Cushing's/Addison's

anatomy of the adrenal glands
-location
-R and L differences
-which one is larger?
- R and L shape

superior to kidneys in the renal fascia
posterior to diaphragm
R adrenal is post to liver and IVC, pyramidal shape
L adrenal is post to stomach and pancreas, semilunar shape, slightly larger

what are the layers of the adrenal gland?

Capsule of connective tissue
Cortex;
-zona glomerulosa
-zona fasciculata
-zona reticularis
medulla

where are the 3 layers of \___ and what in under?

3 layers are in outer cortex
below it is the medulla

what are the 3 layers of the cortex?
what do the secrete?
what is their cell structure?

-zona glomerulosa
mineralocorticoids, blobs of cells
-zona fasciculata
glucocorticoids, strings of cells
-zona reticularis
androgens, networks of cells

what does the outer cortex secrete?
what are its precursors?
what is secretion controlled by?

steroid hormones
cholesterol precursors
controlled by pituitary

which cortex layer secretes mineralocorticoids, what is an example?

zona glomerulosa
aldosterone

which cortex layer secretes glucocorticoids, what is an example?

zona fasiculata
cortisol, corticosterol

which cortex layer secretes androgens, what is an example?

zona reticularis
DHEA, androstenedione

what is the embryological origin of the outer cortex?

mesoderm

what is the embryological origin of the inner medulla?

neural crest

what does the medulla secrete?
what controls secretion here?
what type of tissue is here?

catecholamines: adrenaline, noradrenaline
controlled by sympathetic NS
neuroendocrine

what is the arterial supply of the adrenal glands?
where do they come from?

superior adrenal- from phrenic
middle adrenal- from aorta
inferior adrenal- from renal aa

what is the venous drainage of the adrenal glands?
where do they drain into?

right adrenal- into IVC
left adrenal- into L renal vv

\[medulla]
what neurones control secretion in adrenal glands?
what is the secretory cell equivalent to?
and why is there this structure?

preganglionic neurones control secretion
secretory cell\= post ganglionic neuron
allows quick secretion

what do medullary adrenal secretions act on?
where are these found?

adrenergic receptors
on heart, blood vessel, liver, skm

in term of innervation/ganglion,
what is the adrenal MEDULLA like?

modified neural ganglion
preganglionic fibre ends directly onto adrenal medullary cells

is the ultrastructure across the gland the same?
where?

no its different
peptide secreting cell in medulla
and
steroid secreting cell in cortex are different

ultrastructure of steroid secreting cell in cortex
-ER, granules/droplets, mitochondria?

smooth ER
lipid droplets
tubular cristae mitochondria

ultrastructure of peptide secreting cell in medulla
-ER, granules/droplets, mitochondria?

rough ER + golgi
granules
normal mitochondria

what are the arterioles like in the adrenal gland?
where do the arterioles come from?
what do they give rise to, where do they drain into?

arterioles from capsular arteries
-\> sinusoidal capillaries
-\> medullary vein

what happens in hypoadrenalism?
example

no secretion of any hormones
addisons
adrenal insufficiency

what happens in hyperaldrenalism?
of each type of hormone produced
what can cause this?

over secretion
-mineralocorticoids\=conn's
-glucocorticoids\=cushing's
all 3 in tumout
ectopic ACTH such as in neuroendocrine lung tumout

What is Cushing's syndrome?

^ glucocorticoids

what may be a cause of ectopic ACTH syndrome?
what will this lead to?

neuroendocrine lung tumour, small cell carcinoma
excess glucocorticoids

What is Conn's syndrome?

^ mineralocorticoids

What is a phaeochromocytoma?
what does it cause?
origin?
produces?
symptoms?
diagnosis?

benign adrenal tumour
cause secondary hypertension, CV complications
neuroectodermal origin
produces excessive catacholamine
severe headache, sweating, palpitations
urinary catecholamines, or metabolites

what are adrenal steroid hormones derived from?
what is the process called to make steroid hormone?

cholesterol
sequential, enzymatically-mediated modification

what is the structure of cholesterol?

27C
aromatic rings
lipophilic

where is cholesterol derived from?

plasma LDL
some from cell stores, synthesised from acetyl CoA

which step in steroidogenesis is the rate-limiting step?
what is this step?

1st step
transport of cholesterol from outer to inner mitochondrial memrane

where is the 1st enzyme in steroidogenesis located?
what is this enzyme?
what does it do?

inner mitochondrial membrane
cholesterol 20,22 desmolase (CYP11A1)
side chain cleavage of cholesterol

what does CYP11A1 produce?
how many carbons is this molecule?

pregnenolone
C21

why is there zone-specific steroid hormone synthesis?

differential hormone expression in each zone

where and why does MINERALOCORTICOID production happen here?
what enzyme is needed for MC synthesis?

zona glomerulosa
because there is
no enzyme F
there is enzyme E
enzyme E is needed for MC synth

where and why does CORTISOL production happen here?
what enzyme is involved?
GLUCOCORTICOID

zona fasciculata
enzyme F pushes cortisol synth

what does enzyme F do?

-intermediates generate glucocorticoid synthesis
-F* is for androgen synthesis

where and why does WEAK ANDROGEN production happen here?
what enzyme is involved?

zona reticularis
enzyme F* cofactor only present here
enzyme F* pushes intermediates here

why is enzyme F* not active in zona fasciculata?

lacks needed cofactor

what type of 'enzymes' are involved in the process?
where are they located?

CYP
inner mitochondrial membrane or smooth ER

which 2 steroid hormones have similar structure?
difference between 2 examples?

corticoids and mineralocorticoids
aldosterone\= aldehyde group
cortisol\= methyl group, OH

what is enzyme E?
where does it act?
what does it produce?

aldosterone synthase
C18 of pregnenolone, methyl-\>
aldehyde

what is enzyme F?
where does it act?
what does it produce?

17a hydroxylase
C17
cortisol

what hormone can act as mineralocorticoid and glucocorticoid?
what are its actions?

cortisol
na+ retention\= mineralocorticoid
anti-inflammatory\= glucocorticoid

what are some synthetic glucocorticoids?
what are they used for?

prednisolone, dexamethosone, betamethasone
anti-inflammatory

what is an example of a synthetic mineralocorticoid?
what is it used for?

fludrocortisone
increase Na retention

what controls adrenal hormone levels?
feedback loop?

HPA axis
CRH-\>ACTH-\>cortisol
feedback loop\= cortisol inhibits CRH and ACTH

what does aldosterone do?
stimulated by?
ACTH affects it or not?

Na H20 retention, K loss
acts on DCT and CD
stimulated by high plasma K and RAAS
independent of ACTH

androgens
-examples
-production is related to?
-regulated by
-feedback?

DHEA, androstenedione
related to age, starts at 5-6
regulated by ACTH
no feedback mechanism

what decreases cortisol production?

feedback loop
high cortisol levels

what increases cortisol production?

acute stress
fluid deprivation via ADH-\>ACTH
circadian rhythm via SCN

steroid hormones
-release?
-circulation transport?
-act via?
-effect?

release via simple diffusion
transport in blood via protein carriers
act via intracellular receptors
regulate transcription factors

how do steroid hormones have rapid non-genomic effects?

plasma membrane or cytosolic receptors

actions of cortisol

-Metabolic effects
-Anti inflammatory / immunosuppressive
-adaptation to stress
-Permissive role in action of other endocrine hormones
-Actions on other tissues

what are the metabolic effects of cortisol?
-muscle, adipose, liver
-does what to plasma glucose

breakdown in muscle and adipose\= catabolic
gluconeogenesis, glycogen synthesis in liver
elevates plasma glucose

what are the anti-inflammatory/immunosuppressive effects of cortisol?
-what level of cortisol is needed?
-stimulates prod of?
-effects which cells

occurs at high levels
stimulates lipocortin prod, INHIBITS PLA2, less inflammatory mediators
less t lymphocytes
less cytokines
stabilises lysosomes
less NO prod

what is stress?
what are some stressors?

threatened homeostasis, dysharmony
physiological, emotional, psychological
pain, fever, hypoglycaemia, fluid deprivation, injury

what are some physiological mechanisms to re-establish homeostasis?

redirection of energy
^CV tone
^ventilation
^glucose availably
decrease energy consuming activities like digestion

what brings on the integrated stress response?

SNS+adrenaline
CRH-ACTH-cortisol

what does SNS + adrenaline do as part of the stress response?

increase CO and ventilation
divert blood flow to muscles and heart
mobilise glycogen and fat stores
fight or flight

how does cortisol affect ^^ stress response?

its permissive
without cortisol SNS activation will not have its effects

what does cortisol do as part of the stress response?
makes what avaialble?

makes intermediates available, ^plasma glucose ^glycogen stores
shifts fat and protein stores
makes amino acids available for repair of physical damage

what does cortisol do in stress-immune response?
what does it protect from?

protects from over-stimulation of immune defence mechanisms

what happens to cortisol levels in prolonged stress?

prolonged elevation of cortisol

what do prolonged cortisol levels lead to?

muscle wasting
hyperglycaemia
GI ulcers
impaired immune response

how does cortisol cause GI uclers?

decreases prostaglandins

what is CAH?
what specifically is affected?

Congenital Adrenal Hyperplasia
inherited defect in enzyme involved in cortisol and aldosterone production
usually 21B-hydroxylase
low cortisol and aldosterone, ^ANDROGENS

what happens in CAH?
presentation
what happens to adrenal glands?

ambigious genitalia
precocious puberty
virilisation
adrenal hyperplasia less -ve feedback

treatment of CAH

-hormone replacement
-plastic surgery if necessary

what can cause cushing's syndrome?

excessive glucorticoid activity
endogenous or exogenous
primary or secondary

primary cause of cushing's syndrome
-what happens?
-what may cause it?

autonomous secretion of cortisol
ACTH CRH levels low due to negative feedback
can be due to adrenal tumour

secondary cause of cushing's syndrome?
-what happens?
-what may cause it?

excessive production of ACTH
impaired negative feedback
ACTH secreting tumour

what is cushing's disease, what can cause it?

cause of cushing's syndrome
^ACTH from pit.tumour

signs and symptoms of cushings
due to altered fat deposition
-why?

truncal obesity
buffalo hump
red round face

-cortisol, ^plasma glucose, ^insulin, insulin stores glucose as fat

signs and symptoms of cushings
due to excess adrenal androgens
-why?

acne
female frontal blading
hirsutism
menstrual irregularities

-ACTH dependent cushings

signs and symptoms of cushings
due to breakdown of protein, muscle, collagen loss

testicular atrophy
thin arms and legs
muscle weakness
thin skin
purple striae
hypokalaemia

signs and symptoms of cushings
due to loss of collagen, immunosuppression

poor wound healing
easy bruising
infections in skin

signs and symptoms of cushings
due to mental changes

cognitive difficulties
depression
emotional instability
sleep disturbance

other symptoms of cushings?

osteoporisis, altered bone metabolism
hypertension, ^cortisol, sodium retention
diabetes, insulin resistance

what will glucocorticoid excess in childhood lead to?

growth retardation

diagnosis of cushings
rhythm?

elevated plasma cortisol
loss of diurnal rhythm, high at 9am low at 12am

ACTH levels in \__ cushings?
-primary
-secondary

-primary low ACTH
-secondary high ACTH

what do dynamic tests measure?
example

check endocrine axis
DEX tes

what is the DEX test?

dexamethasone synthetic glucorticoid will act on -ve feedback
low dose/overnight dose\= suppression

what is CRH stimulation test?

distinguishes between pit dependent or ectopic source
if ectopic ACTH syndrome there will be no response to CRH

treatment of cushing's?

if tumour-remove by surgery
or medication to inhibit steroidogenesis
-metyrapone, ketoconazole
not really used

what is Conn's syndrome?
-what happens
-result
-cause
-treatment

primary hyperaldosteronism, mineralocorticoid excess
^^aldosterone
tumour
Na water retention, K loss
hypokalaemia, weakness, hypertension
surgery, aldosterone receptor antagonist

aldosterone receptor antagonist for conn's

spironolactone

what is Addison's disease?
-what happens
-leads to

primary adrenal insufficiency, adrenal gland failure
chronic, autoimmune, HIV, TB

what are the hormone levels in addison's?

low aldosterone
low cortisol
low androgens
high ACTH
high CRH as no negative feedback

signs and symptoms of addisons?

postural hypotension
muscle weakness, fatigue
hyponatremia, hyperkalaemia
increase pigmentation
weight loss/anorexia
nausea/vomiting

why is there increased pigmentation in addison's?
what does this present as on body?

ACTH^
MSH^ \= melanocyte stimulating hormone
melanin in skin^

as ACTH prod ^ so does MSH as both are from POMC

skin creases, scars, gums, cheeks

what are the main tests that should be done for adrenal failure?

cortisol, ACTH levels
ACTH stimulation test
adrenal autoantibodies

treatment of addisons/adrenal insufficiency?

hormone replacement
hydrocortisone (glucoc)
fludrocortisone (mineraloc) daily

how should glucocorticoid replacement be adminstered?
when should dose be increased?

20mg AM
10mg PM
daily\= diurnal rhythm

-if in stress/ill ^ dose

what is secondary adrenal insufficiency?

lack of ACTH
less adrenal gland stimulation

what happens to adrenal hormones in secondary adrenal insufficiency?

low cortisol
normal aldosterone as RAAS intact

what may cause secondary adrenal insufficiency?

tumour, pituitary damage
exogenous glucocorticoid use

how may long term exogenous glucorticoid use cause secondary adrenal suppression?

dampens endocrine axis
-ve feedback looks low ACTH

when will secondary adrenal suppression be a problem?

if there is sufficient exogenous glucocorticoid
but if stress situation then problems

what appearance will excess exogenous glucocorticoids lead to?

cushingoid
truncal obesity, round face, dorsocervical fat pads, striae