Adrenal glands- androgens and the medulla

adrenal androgens

Small amounts synthesised in zona reticularis

DHEA and androstenedione- in females cause growth of pubic and axillary (armpit) hair, female libido?

What is congenital adrenal hyperplasia

Enlarged adrenal glands, most commonly caused by 21 hydroxylase deficiency

Symptoms:

• dehydration, salt loss, weakness

• female: male genitalia, hirsutism

• male: precocious puberty

treatment = corticosteroid replacement

CAH mechanism

• reduced glucocorticoid and mineralocorticoid production 

• reduced -ve feedback —> increased ACTH —> adrenal hyperlasia

• leading to excessive production of adrenal androgens 

outline the spirogenic pathway from 21 hydroxylase deficiency to androgen excess

1. lose CYP21 in hydroxylase deficiency, stops production of cortisol (and mineralocorticoids), no -ve

2. anterior pituitary keeps producing ACTH until adrenal glands start producing DHEA which enlarges adrenal glands

3. more DHEA = more androgens 

give an overview of the adrenal medulla

• part of the autonomic NS

• specialised ganglia supplied by sympathetic preganglionic neurons

• synthesises catecholamines

• main site for adrenaline synthesis

• not essential for life!

Outline the anatomy of the medulla

Alpha and beta androgenic receptors

Chromaffin cells produce adrenaline and noradrenaline

Blood supply = past cortex to the medulla 

PNMT

phenylethanolamine N-methyltransferase

DONT REMEMBER THAT
an enzyme that converted noradrenaline to adrenaline

Outline catecholamine synthesis

OVERALL: tyrosine —> noradrenaline 

1. Tyrosine hydroxylase catalyses the rate limiting step: tyrosin —> L-DOPA

2. L-DOPA —> dopamine

3. Dopamine —> noradrenaline (dopamine beta-hydroxylase w/in the synaptic vessels

4. noradrenaline —> adrenaline w/PNMT 

production of more adrenaline than noradrenaline 

outline the relationship between cortisol and catecholamines

high cortisol —> high concentration in capillary blood

activates PNMT molecules, meaning more molecules w/noradrenaline will have adrenaline

outline catecholamine storage and regulation

• catecholamines transported to synaptic vessels using specialised transporter after synthesis

• vesicles protect hormone from degredation, ensure control can be maintained over how much is released

• high catecholamine levels w/in the nerve terminal inhibit rate limiting step (tyrosine hydroxylase, -ve feedback)

• high level of stimulation from nerves stimulates tyrosine hydroxylase

outline catecholamine release

• cortisol doesn’t care how much adrenaline there is, not -ve

• adrenaline broken down quickly- VMA = waste product excreted in urine

Systemic effects of adrenaline

• differential receptor sensitivity

  • alpha: Adrenaline < noradrenaline

  • beta: adrenaline > > noradrenaline

• adrenal medulla activity- producing lots of adrenaline, primarily activating beta receptors

central nervous system effects of adrenaline

• increased alertness/arousal

• increased anxiety

• increased muscle tremor 

adrenaline effects: cvs and lungs

• Cardiovascular system

  • heart rate increases, force of contraction

  • vasodilation

• bronchodilation of respiratory system

adrenaline effects: metabolism

glycogen breakdown in muscle

increases blood glucose

adrenaline effects: hepatic

increased glycogenolysis/gluconeogenesis

increases blood glucose

adrenaline effects: adipose tissue

mobilisation of free fatty acids

increases blood glucose

phaeochromocytoma

excess catecholamines due to tumour of chromaffin cells (in adrenal medulla)

-→ chronic over-secretion or dramatic episodes from a sudden stressor (exercise, rapid postural changes)

phaeochromocytoma symptoms

episodes of very high BP

sudden, severe headache

palpitations, chest pain

pallor of skin, sweating

anxiousness

phaeochromocytoma treatment

surgery AFTER MANAGING potential catecholamine crisis risk (cardiac arrest)

• alpha blockers to prevent vasoconstriction

• surgery

• then beta blockers after surgery to minimise cardiac stimulation

• no surgery option = anti-hypertensive drugs

Which hormone is most affected in cushing’s syndrome, and is it in excess or deficit?

Cortisol in excess

Extra: some forms of Cushing syndrome caused by Cushing disease or an ectopic tumor —> excess ACTH

What is the most common cause of Cushing’s syndrome?

Cushing’s disease, a tumour on the adrenal gland causing an overproduction of glucocorticoids including cortisol

What are other causes of cushing’s syndrome?

• Long term stress

• Long-term glucocorticoid drug use for autoimmune conditions

• An ectopic tumor anywhere in the body that overproduces ACTH

What medications might a person with cushing’s syndrome be taking long-term?

Steroid medications

Outline the symptoms of Cushing’s and their causes

1. osteoporosis, broken bones

   1. high cortisol reduces calcium absorption and increases calcium excretion

2. muscle weakness, skin fragility, bruising

   1. high cortisol leads to the catabolism of muscle and skin proteins for gluconeogenesis, leading to muscle loss and fragile skin

3. fat redistribution

   1. excess cortisol leads to fat loss from the extremities and fat gain to the trunk and face

4. skin infections

   1. high cortisol levels lead to immunosuppression, leading to increased infection risk and poor wound healing

5. ‘feeling out of sorts’

   1. excess cortisol leads to changes in mood and cognition

Why is an elevated urine glucose level consistent with Cushing’s?

• High cortisol levels —> increased plasma glucose level caused by an increase in hepatic gluconeogenesis

• kidneys unable to filter out all the excess glucose in the blood 

• leads to excretion of glucose in urine

Why is an elevated BP consistent with Cushing’s?

• high cortisol levels means that there are fewer cortisol receptors relative to cortisol molecules, causing cortisol to start binding to mineralocorticoid receptors in the kidneys

• mineralocorticoid receptors increase sodium reabsorption in the kidneys, which in turn —> high blood pressure

• an increase in cortisol leads to an increase in cholesterol production, as cortisol is a cholesterol derivative

• this potentially —> higher levels of aldosterone produciton, as there is too much cholesterol and not enough cortisol-specific enzymes to convert all of the cholesterol to cortisol?

what is phaeochromocytoma

a tumor of the chromaffin cells in the medulla of the adrenal glands that causes an overproduction of catecholamines including adrenaline and noradrenaline

non-specific: can be adrenaline, noradrenaline or both

how is phaeochromocytoma diagnosed?

• through BP measurement to diagnose high BO

• urine test to measure VMA levels produced by the breakdown of adrenaline

• A scan using tracer to look for the tumor itself

Why is elevated heart rate and BP consistent w/phaeochromocytoma?

• catecholamines —> increase in HR through acting upon alpha and beta receptors, which increase the speed and force with which the heart contracts

how can phaeochromocytoma be treated?

• increased activation of alpha receptors through excess adrenaline —> increased risk of catecholamine crisis including a cardiac arrest

• treatment prevents a catecholamine crisis w/alpha blockers

• after this prevention, surgery used to remove tumors

• beta blockers if surgery not an option or to prevent additional complications

what are alpha and beta receptors?

g-protein coupled receptors that are the targets of catecholamines and drugs such as beta blockers