Section 4-adrenal gland Flashcards
Describe adrenal glands: their name, weight, place
v Paired glands v weight of 8-10 g v situated above and medial to the kidneys
What is the structure of adrenal glands
- surrounded by fibrous capsule and adrenal divided into functional layers
- cortex is about 90 % of adrenal mass, inner medulla about 10 %
- cortex has 3 zones: Zona f. is thickest (about 75 % of cortex) there is cortex and medulla,
- In the order from outside to inside
- capsule
- zona glomerulosa
- zona fasciculata
- zona reticularis
- adrenal medulla
which part of the adrenal gland secrete what hormone
for all hormones synthesized in medulla what is the common precursor
cholesterol->pregnenolone
what is the common enzyme thant converts cholesterol into pregnelone
p450scc
On inner mitochondrial membrane, P450scc (side-chain cleavase) betwen carbon 17 and 20 cleaves the
side chain of cholesterol to produce pregnenolone
what specific enzymes are synthesized only by the cells producing cortisol, aldosterone, androstenedione
cortisol- p450c17
aldosterone-aldosterone synthase
androstenedione- 17,20 lyase
sources of cholesterol
Main source is the diet, but
can also be synthesized from acetyl-CoA
what determines what steroid is synthesized in a cell or tissue
Cell specific expression of enzymes determines what
steroid is produced in a cell or tissue
where enzymes in sterod producing cells are located
vSome enzymes are in the mitochondria others in the
endoplasmic reticulum. Steroid intermediates shuttle
back and forth
When steroid is being synthesized, steroid metabolites needs to shuttle between these organelles
How steroids are different from each other
vMost steroids differ by minor modifications of side
groups, often hydroxyl groups
How intitation of steroidogensis happen and describe this process ( by which protein is regulated, where happens)
- The first step common toall steroids is the formationof pregnenolone from cholesterol
- Takes place in the mitochondria
- Uptake of cholesterol is a rate limiting step and
- Regulated by StAR protein (Steroid Acute Regulatory
protein)
- On inner mitochondrial membrane, P450scc (side-chain cleavase) cleaves the side chain of cholesterol to produce pregnenolone
How StAR is regulated
StAR is cAMP-inducible gene and increases in response to tropic hormones
(i.e. ACTH in the adrenal gland and gonadotropins in gonads
When cAMP is increased, STAR concentrations increase, any protein hormone that can increase cAMP
Is cortisol stored?
No
Half life of cortisol is
70-120 min
what happens to cortisol after 70-120 minutes
- Converted to inactive
cortisone and other
metabolites by liver (for
excretion in urine) and by
other target cells
- In some cells, cortisone can
be reconverted to cortisol
How cortisol secretion is regulated
Function of cortisol (brain, CHO, adipose, skin, GI, growth)
Multiple functions depending on cell type
- brain
- depression
- psychosis
- carbohydrate metabolism
- increased hepatic glycogen deposition
- increased peripheral insulin resistance
- increased gluconeogenesis (promotes protein catabolism)
- increased free fatty acid production
- overall diabetogenic effect ( more glucose is circulating, but not uptaken and protein breakdown)
- GI
* peptic ulcerations - Growth and developement
* Decreased linear growth - Skin
- skin thinning
- muscle atrophy
- Adipose
* promotes visceral obesity
on what hormones cortisol has an effect
Decreasaed LH, FSH, TSH release
Decreased GH secretion
How cells save themselves from prolonged action of cortisol
Type 2 11 beta HSD
converts cortisol to cortisone ( more water soluble) can be excreted in kidneys
Why cortisol/cortisone conversion is important in relation to aldosterone
- Cortisol can activate the aldosterone receptor
- vThe plasma concentrations of cortisol are about 100-1000 fold higher than the concentration of aldosterone
- Aldosterone responsive cells therefore have to inactivate cortisol in order to respond specifically to aldosterone
Enzyme deficiency of HSD 11 beta 2 can lead to
vEnzyme deficiency of HSD11B2 → “AME” syndrome
(apparent mineralocorticoid excess)
vAt high concentrations cortisol interacts with MR
leading to Aldosterone- like symptoms
when there is high cortisol , it can act as aldosterone, causing problems
why there are hydrocortisone in creams
Hydrocortisone creams are used on the skin to treat swelling, itching and irritation. They can help with skin problems such as:
eczema
Skin has HSD1, so can convert back to cortisol
where cortisone can be converted back to cortisol , where does it go and what can happen if there is an overload of cortisol
kidney and other cell types inactivate cortisol to prevent inappropriate
activation of the aldosterone receptor – when cortisol levels are too
high HSD2 is
v overwhelmed and cortisol stimulates Na+/K+ exchange in kidney
causing
v hypokalemia and hypertension
How bicohemically cortisol acts on cells
Acts by increasing transcription of specific genes via activating a
cytoplasmic transcription factor (Class I receptor i.e. cytosolic)
needs to dimerize to be active
Effects of cortisol are generally opposite to
Effects are generally opposite to insulin and similar to GH (i.e.
increase in blood glucose) at the expense of protein and fat. Action
depends on the target cells
increased catabolsim in muscles, adipocytes and lymphocytes and increased synthesis of glycogen and gluconeogenesis
What effect cortisol has on liver
vOverall: Anabolic
effect in the liver
vIncrease of blood
glucose despite the
increase in
glycogen storage
How cortisol can be used as an anti-inflammatory drug and what aree the consequences
- Cortisol inhibits the immune response and hence is antiinflammatory
- Widely used to treat inflammatory conditions (i.e. rheumatoid arthritis and other immune disorders)
- Leads to atrophy of the lymph nodes and thymus (activation of apoptosis)
- Decrease in number of lymphocytes and antibody production
- Patients become susceptible to infections
- Cortisol acts by the same dimer system and acts on antibody transcription
How cortisol modulates other hormone action
v Sensitizes arterioles to the action of norepinephrine
v Permissive effect on the action of norepinephrine on
carbohydrate metabolism (glycogenolysis →
hyperglycemia)
(hypertension)
How cortisol can act on CNS
Apart from depression, it can increase activity of CNS leading to euphoria
Can cortisol act as other hormones
v Can act as a mineralocorticoid (increase of extracellular
fluid) because it interacts with the mineralocorticoid
receptor.
Primarily cortisol is regulated by ___
in what time of the day secretion of cortisol is the highest
ACTH
in the early morning, it follows the pattern of ACTH
Why average level of cortisol is increased
Average level is increased due to the summation of more frequent pulses
CRH can be increased by
Diurnal rhytm
Stress, fever, exercise
How cortisol is transported in the body, how much is transported in what form, how proteins protect cortisol
- Corticosteroid Binding Globulin (CBG = Transcortin)
- Synthesized by the liver & has high affinity for cortisol
- Binds about 75 % of all cortisol in the plasma,about 10 % is “free” and 15% is bound to serum albumin
- Bound cortisol is protected from inactivation by the liver i.e.
maintains a pool of circulating cortisol by delaying metabolic
clearance
Increased cortisol leads to what disease
Cushing syndrome
Cyushing syndrome: what happens
Cortisol overproduction can happen in cushing disease because
- v CRH producing tumor
- v ACTH producing tumor
- v Lack of feedback control by cortisol
- v Cortisol producing adrenal tumor
- v Iatrogenic (greek “brought forth by a healer”) - most common cause resulting from chronic glucocorticoid therapy
treatment of cushing syndrome
Treatment is aimed at removing
the cause of hypersecretion
without permanently damaging
the adrenal or pituitary (would
require life long replacement
therapy)
v microsurgery, various forms of
radiation therapy and
pharmacologic inhibition of
ACTH secretion
Adrenal hypofunction leads to what disease
Addison disease
addison disease symptoms
vMost commonly due to destruction of the adrenal
gland by an autoimmune response
vFatigue, weakness, faintness, nausea
vVomiting
vLow blood pressure
vSalt craving (because of low blood pressure and volume)
vPain in muscles and joints
vExcessive freckling (release of MSH as part of
opiomelanocortin)
How addison crisis pathway with cortisol happens
what hormone does zona glomerulosa produce and what is its function
aldosterone
- Recovery of Na+ in the kidney and enhanced K+secretion into the urine to balance charge difference
- Therefore, adjustment of extra-cellular fluid (ECF), including blood volume
how physical attributes in homeostasis of blood correpsond to the control mechanisms of the system
physiological changes that influence postively and negatively sodium appetite
and also thirst
what is the primary resource to restire Na balance ( thirst of sodium appetite)
At first thirst increases and if it is not enough, then sodium increased
what is the major determinant of the blood pressure
The diameter of arterioles (artery, arterioles, capillaries) is a major determinant of the
blood pressure in the arteries and controls the
distribution of the blood supply to tissues
describe RAAS
v Renin from afferent arterioles in kidney
converts angiotensinogen to angiotensin I
v ACE from endothelial cells of lungs
converts angiotensin I to angiotensin II
v angiotensin II stimulates aldosterone
secretion
does ACTH influence aldosterone secretion
Modest effect
Angiotensin II function
v increases Na+ absorption and K+ excretion
v Water retention, higher blood pressure
is angiotensin is secrted somewhere else int he body except kidney-liver-lung
Renin also found in the brain. Local
production of angiotensin II ? Induction of
thirst?
not sure about the answer
what cells secrete renin
Juxtaglomerular cells
what juxtaglomerular apparatus sence
v Macula densa cells detect Na+ levels in kidney tubule
v Juxtagolomerular cells detect blood pressure
aldosterone is under the main influence of
RAAS
how angiotensin is disactivated
renin secretion is stimulated by
decreased renal arterial pressure
decreased sodium in renal tubualr fluid
increased renal sympathetic nerve activity
what 2 destinies angiotensin II has
angiotensin II can have 3 types of responses (speed)
rapid
slow
remodeling
describe acute effects of angiotensin II
Sympathetic nervous system stimulation causes vasoconstriction of most blood vessels
slow response of angiotensin II
what does it mena that angiotensin II have remodeling effects
how aldosterone functions
aldosterone through TF influence->action on structural protein of Na transport ( into the cells) and increasing regulatory proteins-kinases (SGK and K-Ras) that induces K-Na-ATPase
sodium transport happens in
vNa+ transport in
vdistal tubules of kidney
vcolon
vSalivary and Sweat glands
aldosterone will influence all of them
function of aldosterone on the distal tubule cells
Aldosterone activates apical channels and more Na gets into the cell, so more Na-K ATPase
- Na-K-ATPase , which keeps a particular voltage -60 mV),, will shuttle K from blood to the lumen of the distal tubule
- Because Na coming in, aquaporin open and leads to reabsoprtion of water ( increased volume and Na)
aldosterone acts mainly on what types of cells
v Mainly: Distal tubules and collecting ducts of the kidney.
v Also on other secretory systems (sweat glands, salivary glands,colon)
summarize what does aldosterone do what is the net effect and what is a lag period of aldosterone
v Promotes plasma retention of Na+ and excretion of K+
and H+ into the lumen of the tubules
v Sensitizes arterioles to vasoconstrictor agents (to modulate activity of catecholamines ,for example)
v Net effect: Rise in plasma volume and hence blood
pressure
v Response has a lag period of 1h, reflecting that
aldosterone induced enzymes have to be synthesized
de novo
what is conn’s syndrome
Hypersecretion of aldosterone usually caused
by adrenal hyperplasia (60 %) or tumor (40%)
what is happening in conn’s syndrome
- vExcess excretion of K+ and H+
- vSerum alkalosis and neuropathy (hypocalcemia)
- Increased water retention
- Increased Na reabsorption
- Increased blood pressure
what are natriuretic peptides
peptides that increase the excretion of H2O and Na
produced in the heart muscle and stored in granules
How natriuretic peptides function and where the receptors for it are
- Receptors are present in the glomeruli, medullary collecting ducts of the kidney, the zona glomerulosa of the adrenal cortex and in peripheral arterioles
- v Increases glomerular filtration
- v Reduces blood volume and pressure
where do sex steroids are normally synthesized and what role kidneys play in it
- Sex steroids are mainly synthesized in the gonads (Females: estrogens and progestogens; Males: androgens) –regulated by gonadotrophins
- v Adrenal cortex (mainly zonareticularis) contributes to the production of DHEAS and androstenedione – regulated by ACTH and hypothalamic CRH.
- v Can be converted to testosterone in peripheral tissues.
what is the role of sex steroids produced in adrenal gland
Role not entirely clear. Important for
body hair growth in females
.
v Responsible for growth spurt in
middle childhood (adrenarche) -Adrenarche occurs independently of an increase of estrogens, androgens, or gonadotropins associated with puberty
what is congenital adrenal hyperplasia
Excessive androgen production-> Masculinization of genitalia
explain what hormally happens during congention and why there is CAH
what defect in the organism happens that causes congenital adrenal hyperplasia
why congenital adrenal hyperplasia occur, is it frequent , how treated
Frequency of classical CAH 1:13000 in
general population
v Both copies of 21-hydroxylase (P450c21)
mutated
v Many mutations result in partial loss of
function
v And masculinization is not as extreme
v Trt: surgical correction at birth
total mass of medulla is
1 g
how adrenal medulla get its tasks
- vAdrenal medulla and chromaffin cells are part of the
sympathetic nervous system (CNS)
- vCoordinate fight-flight response to alarm by increasing
b. p. and cardiac output, and dilating pupils - vPreganglionic neurons release acetylcholine to stimulate
medulla cells to release hormones (catecholamines)
2 types of catecholamines synthesized in medulla, the pathway, what is the rate limiting step, how epinephrine is converted to noreponephrine and what is the proportion of epinephrine to norepinephrine
- Catecholamines (norepinephrine and epinephrine) synthesized from tyrosine
- Hormones in the adrenal medulla are released in response to appropriate stimuli
- 80 % of released catecholamines are epinephrine to 20 % norepineprine
- tyrosine-> dopamine->norepinephrine
how epineprine and norpinephrine are disactivated
Inactivated by monoamine
oxidase (MAO) and COMT
(catechol-O-methyltransferase)
pathways
what other hormones are secreted from medulla (apart from adrenalin and noradrenalin)
vGranules also contain met-enkephalin and and
leu-enkephalin (related to endorphins).
vThey are co-excreted with the catecholamines
vEnkephalins may block neurotransmitters (like
morphine)
v act as an endogenous analgesics (runners
overcoming pain and being euphoric)
how fight-or-flight response function
what are acute effects of adrenalin and noradrenalin
Acute: integrated adjustment of many complex processes in organs vital to the response (e.g., brain, muscles, cardiopulmonary system, liver)
actiovation of organs during fight-or flight happens at the expense of
Occurs at the expense of other organs less immediately involved (e.g., skin, GI).
what is epinephrine and noradrenalin role in the body
- Epinephrine: rapidly mobilizes fatty acids as the primary fuel for muscle action
- v increases muscle glycogenolysis
- v mobilizes glucose for the brain by increasing hepatic glycogenolysis and gluconeogenesis
- v preserves glucose for CNS by decreasing insulin release leading to reduced glucose uptake by muscle/ adipose
- v Increases cardiac output
- v Norepinephrine elicits responses of the CV system - increasing blood flow and decreasing insulinsecretion.
what receptors bind to adrenalin and noradrenalin
vα and β1 receptors bind
epinephrine and norepinephrine.
β2 receptors bind primarily
epinephrine (GPCR)
what is the drug salbutamol and what is it used for
Salbutamol activates β2 receptors
and dilates bronchioles (relief of
asthma); but does not affect beta1
receptors in the heart.
aplha, beta 1 and 2: potency for e and NE, action and target tissue/cells
differences between epinephrine and NE
v Epinephrine >> norepinephrine – in terms of cardiac
stimulation leading to greater cardiac output (b
stimulation)
v Epinephrine < norepinephrine – in terms of constriction
of blood vessels – leading to increased peripheral
resistance – increased arterial pressure
v Epinephrine >> norepinephrine –in terms of increasing
metabolism
adrenomedullary deficiency can happen due to
surgery, trauma.etc.
v Also if cortisol levels are suppressed for any reason
(high concentration of cortisol req’d for transcription of
PNMT) resulting in epinephrine deficiency
adrenomedullary disorders can happen due to
Hypotension, hypoglycemia (CNS and glucocorticoids are more susceptible)
can we live without E and NE
what is pheochromocytoma
tumor overproducing catecholamines
what is the prevalence of pheochromocytoma and its symptoms
Relatively rare but often not diagnosed until autopsy (about
200-1000 per million) and about 1/3 cause death prior to
diagnosis
• headache
• hypertension
• sweating
• palpitations
• chest pain
• anxiety
• glucose intolerance
• increased metabolic rate
