The adrenal gland?
What is it and why is it important?
Hybrid gland consisting of a cortex and a medulla.
The hormones produced are regulators of metabolism and important in adaptation to stress
How many adrenal glands does one person have?
Each embedded above each idney in a capsule of fat
What is each adrenal gland consist of?
Two endocrine organs
Outer layer composing the adrenal cortex, secrete steroid hormones.
The inner portion the adrenal medulla, secretes catecholamines.
Adrenal cortex consists of?
Zona glomerulosa (outer layer)
Zona fasciculata, the middle and largest portion.
Zona reticularis, the innermost zone.
Adrenal cortex produces what kind of hormones?
They are steroid dervied from the cholesterol.
3 groups of steroid hormones the adrenal cortex produce?
Minerlocorticoids (mainly aldosterone and influence mineral balance.
Glucocorticoids, primarily cortisol, major role in glucose metabolism.
Sex Hormones, similar/identical to those produced by the gonads. Most important dehydroepiandrosterone, an androgen.
Why are the 3 adrenal steroids produced in anatomically distinct portions of the adrenal cortex?
Differential distribution of the enzymes required to catalyse the biosynthesis pathway from cholesterol to the specific hormone.
Definition of a steroid hormone?
All are derived from cholesterol and differ only in the ring structure and side chains attached to it.
Lipid soluble: ie freely permeable to membranes therefore are not stored in cells.
Carried in the blood complexed to specific binding globulin.
Enzymes that produce steroid hormones from cholesterol are located in the mitochondria and smooth ER.
Where does the cholesterol come from to synthesis steroid hormones?
The cholesterol is the free cholesterol in the cell.
This cholesterol is synthesised by the cell itself from acetate that is stored in intracellular lipid droplets.
Where is aldosterone produced in the adrenal cortex?
Where is cortisol produced in the adrenal cortex?
Zona fasciculata and reticularis.
Main site is the zona fasciculata
Where is the sex hormones produced by the adrenal cortex?
The zona fasciculata and reticularis.
Produced in greater levels in the gonads.
What protein moves cholesterol from the outer memebrane to the inner membrane to convert it to what by which enzyme?
Steroidogenic acute regulatory protein (StAR)
Converted it to pregnenolone.
By the enzyme cytochrome P450
Rate limiting, nonreversible step.
What is pregnenolone converted to?
Depends on what hormone you want to produce
What determines which pathway/hormone is produced?
Each step is regulated by a specific enzyme
Different zones have different enzymes.
Regulatory mechanisms control steroid levels?
Each zone has unique aspects concerning its regulation.
stimulus-change detected by receptor- sent info along afferent pathway-control center produces a signal- sent info along efferent pathway-response to return to homeostasis.
Zona fasciculata unique characteristics?
Large and most active zone.
How is free cholesterol stored as lipid droplets
Esterfied by the enzyme acyl CoA cholesterol transferase (ACAT).
Continually converted back hormone sensitive lipase (HSL)
Process is increased by adrenocorticotropic hormone (ACTH).
What are the 5 reactions to converted free cholesterol to cortisol?
StAR moves the cholesterol from the outer membrane to the inner membrane of the mitochondria.
CYP11A1 (located in the inner mitchondrial membrane) converts cholesterol to pregnenolone.
How does ACTH increase the activity of the convertion of chloesterol to cortisol?
Phosphorlation by ACTH-GS-cAMP-PKA.
This increases the activity by helping stimulate the conversion of cholesterol (ester form) to cholesterol and the transfer of this cholesterol to the outer membrane of the mitchondria.
What is cortisol?
Important in carbohydrate, protein and fat metabolism.
Transport of cortisol in the blood?
Bound to corticosteroid-binding globulin
The unbound form exerts biologic effects within target cells and feeds back to the pituitary and hypothalamus.
Transport of aldosterone and dehydroepiandrosterone in the blood?
Bound to albumin (non specific, binds to lots of lipophilic hormones)
What organ is the site for steroid inactivation?
How do steriods impose their action on the target cells?
Most hydrophobic steroid are bound to plasma carriers so cannot diffuse through like unbound hormones.
The unbound hormone activity diffuses from the blood to the cytoplasm.
The steriod hormone receptor is in the cytoplasms.
Once the steriod is bound it produces a complex.
This complex can bind to the DNA and can activate or represses the genes.
Translation occurs/stops and new proteins are produced.
For bound hydrophobic steroids, they need to bind to the membrane receptor and use secondary messengers to expose their action.
What receptors do the adrenal steriod hormones bind to?
Mineralocorticoid binds to mineralocorticoid receptor (MR).
Glucocorticoid, cortisol, binds to glucocorticoid receptor (GR).
Dehydroepianodrosteron binds to androgen receptor (AR).
Each hormone-receptor complex moves to the nucleus and binds with a hormone-response element.
What hormone-response element do each adrenal hormones bind to?
Mineralocorticoid: mineralocorticoid response element.
Glucocorticoid: glucocorticoid response element.
Dehydroepiandreosterone: androgen response element.
Regulation of the mineralocorticoid action of cortisol?
cortisol can bind to the MR with high affinity and activate the 'incorrect' genes.
Cortisol is converted to the inactive form cartisone by 11b-HSD2 present in mineralocorticoid target cells.
Enzyme that converts inactive cortisone to active cortisol is only present in tissues expressing the GR (including liver and adipose, skin & CNS).
MR is free and available in aldosterone-respsive cells.
Primary insufficiency and Addison's disease.
Hypoglycemia: Low blood sugar level.
High cortisol level
Hyperglycemia: high sugar levels.
Metabolic effects of cortisol? ie when no food is around.
Stimulates protein and triglyeride catabolism
Stimulates gluconeogenesis in liver.
Inhibition of glucose uptake by body (NOT BRAIN).
Inhibits bone formation.
Inhibition of non-essential functions, eg. reproduction and growth.
Stimulates protein degradation in many tissues, especially muscle.
Facilitates lipolysis, the breakdown of fat stores in adipose tissue.
Elevation of blood glucose levels when cortisol inhibites the glucose uptake by the body.
Conversion of noncarbohydrate sources (ie. amino acids) into carbohydrate within the liver.
Between meals or during periods of fasting.
Cortisol secretion is regulated by the HPA axis
Regulated by the negative-feedback system involving the hypothalamus and anterior pituitary.
ACTH from the anterior pituitary acting through the cAMP pathway, stimulates the adrenal cortex to secrete coritsol.
ATCH stimulates the growth of the zona fasiculata and reticularis.
What maintains the size of the zona glomerulosa?
Feedback regulation by glucocorticoids?
Inhibits the synthesis of:
ACTH (transcription of POMC)
What happens when there is no ACTH?
zona fasciulata and retiularis shrink and cortisol secretion is drastically reduced.
What happens when there excess amount of ACTH?
What happens when someone is on long term coritcoid treatment?
The zona faciulata no longer responsive to the feedback loop.
1) HPA is overstimulated by stress
Body cannot keep up with the demand for cortisol
2) 21-hydroxylase deficiency symptoms: cholesterol cannot be converted to the steroid hormones.
Hypercorticism (increase in glucocorticoid production)
Caused by either pituitary basophilic adenoma (overstimulation of CRH) or ACTH-secreting tumour located outwith the pituitary gland or adrenal tumour (secrete independent ACTH).
It is when too many amino acids are converted into glucose, suffer from glucose excess.
Extra glucose is deposited as body fat in locations characteristic for this disease (buffalo hump- above the shoulder blades; moon-face- in the face).
Loss of muscle protein leads to muscle weakness and fatigue
What are the independent of ACTH (exogenous) causes of Cushing syndrome?
Taking medicien containing glucocorticoids
Adrenal tumour and other unknown location tumours.
What are the dependent of ACTH (endogenous) causes of Cushing's disease?
Overproduction of cortisol
Rare, chronic endocrine disorder
Adrenal glands do not produce sufficient steroid hormones.
Overproduction of ACTH.
Glucocorticoid deficiency symptoms: changes in mood, muscle weakness.
Mineralocorticoid deficiency symptoms: loss of Na and fluids and retention of potassium.
During period of stress what happens?
Excessive ATCH production.
CNS becomes the primary user of glucose.
The action of the primary adrenocrotical mineralocorticoid, aldosterone? What does it regulate?
Governs the extracellular volume.
Promotes Na retention and enhances K elimination during the formation of urine by the kidneys.
Regulates the blood pressure.
What do Arginine vasopression (AVP) do?
And what are they also known as?
Also known as antidiuretic hormone (ADH)
Regulates osmolality because of its effect on free water balance.
2 ways in which aldosterone secretion is increased to regulate salt/water balance?
1) Activation of the renin-aniotensin-aldosterone system.
2) Direct stimulation of the adrenal cortex by a rise in plasma K conc.
Synthesis of aldosteron?
What cells are the site of this synthesis?
The adrenal cortex synthesised from cholesterol.
Only glomerulosa cells contain aldosterone synthase, exclusive site of aldosterone synthesis.
As with coritsol, no storage pool. Secretion limited to the glomerulosa cells synthsising rate.
Enhance secretion by increasing the activity of enzymes acting on rate-limiting steps (include SCC enzyme and aldosteron synthase).
What sites do aldosterone have its action effects on to increase Na reabsorption and water?
What channels do aldosterone effect it increase Na transport?
Transcription of the Na-K pump.
Expression of apical Na channels and an Na/K/Cl cotransporter.
Where does most of Na reasorption occur?
In the proximal tubule by aldosteron-independent mechanisms
Loss of aldosterone-mediated Na reabsorption can result in?
Significant electrolyte abnormalities.
Hyperkalmeia: too much potassium conc. in serum.
Hypotension: low blood pressure
Excess aldosteron secretion produces what abnormalities?
Hypokalmeia: too little potassium conc. in serum.
Hypertension: high blood pressure
Regulation of aldosterone synthesis?
How is it done?
Water and sodium levels feedback through the RAAS. ang 2 binds to AT1 receptor. Calcium increase depolarising the glomerulosa cells. Voltage-gated Ca channels open.
- High extracellular potassium: depolarise the glomerulosa cells. Voltage gated calcium channels open.
ACTH (binds to MC2R stimulates Ca influx).
- Decrease blood pressure. Detected y baroreceptors in the kidney. Induce renin release and cause activation.
Regulation of aldosterone synthesis?
Feedback regulation of aldosterone synthesis?
Adjustment of circulating volume will feedback on aldosterone synthesis.
What is the adrenal medulla consists of?
Neural crest-derived chromaffin cells migrate into the cortical cells.
Actually a motified part of the sympathetic nervous system.
No ordinary postganglionic sympathetic neurones.
Do not have axonal fibers that terminate on effector organs.
Has potential of develiping into postganglioic sympathetics neurons and synthesise norepinephrine however exposed to high local conc. of cortisol which inhibits neuronal differential.
What chemical messenger does the chromaffin cells produce?
Epinephrine and low levels of norepinephrine.
Coritsol induces phenylethanolamine-N-methyl transferase in chromaffin cells (converting norepinephrine to epinephrine)
Similarities betwen epinepherine and norepinephrine?
In the class of catecholamines
Derived from the amino acid tyrosine.
Epinephrines has a methyl group which norepinephrine does not.
What happens when nephrine and norepinephrine are produced?
Stored in chromaffin granules.
Segregation protects them from being destroyed by cystolic enzymes.
Complexed with ATP, calcium and proteins called chromogranins.
When catecholamines are needed what happens?
Secreted into the blood and act as hormones.
Act as hormones even though they are neurotransmitters.
Where are catecholamines produced?
70-80% of cells in adrenal medulla secrete epinephrine.
20-30% remain produce norepinephrine.
Only 30% of circulating norepinephrine come from adrenal medulla.
The rest from postganglionic sympathetic nerve terminals.
Is the adrenal medulla essential for life?
Regulation of catecholamines?
- descending sympathetic signals in response to various forms of stress.
- Primary autonomic centers that initiate sympathetic responses reside in the hypothalamus and brainstem.
- Chemical signal, ACh,is for catecholamine secretion.
- Levels do not change with a change in sympthetic activity.
- Coritsol regulates epinephrine production
How does ACh signal for catecholamine secretion?
ACh increases the activity of the rate-limiting enzyme, tyrsoine hydroxylase, stimulates exocytosis of the chromaffin granules.
How long is the biological response of catecholamines?
10 seconds and then circulating catecholamines are degraded.
What enzymes take part in the degradation of catecholamines?
And how do they degrade it?
Monoamine oxidase (MAO):
Predominant enzyme in neuronal mitchondria.
Methylation by COMT in non-neuronal tissues such as liver and kidney to metanephrine and metanorepinephrine.
MAO converts these to vanillylmandelic acid (VMA).
Liver and gut conjugation them to sulfate or glucuronide for excretion by kideny.
Mechanism of action of catecholmines?
How many receptor types and what are they?
Act through adrengic GPCRs.
5 receptor types: Alpha 1,2 and Beta 1->3.
alpha and b3: respond better to norepinephrine
b1: response equally.
b2: epinephrine more potent.
What is the consequences of having many receptor types?
A single catecholamine may evoke multiple different responses as a consequence of circulating conc.
Physiologic actions of catecholamine?
The brain needs glucose even if levels are low.
Epinephrine is antagonisitic to insulin.
In response to stress.
Important role in stress response, regulating anterior blood pressure and controlling fuel metabolism.
How fast is the response from the adrenal medulla?
Directly innervated by the autonomic nervous system.
The 3 major physiologic actions of norepinephrine and epinephrine?
Increased blood flow to the muscles.
Increased glucose availability
Decreased energy demand by visceral smooth muscle.
What is pheocromocytoma?
Caused by hyperplasia of adrenal medulla or other chromaffin tissues.
Excessive production of catecholamines