Adrenal Glands

found above the kidneys bilaterally

medulla(epinephrine and norepi. secretion) and cortex (corticosteroid production)

cortex consists of 3 zones: reticulans (androgen synthesis), fasiculata (cortisol synthesis), and glomerulosa (aldosterone synthesis)

Release of Cortisol from the Adrenals

inflammatory cytokines stimulate hypohtalamus to secrete CRH

CRH stimulates anterior pituitary to secrete ACTH in response to stress and on a diurnal cycle

ACTH causes cortisol to be released from the zona fasciulata

cortisol feedback inhibits the release of CRH and ACTH

Adrenal synthesis and release of Aldosterone

regulated by renin-angiotensin system as well as ACTH

juxtaglomerular apparati in kidneys secrete renin in resoponse to poor perfusion/low NaCl content of blood

renin converts angiotensinogen to agniotensin I which is further converted to angiotensin II in the lungs

angiotensin II stimulates adrenal release of aldosterone from the zona glomerulosa

Synthesis of Adrenal Steroids

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Adrenal androgens (sex hormones)

Dehydroepiandrosterone DHEA

Androstenedione

further converted to estrogen, testosterone, estradiol, etc.

derived from cholesterol using the key enzymes 17 alpha hydroxylase and 3 beta hydroxysteroid dehydrogenase

Adrenal Mineral Corticoids

Aldosterone

acts on renal distal tubules and collecting ducts to increase Na+ reuptake, while increasing K+ and H+ excretion-->increases intravascular volume-->raises blood pressure (pressor effect)

high levels result in hypertension, hypokalemia, hypernatremia, and metabolic alkalosis (low levels produce opposite effects)

renin-angiothensin-aldosterone system involves the kidneys, lungs, adrenals and cardiovascular system to regulate blood pressure and fluid homeostasis

Adrenal  Glucocorticoids

Cortisol

metabolic effects: increases plasma glucose levels by stimulating hepatic gluconeogenesis, increases hepatic glycogen production, decreases peripheral use of glucose, enhances protein catabolism in muscle, enhances lipolysis in fat

anti-inflammatory effects: inhibits the synthesis/release of leukotrienes, prostaglandins, interleukins, cytokines, MCF, MAF, MIF, histamine, reactive oxygen species, and lytic enzymes; generally down-regulates every aspect of the inflammatory response and immune system to prevent unneccessary tissue damage in response to normal inflammation--this is often the therapeutic goal when corticosteroids are used pharmacologically

Metabolic Function of Diurnal Cortisol Cycle

normally the metabolic effects of cortisol provide circulating glucose for the heart and brain during times of stress or between meals while preventing glucose utilization by peripheral muscle and adipose

cortisol helps the body withstand fasting

under normal conditions 2/3 of a person's daily cortisol output is released from the adrenals in the early morning (in case breakfast is not available) and 1/3 in the late afternoon (in case dinner has to be skipped, so glucose levels won't plummet overnight)

over time elevated cortisol levels cause steroid diabetes, truncal fat accumulation, and muscle wasting

 metabolic effects are often the unwanted iatrogenic reactions when glucocorticoids are used pharmacologically

17 alpha hydroxylase deficiency

17 alpha hydroxylase is an important adrenal enzyme in the path from cholesterol to DHEA and Androstenedione (androgens)

it also forms a key precursor to cortisol

if deficient androstenedione and cortisol levels will be decreased (or normal for a while if compensatory mechanisms adequate)

ACTH levels will be high in response to low cortisol

this will stimulate adrenal hyperplasia

Aldosterone levels will be high as cholesterol is shunted into unimpaired mineral corticoid pathway

but renin levels stay low 

sign and symptoms: blood pressure high and worsening (excess aldosterone), hypokalemia and metabolic alkalosis, adrenal hyperplasia, delayed or absent puberty (ambiguous genitalia in males)

a rare form of congenital adrenal hyperplasia

tx: reset homeostasis with exogenous glucocorticoid administered daily (100mg/day to start then taper to replacement therapy at 30-40mg/day)

ACTH levels will drop and Aldosterone will come back under control by renin-angiotensin system

exogenous estrogen and progestin for females if needed to induce puberty

exogenous testosterone and optional surgery as needed for males with ambiguous genitalia or absent puberty

fertility problems likely in both genders

21 hydroxylase deficiency

most common form of congenital adrenal hyperplasia

21 hydroxylase is involved in the production of cortisol (glucocorticoid) and aldosterone (mineral corticoid)

initially cortisol and aldosterone levels will be low

ACTH secretion will rise in response-->adrenal hyperplasia

cortisol and aldosterone levels normalize

increased activity by hyperplastic adrenal glands shunts more cholesterol into functional adrogen synthesis pathway-->elevated androstenedione and DHEA

signs and symptoms: masculinization of females or early puberty for males (androgen excess), adrenal crisis if severe (hyponatremia, shock, due to aldosterone deficiency), rapid growth in childhood but stunted height as adults

tx: reset homeostasis with exogenous glucocorticoid (100mg/day to start then taper to replacement therapy at 30-40mg/day)

ACTH levels will drop and adrenals will return to normal size, overproduction of androgens will decrease

exogenous mineral corticoids may also be neccessary if hyponatremia is a symptom

optional genital surgery for virilized females

11 beta hydroxylase deficiency

rare form of congenital adrenal hyperplasia

cortisol low, ACTH high, adrenal hyperplasia

androgen production high-->virilization like that seen in 21 hydroylase deficiency

aldosterone low, which may lead to salt wasting and adrenal crisis in infancy,  but other mineral corticoids may reach high enough levels due to overproduction in hyperplastic adrenals to cause hypertension as disease progresses

tx: exogenous glucocorticoids (100mg/day to start then taper to replacement therapy at 30-40mg/day)

optional genital surgery for virilized females

Therapeutic Indications for Synthetic Adrenocorticosteroids

Replacement therapy for primary deficiencies (i.e. glucocorticoids for congenital adrenal hyperplasias, or glucocortiocoids +/- mineral corticoids for Addison's)

Anti-inflammatory therapy with glucocorticoids (i.e. rheumatoid arthritis or psoriasis tx)

Immunosuppressive therapy with glucocorticoids (i.e. steroid inhalers for asthma, or oral steroids for ulcerative colitis and Chron's dz)

Diagnostic tests (i.e. dexamethasone supression test)

Cortisol

prototypic glucocorticosteroid against which all synthetic corticosteroids' glucocorticoid activity is compared

very minor mineral corticoid activity (1/300th vs. aldosterone, but still technically a mixed function cortiocsteriod)

secreted from adrenals in response to ACTH

anti-inflammatory, immunosuppressive, raises blood sugar, decreases peripheral glucose utilization

MOA: acts as a transcription factor intranuclearly in target cells, altering gene expression

Adverse effects of excess (endogenous or exogenously derived): euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress

Fludrocortisone (9 alpha-fluorocortisol)

mixed function corticosteriod

10X more potent glucocorticoid vs. cortisol

about half the mineral corticoid activity of aldosterone

anitinflammatory, immunosuppressive, causes Na+ retention and raises blood pressure

contraindicated in patients with essential hypertension

useful in treating patients with Addison's disease with a significant salt-wasting hypotension component

MOA: acts as a transcription factor in target cells, altering gene expression

Adverse effects: euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress, hypertension, hypernatremia, metabolic alkalosis

Aldosterone

prototypic mineral corticoid

some glucocorticoid activity (about 1/3 the potency of cortisol, so considered a mixed function corticosteroid)

secreted from adrenal glands in response to elevated angiotensin II (and to a lesser extent in response to ACTH)

MOA: acts on distal tubules and collecting ducts of nephrons to increase Na+ reabsorption and decrease K+/H+ reabsorption, this increases intravascular volume and blood pressure

Adverse effects of excess: hypertension, hypokalemia, hypernatremia, metabolic alkalosis

Prednisone

a double bond derivative corticosteroid--more potent glucocorticoid activity but some residual mineral corticoid activity

4X the anti-inflammatory action of cortisol

MOA: acts as a transcription factor altering gene expression

anti-inflammatory, immunosuppressive

Adverse effects: euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress

Triamcinolone

synthetic steroid with pure glucocorticoid activity

5X the anti-inflammatory action of cortisol

MOA: acts as a transcription factor altering gene expression

anti-inflammatory, immunosuppressive

Adverse effects: euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress

Dexamethasone

synthetic steroid with pure glucocorticoid action

30X the anti-inflammatory action of cortisol

MOA: acts as a transcription factor altering gene expression

anti-inflammatory, immunosuppressive

Adverse effects: euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress

Betamethasone

synthetic corticosteroid with pure glucocorticoid activity

25X the anti-inflammatory action of cortisol

MOA: acts as a transcription factor altering gene expression

anti-inflammatory, immunosuppressive

Adverse effects: euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress

Beclomethasone

a synthetic glucocorticoid

 MOA: acts as a transcription factor altering gene expression

anti-inflammatory, immunosuppressive

Adverse effects: euphoria, diabetes, osteoporosis, opportunistic infections, ulcers, delayed wound healing, adrenal atrophy, increased sensitivity to stress

Addison's Disease

autoimmune disease causing primary adrenal insufficiency 

signs and symptoms: hypoglycemia, hypotension and faintness, skin hyperpigmentation, muscle weakness, fatigue, nausea, vomiting, diarrhea, salt craving, muscle/joint pain, irritability, depression

adrenal crisis: life-threatening acute hypocortisolism, hypotension, shock, confusion, coma, abdominal pain, dehydration, skin darkening

JFK suffered from Addison's dz

treat with 30-40mg of cortisol per day (replacement therapy) 2/3 in the morning and 1/3 in the evening to mimic natural dirunal cycle

cortiosl usually sufficient to stimulate mineral corticoid activity but if hypotension persists add fludrocortisone

increase dose of cortisol before or in response to stress (surgery, sleep deprivation, infection)

Primary adrenal insufficiency

impairment of the adrenal glands-->reduced cortisol and possibly aldosterone

70-80% caused by Addison's dz

also caused by TB and other infections, congenital adrenal hyperplasias (genetic enzyme insufficiencies), surgery, injury, and tumors

signs and symptoms: hypoglycemia, hypotension and faintness, skin hyperpigmentation, muscle weakness, fatigue, nausea, vomiting, diarrhea, salt craving, muscle/joint pain, irritability, depression, adrenal crisis

treat with exogenous cortisol (replacement therapy) 2/3 in the morning and 1/3 in the evening to mimic diurnal cycle

cortiosl usually sufficient to stimulate mineral corticoid activity but if hypotension persists add fludrocortisone

increase dose of cortisol before or in response to stress (surgery, sleep deprivation, infection)

Steroid Osteoporosis

glucocorticoids reduce Ca++ absorption from the GI tract

PTH levels increase

bone resorption accelerates

osteoporosis develops

How to reduce the Adverse Effects of Glucocorticoid Therapy

alternate day therapy when using glucocorticoids for chronic anti-inflammatory or immunosuppressive effects

use double the daily dose and an intermediate acting steroid (i.e. prednisone or prednisolone) in the morning

there will be less adrenal atrophy and a more normal stress response

if at all possible use inhaled corticosteroids to control asthma, since this will restrict adverse effects to the respiratory tract, greatly reducing adverse outcomes

Cushing's Syndrome

may be due to a pituitary adenoma (easily treatable Cushing's Disease), dedifferentiated non-endoncrine ACTH secreting tumor, hyper-active adrenal glands, ectopic adrenal tissue=metastasized adrenal carcinomas, or overuse of exogenous corticosteroids

symptoms: truncal obesity, abdominal striae, buffalo hump, muscle wasting, moon face, steroid diabetes, bone demineralization (often seen on dental x-ray), growth retardation, hypertension, delayed wound healing, hypokalemic alkalosis

Diagnosing Cushing's Syndrome and Disease

urine free cortisol test will be >50-100mg/day in both

Dexamethasone Supression test: low dose dexamethasone suppresses ACTH secretion in normal patients, 4X higher dose is needed to suppress ACTH in patients with Cushing's disease, and if ACTH levels don't respond to low or high dose dex. susupect an advance cancer secreting ACTH or steroids ectopically

Petrosal sinus testing: exogenous CRH is given, then petrosal sinus blood draining the pituitary is sampled and compared to peripheral venous blood, ACTH will be higher in the petrosal sinus in Cushing's disease (pituitary adenoma), but equal in other forms of Cushing's syndrome

Treatment for Cushing's Disease

Removal of the pituitary adenoma followed by replacement therapy with exogenous corticosteroids

surgical resection of the pituitary adenoma or pituitary irradiation 

 pharmacologic intervention with adrenostatic drugs to inhibit glucocorticoid production should only be used as a bridging therapy between diagnosis and removal of the adenoma

Why adrenostatic drugs are not used chronically to manage Cushing's disease

adrenostatic drugs decrease cortisol secretion, causing more ACTH to be secreted from the pituitary adenoma, over-riding the initial effect of the drug

the increasing ACTH levels cuase aldosterone and androgen secretion to increase as well-->hypertension and sex hormone disruption

best to use these drugs to manage the symptoms of Cushing's between diagnosis and pituitary ablation therapy

Therapies for other forms of Cushing's Syndrome

aggressive tumor ablation therapy (chemo., radiation, surgery) for tumors secreting ectopic ACTH

adrenalectomy if the tumor is confined to the adrenal gland

adrenostatic drugs may be used as temporary bridging therapy to improve symptoms between diagnosis and tumor ablation therapy

Mitotane

adrenostatic drug, somewhat specific for zona reticulans and zona fasiculata (androgen and glucocorticoid production more inhibited that mineral corticoid synthesis)

DDT derivative, highly toxic, no longer used in the U.S.

not overridden by ACTH upregulation, but destroys adrenal tissue

MOA: reacts with CYP450 components of hydroxylase rxns. nonspecifically (21, 17 alpha, and 11 beta hydroxylases affected)

Amphenone B

adrenostatic drug

more potent derivative of mitotane

MOA: blocks 21, 17 alpha, and 11 beta hydroxylases

does not destroy adrenal tissue

ACTH upregulation causes adrenal hypertrophy and loss of therapeutic effect

highly toxic, removed from U.S. market

Metyrapone

adrenostatic drug

MOA: 11 beta hydroxylase inhibitor (blocks conversion of 11-deoxycortisol to cortisol)

Adverse effects: dizziness and GI disturbances

occasionally used to temporarily treat symptoms of hypercortisolism (Cushing's Syndrome) until more definitive treatment can be undertaken

sometimes used to test pituitary ACTH reserve: after administration of metyrapone cortisol levels should drop and ACTH levels should rise

Aminoglutethimide

adrenostatic drug

MOA: inhibits the conversion of cholesterol to pregnenolone (very early step in corticosteroid synthesis)

not specific to adrenal glands

inhibits secretion of glucocorticoids, mineral corticoids, and adrenal androgens alike

effect can be overcome by upregulation of ACTH

most often used to treat hypercortisolism secondary to adrenal cancers

also used with dexamethasone to decrease adrogen secretion in some instances

Ketoconazole

adrenostatic drug at high doses

MOA: inhibits many CYP450s involved in steriod synthesis

compensatory increase in ACTH-->adrenal hyperplasia and overproduction of aldosterone and androgens

displaces estrogen and testosterone from binding proteins, increases estrogen:testosterone ratio

Adverse effects: feminization in men (gynecomastia and oligspermia), masculinization in women (and altered menstrual cycles), hypertesion

Mifepristone (RU486)

glucocorticoid receptor antagonist sometimes used to treat refractory Cushing's syndrome

also a progesterone receptor antagonist, and thus can be used as an emergency contraceptive or as an abortion-inducing agent during early pregnancy

Spironolactone

mineral corticoid (aldosterone) receptor antagonist

anti-pressor activity (reduces blood pressure) 

used to treat excessiver aldosterone secretion

K+ sparing diuretic

Captopril

ACE inhibitor

anti-pressor activity

decreases aldosterone secretion

Losartan

angiotensin II receptor antagonist

anti-pressor activity

reduces aldosterone secretion