Adrenocorticosteroids & Adrenocortical antagonists

morphology of the adrenal gland from outside in

• connective tissue capsule

• Z.glomerulosa [aldosterone]

• Z.fasciculata [cortisol] (largest part)

• Z.reticularis [DHEA & estrogen]

• medulla

Aldosterone

steroid hormone from cholesterol

how many systems regulate aldosterone synthesis

3

what 3 systems regulate aldosterone synthesis

• renin-angiotensin system (main system)

• blood potassium levels

• ACTH

what does the renin-angiotensin system regulate

Extracellular fluid (ECF) volume 

steps of renin-angiotensin regulation

drop in ECF volume = drop in perfusion pressure at the afferent arteriole of the renal glomerulus (baroreceptor)

this stimulates the juxtaglomerular cells to secrete renin, a protease that cleaves angiotensinogen → angiotensin I → angiotensin II 

angiotensin II has direct arteriolar pressure effects, and it stimulates aldosterone synthesis by binding to a G-protein coupled receptor in the zona glomerulusa

biotransormation of P5 to glucocorticoids

how does cortisol exist

• 5% free

• 75% transcortin (CBG)

• 20% albumin

how does aldosterone exist

almost no binding

what are binding proteins fundamental for

transport in bloodstream and maintaining lifespan

steps of adrenocorticosteroid transport

1. hormone bound to binding protein in the blood dissociates at cell membrane in order to enter

2. when inside the cell, the hormone needs to be bound to chaperone protein to prolong lifespan

3. binds to chaperone protein + receptor

4. eventually chaperone dissociates and hormone is bound to receptor

5. hormone and receptor enter the nucleus where they come apart

Cortisol (hydrocortisone)

• numerous effects; direct and permissive

• CHO, protein, and lipid metabolism

• increase blood glucose overall; protects heart/brain 

• liver - gluconeogenesis, glycogen storage 

• periphery decrease glucose use, increase protein and lipid breakdown (to increase blood glucose)

• anti-inflammatory and immunomodulatory effects

• inhibit production of proinflammatory mediators

• stress coping support (stress increases cortisol)

• CNS; sense of well-being, mood and behaviour

• cardiovascular integrity

• stimulation for development of fetal lung-surfactant (used in last trimester of pregnancy when risk of preterm labour)

what does aldosterone regulate

fluid and electrolyte balance; Na+ and K= homeostasis

• rapid activation of Na+ channels in the apical membrane of principal cells (Distal Collecting Tubes + Collecting ducts) 

• promotes Na+ reabsorption, H+/K+ excretion

• cardiovascular support; blood pressure

can aldosterone and cortisol have similar effects when working on receptors

Yes, aldosterone and cortisol receptors are very similar, thus cortisol can have similar effects when working on aldosterone receptors

distal tubule

• reabsorption of 7% of Na+

• Impermeable to water → further decreases in concentration to a value lower than plasma

Collecting duct

• reasborption of 2-3% of Na+; permeability to water and of concentrated vs. dilute urine dependent on presence of vasopressin (ADH)

topically active glucocorticoid

Fluticasone Proprionate (flonase)

Glucocorticoid and Progesterone antagonist

Mifepristone (Ru486)

Hyperadrenocorticism a.k.a

Cushing’s syndrome

what is cushings syndrome marked by

the presence of elevated cortisol levels in the body — clinical signs of hypercortisolism

clinical signs of hypercortisolism

• upper body obesity

• moon face, buffalo hump

• thinning of skin; easily bruised

• muscle wasting (thinning) of arms and legs

• weakening of bones; osteopenia

• elevated liver enzymes

causes of hyperadrenocorticism (cushings)

• pituitary adenoma; women>men by 5x

• iatrogenic; long term steroid treatment for another problem 

• ectopic ACTH syndrome

• adrenal gland tumors

diagnosis of cushings

• clinical signs, blood tests, imaging

• 24 hr urine collection; elevated cortisol (if elevated @ one time, could just be a peak due to circadian, thus, monitor over 24 hours)

• provocative tests to rule out adrenal vs. pituitary vs. ectopic

therapy for cushings

surgery (in case of tumor) → resectable tumors; pituitary, adrenal, ectopic

Radiation (if malignant) → alone or follow up to surgery of tumor

adrenocorticosteroid inhibitors → used when cortisol is elevated due to medical treatment → Mitotane, Adrenolytic; specific for adrenals

therapy for cushings

• hormone synthesis inhibitors

• glucocorticoid receptor antagonists

hormone synthesis inhibitors

• ketoconazole; most effective inhibitor; liver damage

• aminoglutethimide; inhibits conversion of cholesterol to pregnenolone; adrenal tumors (1st limiting step)

• trilostane; inhibits conversion of pregnenolone to progesterone (step down from above, less drastic side effects, but still lots)

what is the limiting step in production of lots of hormones 

the conversion of cholesterol to pregnenolone

→ also stops the production of aldosterone and other hormones

glucocorticoid receptor antagonists

• mifepristone; at higher doses may be effective

• used on inoperable patients with ectopic or adrenal tumors not responding to other therapies

hypoadreocorticism

adrenal insufficiency → addison’s disease

what is primary adrenal insufficiency most commonly caused from

autoimmune disease and adrenal destruction (used to be common in cases of tuberculosis)

what are other possible causes of Addison’s diease

• abrupt steroid withdrawal

• possible following surgery for adrenal tumors or pituitary tumors

acute vs chronic adrenal insufficiency

• acute adrenal crisis is often due to abrupt withdrawal of long-standing glucocorticoid therapy, but can also precipitate from exacerbation of chronic adrenal insufficiency

acute adrenal insufficiency treatment

• emergency often 

• IV fluid support (isotonic NaCl) and IV corticosteroids (hydrocortisone), other supportive care as needed e.g. antibiotics

chronic adrenal insufficiency treatment

• similar signs to acute but less severe

• long-term glucocorticoid (hydrocortisone or prednisone) replacement therapy 

• Fludricortisone (mineralocorticoid) if primary addison’s disease present

Non-endocrine use of glucocorticoids

Anti-inflammatory and anti-allergy therapy 

• mainstay of glucocorticoid use/misuse in medicine

• plethora of allergic conditions; most organ systems 

• reduce proinflammatory mediators by multiple mechanisms

Intensive short-term or emergency therapy 

• anaphylaxis, shock, heat stroke 

• rapidly acting IV preparations of glucocorticoids

• usually given in high doses for pronounced effects

more non-endocrine uses of glucocorticoids

immunosuppressive therapy

• used to quiet an overzealous immune system that is detrimental - organ transplants (prevent rejection), autoimmune ds 

Neoplasia

• glucocorticoids have antilymphoproliferative effects

• useful for certain hematologic malignancies such as lymphoma, certain leukemias

• adjunct therapy for inflammation following radiation and with mast cell tumors 

do glucocorticoids used in non-endocrine diseases treat the underlying problem?

No, they merely mask the symptoms of condition being treated; need to correct underlying problem

how can adverse effects of steroid therapy can be minimized

• lowest dose possible 

• low potency steroids; prednisone

• alternate day therapy; give HPA a day off

• tapered reduction of steroid therapy to allow HPA axis time to recover following treatment

main cause of primary aldosteronism

adrenal adenoma is usual cause

what is primary aldosteronism a sign of

hypertension and hypokalemia

treatment of primary aldosteronism

usually surgical; can be curative

what else can treat primary aldosteronism

blockade of aldosterone can be accomplished also with drugs

• spironolactone 

• eplerenone

what else can mineralocorticoid antagonists treat

• hypertension and heart failure; increased aldosterone contributes to adverse effects

• eplerenone

take home messages

• adrenal steroids are very powerful, affecting entire body 

• aldosterone (Z. Glomerulosa)

• cortisol and androgens (Z fasciculata and Z reticularis)

what are aldosterone and cortisol controlled by

aldosterone (mineralocorticoid) controlled by kidney renin-angiotensin system. 

Cortisol (glucocorticoid) by hypothalamic-pituitary ACTH

what does aldosterone control

kidney sodium and water retention

what does cortisol control

metabolism, promoting glucose regeneration and entry to the blood

are cortisol and aldosterone carried in the blood bound to proteins

cortisol, but not aldosterone, largely carried bound to proteins in the blood

pharmacological targets

enzymes involved in steroid synthesis, as well as steroid receptors

are mineralocorticoid (MR) and glucocorticoid (GR) receptors similar?

yes, very similar, so high cortisol increases sodium retention

what types of different synthetic corticosteroids are available

MR as well as GR specific, differing in duration of action, some only surface active, as well as some antagonists (mifepristone, GR antagonist; spironolactone, MR antagonist)

what else are these drugs used for

widely used as anti-inflammatories, immune suppressants, treatment of glucocorticoid insufficiency, treatment of women in premature labour

what happens to those taking glucocorticoids long term

they are very powerful drugs, so long term glucocorticoids suppress ACTH, and must be tapered off slowly - or the patient may suffer an adisonian crisis when the glucocorticoid is stopped