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distinct zones of the adrenal cortex

zona glomerulosa, zona fasiculata, zona reticularis


What regulates cortisol production

Role of HPA (CRF, ACTH, etc.). POMC and other substances it is a precursor for

Normal rates of secretion and circadian rhythm: morning highest

role of stress/inflammation

rate limiting step

enzymes involved


Why doesn't cortisol activate the mineralocorticoid receptors as well?

Cortisol-cortisone shuttle (HSD1 and HSD2)


What regulates aldosterone production?

Role of kidney

normal rate of production

role of RAS

Ion changes


Mechanisms of action of corticosteroids

bind to cytoplasmic receptor, which is a ligand activated transcription factor

activate/inhibit the levels of various genes


glucocorticoid effects metabolism:

glucose regulation induce hyperglycemia via a combination of mechanisms

Liver: increased glucose synthesis from amino acids and glycerol, increased glycogen storage

Peripheral tissues: stimulating protein breakdown, increased synthesis of glutamine, promotes lipolysis (all building blocks for glucose), decreased utilization of glucose, decreased uptake of glucose (skin/adipose/fibroblasts/thymocytes/PML)

lead to atrophy of lymphoid tissue decreased muscle mass, negative nitrogen balance and thinning of the skin

fats: redistribution of body fats: round face, and back fat (moon face and buffalo hump) most common. Marked central obesity, reduced peripheral fats

promote lipolytic effects of other agents (GH)


glucocorticoid effect Ca2 balance and cardiovascular and blood

Ca: Induces a negative Ca balance, decreased Ca uptake in the gut, increased Ca secretion by the kidney

Cardiovascular and blood: most glucocorticoids have some mineralocorticoid activity, decreased Na excretion can promote hypertension. Enhances the action of other vasoactive substances (ANG II) (possibly via increased receptor levels). Increase smooth muscle expression of alpha 1 and beta 2 adrenergic receptors. Induceds a mild polycythemia by decreased circulating levels of lymphocytes, eosinophils, monocytes, and basophils, redistribution to tissues not a loss of cells, can be prolonged.


Glucocorticoid effect antiinflammatory

In addition to regulating immune cell number, glucocorticoids have a profound effect on other components of the immune system.

mechanisms partially due to the effect on lymphocyte number

inhibit the production of a number of factors essential for generating inflammatory response: proteolytic enzymes, vasoactive and chemoattractant factors (cytokines). Pro-inflammatory enzymes such as COX-2 and NOS.

Stimulates the synthesis of lipcortin, inhibit phospholipase A2 activity, decreased arachidonic acid release and subsequent production of eicosanoids


Glucocorticoid: endocrine

inhibit thyroid stimulating hormone (TSH) release, can lead to misinterpretation of TSH assays for hyperthyroidism

decreased serum levels of thyroxine binding globulins

inhibits extrathryoidal monodeiodination of T4 leads to decreased T3 levels

pharmacological levels inhibit growth, via inhibition of IGF-1 and its signaling pathways

prolonged glucocorticoid xposure inhbits FSH and LH surge: irregular menses, reduced testosterone in men and women


glucocorticoid effect: Bone/ connective tissue/ skin

inhibits osteoblast function, decreased collagen and osteocalcin synthesis, increased bone reasborption- promotes osteoperosis.

inhibit fibroblast function, dereased synthesis of collage, fibronectin, etc, promotes STRIA and bruising


Mineralcorticoid effects

water and Ion balance. Increased Na/K ATPase expression on the distal tubules and the collecting duct to enhance Na reabsorption and K excretion.

Promotes H excretion and H20 reabsorption


Pseudo cushing's syndrome

physiological hypercortisolism associated with disorders other than cushing's syndrome, can be seen in:

significant physical inflammatory stress, such as by a severe bacterial infection.

severe obesity, especially visceral obesity or polycystic ovary syndrome

malnutrition, anorexia nervosa or with intense chronic exercise

psychological stress, severe major depressive disorders and melancholic symptoms

occasionally in chronic alcoholism


Cushing's syndrome ACTH Dependent

associated with excessive ACTH secretion leading to adrenocortical hyperplasia

Cushing disease (pituitary hypersecretion of ACTH): 65-70%

ectopic secretion of ACTH by nonpituiitary tumor- 10-15%

ectopic seretion of CRH by nonhypotalamic tumors causing pituitary hypersecretion of ACT- less than 1%

iatrogenic or factitious cushing's syndrome due to administration of exogenous ACTH less than 1%


Cushing's syndrome ACTH independent

Iatrogenic or factitious cushing's syndrome, the most common predominantly due to long term glucocorticoid use

adrenocortical adenomas and carcinomas 18-20%

primary pigmented nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular yperplasia: <1%

bilateral acronodular adrenal hyperplasia: <1%


Cushing's syndrome SX

central obesity, round face "moon face", growth of fat pads around neck "buffalo hump," excessive sweating, muscle wastage, skin strae neurological complaints including euphoria psycosis and depression


diagnosis of cushing's syndrome:

1. rule out exogenous glucocrticoids or other pharmacological reasons

2. 24 hour urine cortisol: accurate 24 hour series of urine samples. False + in physiologic and people who drink lots of water (5L/day stimulates cortisol production) Problems with people who work night shifts

3. late night salivary cortisol: late night cortisol should be at nadir, this is preserved in obese and psychiatric patients. Not useful in patients with sleep disorders of shift workers


diagnosis cushing syndrome: dexamethasone test

suppression test are used to assess the status of HPA axis and for the differential diagnosis of adrenal hyperfunction

theory: dexamethasone is a high potency glucocorticoid that will promote the feedback inhibition of the HPA leading to a decrease in ACTH production and then cortisol. If cortisol levels are reduced by dexamethasone then the feedback system is operative. Dexamethasone is used as it does not interffere with the lab test for cortisol

Low dose test: differentiates if cushing's or not.

baseline cortisol measures over a 48 hr period. In cushing's no suppression of cortisol. In normal and stressed/obese induced cortisol patients, cortisol levels will be suppressed.

High dose test: differentiates type of cushing

ACTH undectectable but no suppression of cortisol: adrenal tumor

ACTH elevated and no suppression of cortisol: ectopic acth syndrome

ACTH normal to mildly elevated and suppression of cortisol: Cushing's disease


Metyrapone test cushing syndrome

Inhibit CYP11B1

cushing's disease indiciated when cortisol reduces and ACTH increases.

if nonpituitary based cushing's no change in ACTH


TX options cushing syndrome


block and replace: total ablation of cortisol secretion with addition of replacement glucocorticoid therapy when cortisol levels are extremely low. Most useful in patients with erratic cortisol secretion

normalization: goal is to reduce cortisol levels to normal. Useful in patients with invariant hypercorticolism



Mech: Inhibits CYP11A1 and to a lesser degree CYP11B1. reduces the ysntehsis of all corticosteroids

use: controlling hypercortisolism in patients with cushing's syndrome caused by adrenal tumors secreting cortisol or acth dependent causes (recently withdrawn, may still be on step 1)

pharmocokinetics: orally

SX: overtime can induce adrenal insufficiency. may need to supplememnt with corticosteroids and fludrocortisones to replace mineralocorticoids. Drowsiness, morbilliform skin rash, nausea/vomiting, anorexia, adrenal insufficiency, hypothyrodism, masculinzation, hirstim, HA, dizziness, hypotension, pruritus, myalgia, fever, actue generalized exanthematous pustulosis

Drug interactions: induce hepatic microsomal enzymes leading to increased metabolism of other drugs such as warfarin, theophyllin and digitoxin



Mech: antifungal, at higher doses than those employed in antifungal therapy inhibits CYP17 (inhibits glucocorticoid and androgen synthesis). Even higher doses inhibits CYP11A1 thus inhibiting all steroidogenesis. Inhibits corticotroph adenylate cyclase activation (reduces ACTH secretion at therapeutic doses)

use: cushing's disease

drug interaction: Strong inhibitor of CYP1A2, CYP2C9, and CYP3A4 so considerable potential of drug-drug interactions. inhibits P-glycoprotein so may increases levels of P-gp substrates.

SX and pharmaco: other lecture

contraindicated with ergot derviatives, cisapride, or triazolam due to risk of potentially fatal cardiac arrhythmias



Mech: selective inhibitor of CYP11B1 reducing the biosyntehsis of cortisol

use: hypercorticism resulting from either adrenal neoplasms or tumors producing ACTH ectopically. Diagnostic test for cushing's syndrome

pharacokinetics: oral and half life of 20-26min

SX: hirsutism: due to increased syntehsis of adrenal androgens upstream from the enzymatic block, nausea, HA, sedation and rash



anesthetic drug that blocks 11 beta hydroxylation of dexoycortisol to produce cortisol (will cover in neuro)

given IV at nonhypnotic dose in hospital setting



acts on adrenocortical cell mitochondria to inhibit CYP11B1 and cholesterol side chain cleavage enzymes.

metabolized into an acyl chloride that binds to important macromolecules inthe mitochondria causing mitochondrial destruction and necrosis of adrenocortical cells

distributes to fatty tissue and has a long term effect

not used during pregnancy

need to supplement with exogenous glucocorticoids


Mifepristone (RU-486)

Mech: Inhibit the release of the glucocorticoid receptor from the HSP chaperone proteins: reduces the transcriptional effect of glucocorticoids. Also progesterone antagonist (abortion pill)

Use: controlling hypercortisolism in patients with CUshing's syndrome caused by: inoperable ectopic ACTH secreting tumors, adrenal carcinomas unresponsive to other therapies (rarely used)

pharmokinetics: rapid oral availability, long half life (20Hr)

SX: vaginal bleeding vey common. ranges from spotty bleeding from 9-16 days up to 30 days and can be quite heavy and prolonged leading to hypovolemic shock. HA, dizziness, abdominal pain, nausea, vomiting, diarrhea, abdominal cramps

drug interactions: induces hepatic microsomal enzymes leading to increased metabolism of other drugs such as warfarin, theophylline, and digitoxin


Adrenal insufficiency

Primary: structural or functional deficiency of the adrenal cortex (addison's disease): high ACTH levels and low glucocorticoids and mineralcorticoids

secondary: pituitary or hypothalamic deficiency: low ACTH and low normal glucocorticoid/androgens, normal mineralocorticoids

congenital adrenal hyperplasia (CAH)- mutation in enzymes involved in corticosteroid synthesis


Cosyntropin test determine primary and secondary adrenal insufficiency

Cosyntropin is a synthetic ACTH analog: high dose of 250 uG, cosyntropin maximally stimulates adrenocortical steroidogenesis. Cortisol is measured just before administration (baseline) and 30 to 60 minutes after cosyntropin administration (increased levels of circulating cortisol indicates that the adrenal cortex is working)


Primary insufficiency:

combination fo glucocorticoids and mineralocorticoids is required.

hydrocortisone or cortisone are preferred treatment.

supplementation with fludocorrtisone for mineralcorticoid effect


secondary insufficiency

hydrocortisone, cortisone or prednisone, mineralocorticoids are not necessary


replacement therapy with corticosteroids

therapeutic goal is to provide sufficient hormone to maintain normal function

mimic natural levels of glucocorticoids

stimulate the natural circadian rhythm by dividng the dose, 2/3 dose in AM and 1/3 in PM.

mineralocorticoids are given once a day, because their relase does not show circadian effects normally



deficiency in CYp21 most common (90%): redced levels fo corticosteroids, increased 17 hydroxyprogesterone (clincal test) DHEA and androgens due to lack of feedback inhibition and xs ACTH.

classic severe deficit: females pseduohermaphorditism. . males normal at birth precocious puberty

nonclassic post pubery presentation, (mild androgen excess hirsuitism, amenorrhea)

treat with corticosteroids, females with classic can be treated in utero



excessive production of aldosterone leading to hypertension and hypokalemia

most common form: aldosterone producign adenomas and bilateral idiopathic hyperaldosteronism

less common: unilateral hyperplasia or adrenal hyperplasia, familial hyperaldosteronism, and pure aldosterone producing adrenocorticol carcinomas and ectopic aldosterone secreting tumors

TX: surgery: aldosterone producing adenomas if unilateral. Unilateral hyperplasia.

Aldosterone antagonst


Spironolactone aldactone

Mech: blocks renal aldosterone receptors. Also progesterone agonist and androgen antagonist

Use: diagnostic for aldosteronism and treatment of aldosteronism for non surgical candidates

pharmacokinetics: Oral administration (2-3 days) active metabolite.

SX: brest tenderness and menstrual irregularities in women. impotence, decreased libido, and gynecomastia in men.


Glucortcicoids 1

used to treat a host of disease states, especially those with an inflammatory component. With the exception of replacement therapy, glucocorticoid therapy is empirical. Glucocorticoids have a large number of side effects so the minimal effective does is the gaol of therapy. In long term administration this requires trail and error with frequent re evaluation.

Considerations for starting, maintaining and finishing glucocorticoid therapy: excellent anti-inflammatory activity, underlying cause is still present, corticosteroids are palliative not curative, use for steroid responsive conditions, use only when less toxic substances are ineffective, use the minimum effective dose, (a special large dose will have less side effects), administer locally if possible, topical administration wil lessen systemic effects, avoid rapid withdrawl, glucocorticoids may suppress signs and symptoms of diseases or interfere with diagnostic test, once in remission, use every other day therapy (administer in the morning, duplicate circadian rhtym, reduces suppression of HPA axis, better compliance, less side effects)


Glucocorticoids for rheumatic disorders

Vasculitisis: start with high doses and then taper to minimal effective dose. Used in conjunction with other immunosuppressants.

Arthritis: temporizing agents in progressive disease unresponsive to physiotherapy and NSAIDS. Can be used intraarticular injections for localized control


Gluco: respiratory disorders (asthma)

inhaled, used daily as a prophylactic in moderate to severe asthma. Never the sole medication also still have rescue inhaler


Gluco: allergies

never use to treat severe actue allergy attacks. useful to control short duration allergic disorders. In haled and oral generally but in severe conditions IV.


Gluco: respiratory distress syndrome

given to mothers of babies likely to be premature (24034 weeks). Starting at 48 hr pre birth.

Beclamethasone- 2 doses IM to mother 48 hrs and then 24 hr prior to delivery

dexamethasone: 4 doses IM starting at 48 hr pre then every 12 hours.


gluco: dermatologic problem

useful as a topical application in numerous skin conditions like eczma. Can also be used in skin auto immune diseases.


gluco (crohn's disease)

used only if other treatment fail. Given orally or via enema (depending on severity). Often high doses given.


gluco: organ transplant

high doses given at time of surgery to prevent rejection, taper to effective dose. Given in conjunction with other immunosupressents. Also used in acute and chronic rejection


rank order of anti-inflammatory potency ****


Hydrocortisone and cortisol

Prednisone and prednislone



Fludocortisone (high mineralcorticoid effect

Bethmeclasone and dexamethasone


glucocorticoids: absorption

many corticosteroids are orally active. water soluble esters can be given rapidly via iv. A more prolonged effect is seen if given im.

Absorption from local sites (skin etc) is also possible. 90% of cortisol bind % to corticosteroid binding globulin and albumin in the plasma.

Binding affinity for other corticosteroids varies with cortisol highest and aldosterone the lowest (low binding of glucoronide conjugates).

CBG levels raised in pregnancy and in estrogen therapy


glucocorticoids: metabolism and activation/deactivation

all hepatic conjugation with glucoronides/sulfate. First pass effect varies by steroid. Renal excretion.

HSD1, 11 beta hydroxysteroid dehydrogenase type 1 isoenzyme activates (cortisone-cortisol) and found in most glucocorticoid target tissues

HSD2, 11 beta hydroxysteroid dehydrogenase type 2 isoenzyme deactivates (cortisol-cortisone): found in mineralcorticoid target tissues, and kidney, colon, salivary glands, and also placenta.


Preparations and route of administration ****

Oral: all

Aerosol: becla, flusonide, flutacisone, trimecinolone

Topical: becla, dexame, hydrocortisone, trimic

Iv and im: dexa, hydro, methyl, prednisone

Im: cortisone, deoxycortisone, triaminoclone


gluocorticoids SX

adverse reactions due to long term use/high dose.

probability of adverse reactions are dependent on the dose, period of treatment and type of administration.

example of likelihood of adverse reaction to long term steroids based on dose.

Cushing's syndrome


Cushing's syndrome

Cardiovascular: hypertension, edema, Na and Water retention, dependent on mineralocorticoid activity of corticosteroid, hypokalemia

CNS: Euphoria, depression, psychosis, insomnia

immune system: increase susceptibility to infection, especially viral and fungal

GI: peptic ulcer

metabolic: hyperglycemia, muscle catabolism, hyperlipidemia altered fat deposition (moon face), striae

eye: cataracts, glaucoma

osteoporosis: negative ca balance (caused increased parathyroid hormone secretion, cause bone resorption) and inhibition of osteoblasts


adverse reactions of glucocorticoids after withdrawl

HPA suppression lead to adrenal insufficiency

suppression of HPA axis due to feedback loop that inhibits ACTH release.

Decreases acth induced cortisol secretion, promoting secondary adrenocortical insufficiency.

severity depends on individual/ dose/ duration of therapy, can last up to 12 months.

to prevent this should have a "weaning of perod": gradual reduction of steroid following prolonged therapy, including switching to every over the day therapy

potential flare up of underlying disease processes can occur: corticosteroids are palliative and not a cure


contraindications and precautions of corticosteroids

pediatric use should be approached with care because of the potential for growth and development inhibition. Also the negative calcium balance can cause problems with bone growth and strength.

corticosteroids are highly immunosuppressive and can mask viral and fungal infections so should be used with extreme care in these patients and should be avoided if possible. Can be combined with anti infective agents. Patients on prolonged corticosteroids should avoid exposure to viral infections. Ophthalmic use is contraindicated with the presence of either fungal or viral infections

do not use in conjunction with live virus vaccinations