catecholamines responsible for?
What is cortisol responsible for?
- catecholamines = short term response: increased cardiac output, bronchodilation, and elevated blood glucose
- cortisol = long term response: mobilization of glucose, fatty acids, and amino acids, and suppression of the immune system
How are catecholamines broken down?
What is the end product, and how is it disposed of?
- COMT and MAO
- vanillymandelic acid (VMA), excreted in the urine
How do you assess catecholamine synthesis by the adrenal medulla?
measure the levels of catecholamines, metanephrines (intermediate), and VMA in the urine
What is the issue with pheochromocytoma?
Associated symptoms?
- a secretory tumor of the adrenal medulla that hypersecretes catecholamines in episodes
- transient hypertension, palpitations, sweating, increased body temperature, and increase blood glucose
Where are endocrine cells located in the pancreas?
What are the major cell types located there, where are they located, and what do they make?
- islets of Langerhans
- a cells: periphery of islets, secrete glucagon
- B cells: center of islets (majority), secrete insulin, proinsulin, and C peptide
- delta cells: in the middle (few), secrete somatostatin
How can you tell the difference between too much endogenous insulin (insulinoma) vs overdose of exogenous insulin?
Measure C peptide. C peptide and insulin levels will match if the issue is with endogenous secretion.
Why is the arrangement of cells in the islets of Langerhans important?
Blood flows from the center (B cells) to the periphery (a cells). This allows the insulin to bathe the a cells, thereby suppressing glucagon secretion.
When you cleave proinsulin, what are the products?
1 insulin and 1 C peptide
What effect does insulin have on the liver?
- increases metabolism of glucose as fuel
- increases storage of glucose as glycogen
- converts glucose to triglycerides
- stimulates hepatic protein synthesis (and inhibits breakdown)
What effect does insulin have on skeletal muscle?
- increases glucose uptake by stimulating GLUT4
- increases usage of glucose as fuel
- increases glycogen synthesis
- reduces use of circulating triglycerides as fuel (allowing storage in adipose)
Which GLUT transporter is insulin sensitive?
Where is it found?
- GLUT4
- skeletal muscle and adipose tissue
What effect does insulin have on adipose tissue?
- stimulates glucose uptake via GLUT4
- increases glucose storage as triglycerides
- increases expression of lipoprotein lipase, which releases fatty acids from circulating CM and LDL, so they can be stored as triglycerides
What effect does insulin have on ion balance?
insulin increases cellular uptake of K
How would you rapidly treat a patient with hyperkalemia?
insulin infusion (to bring K down) with glucose infusion (to prevent hypoglycemia)
What is an important determinant of the cellular response to insulin?
In what population is this in jeopardy?
- the number of available insulin receptors, the receptor tyrosine kinase
- obesity can reduce expression of insulin receptors
What is the primary regulator of insulin secretion?
blood glucose concentration
What are the steps in the stimulation of insulin secretion in B cells?
- glucose taken up via GLUT2 to make ATP
- increases in cellular ATP/ADP ratio inhibits ATP-sensitive K channels, depolarizing the membrane
- this activates voltage-sensitive Ca channels, causing influx of Ca
- Ca-induced Ca release from ER triggers exocytosis of granules containing insulin
What do sulfonylureas do?
How do they work?
What is a limitation?
- stimulate release of stored insulin, reducing blood glucose
- bind and inhibit the ATP-sensitive K channels (artificially starting the process)
- they do NOT cause increase in insulin synthesis
What things stimulate insulin release?
- blood glucose rise
- increase in arginine, leucine, or lysine
- GIP and GLP-1 (from small intestinal response to glucose)
What are the major incretins?
What is their role?
- GIP and GLP1
- minimize spikes in blood sugar
What can be made from preproglucagon?
What cells makes them?
- alpha cells make glucagon
- intestinal L cells make GLP-1
What organ is the main target for glucagon?
What is its primary effect?
What can glucagon do during starvation (high concentrations)?
- the liver
- to increase hepatic production of glucose (stimulated via gluconeogenesis and glycogenolysis) and ketones
- stimulate lipolysis in adipose and proteolysis in muscle to maintain substrate supply
What are the major ketones?
How do you make them?
- B-hydroxybutyrate and acetoacetic acid
- The breakdown of fatty acids gives off lots of acetyl CoA’s. Put 2 together to make a ketone.
What is glucagon secretion stimulated by?
Inhibited by?
- hypoglycemia, protein (especially arginine and alanine)
- hyperglycemia and insulin
If you eat only protein, how do insulin and glucagon levels change?
both increase, keeping the ratio comparable
What things rapidly counter hypoglycemia?
What things support a sustained response to hypoglycemia?
- rapid: glucagon and catecholamines
- sustained: cortisol and GH
Why are Ca and phosphate homeostasis linked?
they are both present in hydroxyapatite crystals, which form the major mineral component of bone
Why is Ca important?
it is necessary for bone structure, muscle contraction, exocytosis, intracellular signaling, and nerve conduction
What processes put Ca and phosphate into the circulation?
What processes take them out?
- IN: GI inputs and resorption of bone
- OUT: renal excretion and bone formation
In what forms does Ca exist in plasma?
- 45% as free ionized Ca (tightly regulated levels)
- 45% bound to plasma proteins, especially albumin
- 10% complexed with low molec weight ions, like citrate and oxalate
How does the acid/base status of a patient affect free Ca in the blood?
by changing the Ca’s ability to bind to protein, as H competes with Ca to bind to albumin in acidic states
Metabolic acidosis can cause hyper- or hypo-calcemia?
hypercalcemia
In what forms does phosphate exist in plasma?
- 80% as alkaline phosphate (HPO₄²⁻) at normal pH
- 20% as acid phosphate (H₂PO₄⁻)
Which concentration is more tightly regulated in the plasma, Ca or phsophate?
Ca
What exerts dominant control of Ca and phosphate homeostasis?
Secondary control?
Minor control?
- PTH
- vitamin D
- calcitonin
What produces PTH?
chief cells of the parathyroid gland
What does PTH do?
What is the net effect?
- stimulates bone resorption, adding Ca and phosphate to plasma
- decreases renal Ca excretion
- increases renal phosphate excretion
(4. stimulates the final step in vit D synthesis in the kidney)
- increase plasma Ca and decrease plasma phosphate
How is PTH secretion controlled?
- decrease in plasma free Ca (sensed by CaSR) is the most potent stimulus for PTH secretion
- prolonged increase in plasma phosphate stimulates PTH secretion
- vit D has a negative feedback action on PTH secretion
Where does activation of vitamin D take place?
What stimulates the activation?
- in the kidney by 1-hydroxylation
- strongly by PTH, somewhat by low plasma phosphate concentration
What is the activated form of vitamin D called?
What is its function?
- calcitrol
- simulation of dietary Ca and phosphate absorption in the small intestine (and kidney)
What makes calcitonin?
What stimulates its production?
What does it do?
- parafollicular cells in the thyroid
- hypercalcemia
- probably nothing in humans, as it has a weak effect on Ca and phosphate homeostasis
What are the general signs and symptoms associated with hypercalcemia?
“bones, stones, moans, groans, and psychiatric overtones”
- bones: bone pain
- stones: kidney stones
- moans: abdominal pains from constipation or pancreatitis
- groans: general malaise and weakness
- psychiatric overtones: depression, delirium, and coma
What is Metabolic Syndrome?
What does it put you at a higher risk for?
- type 2 diabetes, hypertension, and hyperlipidemia
- cardiovascular disease and stroke
What do acidophils secrete?
Where are they located?
- GH and prolactin
- the anterior pituitary
What do basophils secrete?
Where are they located?
- FSH, LH, ACTH, TSH (FLAT Back)
- the anterior pituitary
