week 3, lecture 2 Flashcards
what are glucocorticoids (i.e. cortisol) do
regulation of blood sugar and physiologic response to stress
what do mineralocorticoids (i.e. aldosterone) do
maintain extracellular fluid (ECF)
volume, sodium and potassium balance
what are catecholamines examples
epinephrine and norepinephrine
glucortcioud example
cortisol
mineralocorticoid example
aldosterone
main vasculature for adrenal glands
▪ Suprarenal artery and vein
* Supplied by abdominal aorta
2 parts of the adrenal glands
cortex (outer) and medulla (middle)
what hormones are found in cortex and medulla
cortex= steroid hormones
medulla= catecholamines (NE and E)
where is adrenal glands located
on top each kidney
blood supply of adrenal glands
- Superior suprarenal arteries - These come from the lower part of the diaphragm
- Middle suprarenal artery - This comes directly from the abdominal aorta (the main artery that supplies blood to the lower half of the body).
- Inferior suprarenal arteries - These come from the renal arteries, which also supply the kidneys.
venous system of adrenals
leave through central vein
right side: goes to inferior vena cava
left side: goes to renal vein
what is the adrenal medulla derived from
neural crest cells
what is the adrenal cortex derived from
mesoderm
derivation of adrenal cortex and medulla
medulla= neural crest cells
cortex= mesoderm
what type of cells can neural crest cells differentiation to in the adrenal medulla
chromaffin cells
what does chromaffin cells prodcue
catecholamines (norepinpehirn and epinephrine)
which nervous system is adrenal medulla very similar too
SNS “overgrown sympathetic ganglion”
Because the medulla originates from the neural crest, its function is closely related to the sympathetic nervous system, which also arises from the neural crest. This connection explains why the adrenal medulla acts like a large sympathetic ganglion.
how does medulla and SNS differ in how it releases signals/hromones
Instead of sending signals through nerve fibres to organs, the adrenal medulla directly releases hormones (epinephrine and norepinephrine) into the bloodstream.
This leads to a system-wide response, increasing heart rate, blood pressure, and energy availability, just like the sympathetic nervous system does, but through chemical signals instead of nerve impulses.
SNS vs medulla
SNS is nerve impulses while medulla is chemical signals (NE and E)
where is adrenal cortex derived from
mesoderm
where are steroid hormones produced
adrenal cortex
aldosterone function
a hormone that regulates blood pressure by controlling sodium and water balance
cortisol function
which helps regulate metabolism, immune responses, and the body’s stress response.
androgens function
which are precursor hormones for sex steroids like testosterone and estrogen.
zona glomérulosa produces
aldosteronez
zona fasciculata produces
cortisol
zona reticualaris produces
androgens
zona glomerulosa
zona fasciculata
zona reticularis
aldosterone
androgens
cortisol
match!!
zona glomerulosa– aldosterone
zona fasciculata– cortisol
zona reticularis– androgens
medulla vs cortex functions
The medulla is more closely tied to the nervous system, while the cortex deals with hormonal regulation of various body systems, especially in response to longer-term stress and metabolic demands.
which zona is the largest and which is the smallest
zona fasciuculata for cortisol is the largest
zona glomérulosa for aldosterone is the smallest
which zone are catecholamines made
medulla (NE and E)
HPA axis overview
- Hormones released by the hypothalamus regulate hormone release from the anterior pituitary
- Anterior pituitary hormones regulate the activity of a range of target endocrine glands
Hypothalamus
* Releases hormones (like CRH, TRH, GnRH).
* These hormones travel to the —-> Anterior Pituitary
* Stimulate the release of pituitary hormones (like ACTH, TSH, LH, FSH).
* Anterior pituitary hormones then act on target endocrine glands (adrenal cortex, thyroid, gonads) to regulate the production of further hormones (like cortisol, thyroid hormones, sex hormones).
what hormones does the hypothalamus release
CRH, TRH, GnRH, GHRH, GHIH, dopamine (prolactin inhibiting factor)
what hormones does the anterior pituitary release
ACTH, TSH, LH, FSH, GH, prolactin
HPA axis purpose
managing responses to stress, regulating metabolism, controlling reproductive functions, and maintaining overall homeostasis.
corticotropin release hormone (CRH) function
[released by the hypothalamus]
stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary.
thyrotropin-releasing hormone (TRH) function
[released by the hypothalamus]
Stimulates the release of thyroid-stimulating hormone (TSH).
Gonadotropin-releasing hormone (GnRH) function
[released by the hypothalamus]
Stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
growth hormone-releasing hormone (GHRH) function
[released by the hypothalamus]
Stimulates the release of growth hormone (GH).
somatostatin (GHIH) function
[released by the hypothalamus]
Inhibits the release of GH and thyroid- stimulating hormone (TSH).
dopamine (prolactin-inhibiting factor) function
[released by the hypothalamus]
inhibits the release of prolactin.
Adrenocorticotropic hormone (ACTH) function
[released by the anterior pituitary]
Stimulates the adrenal cortex to produce cortisol, a key hormone in the stress response and metabolism regulation
Thyroid-stimulating hormone (TSH) function
[released by the anterior pituitary]
Stimulates the thyroid gland to produce thyroid hormones (T3 and T4), which regulate metabolism and energy levels
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) function
[released by the anterior pituitary]
Target the gonads (testes in males and ovaries in females), regulating reproductive functions and the production of sex hormones (testosterone, estrogen, and progesterone).
Growth hormone (GH) function
[released by the anterior pituitary]
Stimulates growth, cell reproduction, and regeneration, targeting bones and muscles primarily.
Prolactin function
[released by the anterior pituitary]
Promotes milk production in the mammary glands
how is epinephrine release in the adrenal medulla regulated
by the SNS
how is cortisol release in the adrenal cortex regulated
by ACTH from the anterior pituitary gland
how are mineralcorticoid (aldosterone) release in the adrenal cortex regulated
secretion of angiotensin II
and
serum K+ levels
how are steroid hormone secretion regulated
through enzymatic activationw
why dont we need exocytosis for secretion of steroid hormones
Steroid hormones are hydrophobic and can cross
the cell membrane via simple diffusion
how are catecholamines (NE and E) secretion regulated
▪ a) Enzymatic activation
▪ b) Exocytosis of vesicles containing epinephrine and norepinephrine
what are steroid hormones derived from
Steroid hormones (like cortisol, aldosterone, and sex hormones such as estrogen and testosterone) are derived from cholesterol.
how are steroid hormones made ? why cant they be stored?
derived from cholesterol
not stored in cells
made on demand when body needs
lipid soluble, so easily pass through cell membranes, making storage in vesicles hard
how is the rate of hormone secretion for steroid hormones controlled?
- how active these enzymes are
- When the body signals a need for more of a specific steroid hormone (e.g., cortisol during stress), the enzymes responsible for synthesizing that hormone become more active, increasing production.
how do we know which steroid hormone will be produced?
different cell types express different enzymes
- In the adrenal cortex
- the zona glomerulosa expresses enzymes that convert cholesterol into aldosterone(which regulates salt and water balance).
- In the zona fasciculata, other enzymes are expressed that lead to the production of cortisol (which helps regulate metabolism and stress responses).
- In the gonads (testes or ovaries), enzymes convert cholesterol into testosterone or estrogen (which regulate reproductive functions).
HPA axis- glucocorticoid secretion overview? what hormones in hypothalamus and anterior pituitary cause cortisol release in adrenal
CRH in hypothalamus –> ACTH on anterior pituitary –> cortisol in zona fasciculata
how cortisol is secreted
- ACTH from anterior pituitary binds GPCR in zona fasciculata
- alpha subunit of GCPR dissociates and activates adenylyl cyclase
- increased cAMP
- activate PKA
- PKA phosphorylates target proteins…
…
make cholesterol-derived cortisol
where are the 2 spots cholesterol comes from
- most cholesterol used for steroid hormone synthesis comes from LDL uptake (exogenous pathway) rather than intracellular synthesis
–> i.e. food
what is the exogenous pathway of cholesterol
- cholesterol esters are taken up from LDL/IDL via upregulation of the LDL receptor
–> Cholesteryl esters are stored in a lipid droplet if not needed - Cholesteryl ester hydrolase (CEH) removes the fatty acid
- Cholesterol is released and can be used for steroid hormone synthesis
what form is cholesterol stored as and where?
as cholesterol esters in a lipid droplet
what enzyme to remove the fatty acid from cholesterol esters (storage form) to turn it into cholesterol so it can be used for steroid hormone synthesis
cholesterol ester hydrolase
what is needed to mobilize stored cholesterol? where does it move into?
PKA and goes into the mitochondria
PKA stimulates the release of cholesterol from intracellular stores (such as lipid droplets). Cholesterol is transported into the mitochondria, the site where the first steps of steroid hormone production take place.
where in a cell does steroid hormones production begin
inner mitochondrial membrane
what helps PKA and gets the cholesterol into the inner mitochondrial membrane
Steroidogenic acute regulatory protein (StAR): PKA enhances the activity of StAR, a crucial protein that helps transport cholesterol into the inner mitochondrial membrane.
where does steroid hormone synthesis begin? what does cholesterol get cleaved into?
All steroid hormone synthesis begins at the inner membrane of the mitochondria with cleavage of the cholesterol side chain and formation of pregnenolone
what is the enzyme that cleaves cholesterols side chain into pregnenolone?
side chain cleavage enzyme (SCC)
what is the rate limiting enzyme/ step in cortisol synthesis
cholesterol –> pregnenolone via side chain cleavage enzyme (SCC)
after cholesterol is converted into pregnenolone where do the rest of the steps of glucocorticoid formation occur
The remaining steps of glucocorticoid synthesis occur in the inner mitochondrial membrane and smooth endoplasmic reticulum
what are the 2 end products that pregnenolone eventually gets converted into
Pregnenolone is eventually converted into cortisol or corticosterone
▪ Cortisol is the more potent glucocorticoid and its production is higher!
how does ACTH upregulate the synthesis of glucocorticoids in the zona fasciculata
- ACTH upregulates the following steps:
▪ Increased LDL receptor expression
▪ Increased activity of CEH and StAR
▪ Increased activity of the side chain cleavage enzymes - ACTH also is trophic for the adrenal gland – it makes it grow
What were the roles of the SCC (side chain celavage) enzymes
steroidogenesis, which is the process by which cholesterol is converted into steroid hormones like cortisol, aldosterone, estrogen, testosterone, and others.
diurnal cycles of ACTH and cortisol
Fluctuations in plasma ACTH and glucocorticoids (11- OHCS) throughout the day. Note the greater ACTH and glucocorticoid rises in the morning before awakening.
how is CRH (hypothalamus) and ACTH (anterior pituitary) release regulated?
- circadian rhythm
- stress
- negative feedback
▪ Circadian rhythm – we have a “central clock” located in the suprachiasmatic nucleus of the hypothalamus (SCN) that is “calibrated” by melatonin secretion in response to darkness
* Contributes to regulation of CRH release
▪ Stress – CRH and ACTH are secreted in response to a wide range of (significant) stressors including:
* Surgery, hypoglycemia, inflammatory cytokines (physiologic stressors)
* Pain, unpleasant mood (psychologic stressors)
▪ Negative feedback
* Cortisol negatively feeds back to limit ACTH as well as CRH secretion
where are glucocorticoid receptors found?
- Glucocorticoid receptors are found within the cytosol in almost all tissues in a wide range of cells
▪ Cortisol binds to the glucocorticoid receptor
▪ Stimulate transcription at the hormone responsive element (HRE)
▪ Review from BMS100: Binding of cortisol displaces the heat shock protein (HSP) —> Receptor & hormone then form a dimer and translocate the the nucleus —> stimulate transcription at a HRE
how do glucocorticoids increase energy availability?
increase hepatic gluconeogenesis
increase hepatic and adipose lipolysis
decrease glucose uptake in muscle and adipose tissue
increase appetitie
▪ Increasing hepatic gluconeogenesis by:
* Stimulating gluconeogenesis enzymes (PEPCK and G-6-
phosphatase)
* Increased hepatic responsiveness to glucagon
▪ Increasing hepatic & adipose lipolysis
* More to be available for glycerol for gluconeogenesis * Increased free fatty acid release
▪ Can be broken down through which pathway for energy? A: free fatty acids can be broken down in Beta-oxidation
▪ Decreasing glucose uptake in muscle and adipose tissue * Chronically this will contribute to increased insulin secretion
▪ Increasing appetite
how do glucocorticoids effect the fetus?
▪ Combinations of glucocorticoids and a wide variety of other hormones are important in the fetal development of the lung and the liver
how do glucocorticoids effect the bone?
▪ Physiologic levels of glucocorticoids do not impair bone, but excess glucocorticoids can inhibit bone formation through multiple different pathways:
- Osteoblast inhibition & overactivation of osteoclasts
- Potentiation of the effects of parathyroid hormone,
reduction of calcium absorption
what affects do glucocorticoids have on healing tissue?
Physiologic concentration of glucocorticoids can be helpful in healing tissue, but excess glucocorticoids inhibit fibroblasts and impair healing
- causing thinned skin and increased bruising
how do glucocorticoids affect peripheral vessels, heart and kidneys (“hypertension inducing”)
▪ Increasing cardiac output, increasing blood pressure
▪ Also seem to increase salt and water retention at high
doses, independently of mineralocorticoids
▪ May also increase the activity of angiotensin II
how do glucocorticoids affect the central nervous system
▪ Supraphysiologic levels result in euphoria initially and then later an array of mood disturbances:
* Irritability & emotional lability * Depression
* Rarely psychosis
▪ Low levels invariably result in fatigue and depression
physiologic, short term elevations in glucocorticoids effect:
-increase neutrophil number and activity
-increase diapedesis of:
▪ Monocytes, eosinophils
▪ Lymphocytes
▪ May also increase the function of innate immune cells, but this is difficult to prove
supra-physiologic or long-term elevations of cortisol impact on immune system:
▪ Impaired macrophage activity and healing
▪ Impaired lymphocyte production and antibody production
▪ Decreased migration of cells to damaged sites
▪ Inhibit phospholipase A2 (this decreasing prostaglandin production)
how are mineralocorticoids synthesized?
same beginning steps as glucocorticoids…
cholesterol –> prognenalone via CSS enzyme then get converted into corticosterone (not cortisol)
Corticosterone is converted to aldosterone
how is corticosterone converted into aldosterone?
what enzyme is needed and what location?
aldosterone synthase enzyme
- located on the inner mitochondrial membrane
- only expressed by cells of the zona glomerulosa
what are the major regulators of aldosterone secretion?
(not primarily ACTH, but can help)
- Major regulators of aldosterone secretion are:
▪ Angiotensin II within the renin-angiotensin-aldosterone system (RAAS)
▪ Elevations in serum K+
aldosterone regulated by
K+ and angiotensin II (RAAS)
what is the renin angiotensin aldosterone system
▪ Decreased perfusion to the kidney stimulates renin release –> renin catalyzes the conversion of Angiotensin to Angiotensin I –> angiotensin II –> vasocontriction
triggers for renin release: decrease plasma volume, decreased afferent arteriole pressure, increased SNS stimulation
what are the effects of angiotensin II (end of RAAS)
▪ Vasoconstriction
▪ Stimulates secretion
of aldosterone
▪ Stimulates secretion of ADH/AVP from posterior pituitary gland
▪ Increases reabsorption of Na+ and secretion of K+ in the kidneys
what are the major effects of aldosterone
▪ Increased sodium reabsorption and increased potassium
secretion from the kidney
* Sodium reabsorption causes increase water retention and overall increased ECF volume
▪ Decreased potassium reabsorption from the GI tract
▪ Increased activity of the sodium/potassium pump in many cells
* Helps to decrease K+ concentrations in the serum to avoid severe electrolyte imbalances (hyperkalemia)
How are these hydrophobic steroid hormones (cortisol and aldosterone) carried in the circulation?
- Cortisol and aldosterone will bind somewhat to albumin
- The majority of cortisol is carried by cortisol binding protein (CBG)
- Aldosterone circulates in a primarily unbound state, and its clearance is much more rapid than that of cortisol
how do adrenal steroids get metabolized (i.e. then to eventually get excreted)
Both cortisol & aldosterone need to be glucuronidated by the liver before being excreted by the kidneys
▪ How does glucuronidation help with excretion?
▪ A: glucuronidation makes the hydrophobic steroid hormones more polar & therefore more easily excreted by the kidney
why do cortisol and aldosterone need to be glucoconidated?
makes the hydrophobic steroid hormones more polar and can be excreted by the kidneys
what are the forms of cortisol and aldosterone metabolite that are measured in the urine called?
- Eliminated forms of cortisol are known as 17-hydroxycorticosteroids
- Aldosterone as 18-glucuronide
what are catecholamines (NE and E) synthesized from?
tyrosine
what is the only tissue that produces epinephrine?
Adrenal medulla
what is the difference between the receptors that norepinephrine and epinephrine stimulate?
▪ Epi stimulates both alpha & Beta receptors.
▪ NE stimulates alpha 1 & 2, Beta 1 but has very little effect on B2
how are catecholamine (NE and E) synthesis regulated?
Sympathetic stimulation, ACTH, and cortisol all stimulate the synthesis of catecholamines
what does sympathetic stimulation trigger for catecholamines?
- Exocytosis of NE & E
▪ Sympathetic stimulation triggers exocytosis granules containing E & NE
Stress Response and ACTH-Cortisol Pathway (Chronic Regulation): [[catecholamine synthesis]]
- Stress activates the hypothalamus, which releases corticotropin-releasing hormone (CRH).
- CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH).
- ACTH targets the adrenal cortex to increase the production of cortisol.
- Cortisol, produced in the adrenal cortex, reaches the adrenal medulla via the intra- adrenal portal system.
- Cortisol induces the enzyme phenylethanolamine-N-methyltransferase (PNMT), which converts norepinephrine (NE) into epinephrine (Epi).
- Chronic regulation refers to how long-term stress or sustained ACTH and cortisol levels affect catecholamine production over time.
what is the enzyme that converts NE to E? what induces it?
Cortisol induces the enzyme phenylethanolamine-N-methyltransferase (PNMT), which converts norepinephrine (NE) into epinephrine (Epi).
what is the acute regulation of catecholamine synthesis? neuron signaling
- Neurons stimulate the adrenal medulla through the release of acetylcholine.
- Acetylcholine binds to receptors on chromaffin cells (the cells that produce catecholamines), causing an influx of calcium (Ca2+) into the cell.
- Calcium promotes the exocytosis (release) of catecholamines stored in neurosecretory granules.
- This mechanism is acute regulation, as it responds to immediate stress or neuronal stimuli, rapidly increasing the release of norepinephrine and epinephrine into the bloodstream.
what influx into the cell causes exocytosis (release) of catecholamines from their granules?
calcium
what is the catecholamine (NE and E) biosynthesis pathway inside chromaffin cells?
- The process begins with tyrosine, an amino acid that undergoes several enzyme-driven reactions to produce catecholamines:
- Tyrosine Hydroxylase (TH): Converts tyrosine to L-DOPA.
- DOPA Decarboxylase (DD): Converts L- DOPA to dopamine (DPN).
- Dopamine β-hydroxylase (DH): Converts dopamine into norepinephrine (NE).
- In the presence of cortisol, PNMT converts norepinephrine into epinephrine (Epi).
- Catecholamines are then stored in neurosecretory granules until they are released in response to neuronal signals.
overview of catecholamine biosynthesis in chromaffin cells
tyrosine –> L-DOPA–> dopamine –> NE –> E
NE –> E if cortisol is present
where are catecholamines stored inside chromaffin cells
- Catecholamines are then stored in neurosecretory granules until they are released in response to neuronal signals.
actions of catecholamines “fight or flight”
- Heart
▪ Increased contractile force
▪ Increased heart rate - Vessels
▪ Vasoconstriction in skin, visceral tissue
▪ Limited vasoconstriction or vasodilation in skeletal muscle, cardiac muscle - Energy metabolism
▪ ↑ blood glucose and “circulating” energy stores - Gluconeogenesis, glycogenolysis, ketogenesis in the liver
- Lipolysis in adipose tissue
- Lungs
▪ Bronchodilation, decreased mucous production
what is the form of NE and E that get excreted in the urine
metanephrine (from E) and noremetanephrine (from NE) then get broken down into vanillylmandelic acid (VMA) which is excreted
what are the enzymes that’s breakdown catecholamines (NE and E)? which enzyme acts first?
monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)
COMT first to make the intermediates (metanephrine/normetanephrine) and then MAO to breakdown into final urination product (VMA)
- Monoamine oxidase (MAO): An enzyme that breaks down catecholamines by removing an amine group.
- Catechol-O-methyltransferase (COMT): Another enzyme that helps by adding a methyl group to catecholamines, making them easier to break down.
what is the main catabolic pathway from catecholamine (NE and E) breakdown?
- Epinephrine and norepinephrine are first degraded by COMT, producing an intermediate called metanephrine (from epinephrine) or normetanephrine (from norepinephrine).
- Then, MAO breaks down these intermediates into vanillylmandelic acid (VMA), which is a final breakdown product.
- VMA is excreted in the urine.
where do catecholamines get broke down?
- Catecholamines are broken down primarily in the liver, kidneys, and nerve endings.
- This process ensures that catecholamines do not remain in the body too long after their effects are no longer needed (like after stress or a fight-or-flight response).
Prolactin Releasing Factors??
there are other things too…
Prolactin Releasing Factors (TRH, oxytocin, vasoactive intestinal peptide)
