The Adrenal

Adrenal Anatomy Composed of a cortex and

medulla, which have separate embryology.

Adrenal Anatomy The adrenal cortex arises fro m the

coelomic mesoderm between the fourth and sixth weeks of gestation.

Adrenal Anatomy The adrenal medulla is derived from cells of

the neural crest that also form the sympathetic nervous system and the sympathetic ganglia.Some of these neural crest cells migrate into the adrenal cortex to form the adrenal medulla, but chromaffin tissue may also develop in extraadrenal sites.

The most common site of extraadrenal chromaffin tissue is the organ of Zuckerkandl, located adjacent to the aorta near IMA.

Adrenal Anatomy The glands weigh about 4g each,

located in the retroperitoneum along the superior-medial aspect of the kidneys.

Yellow appearance because of their high lipid content.

3-5 cm in length, 4-6mm in thickness

Adrenal Glands (Normal)

Adrenal Anatomy Left>right Receive arterial blood from branches of the

inferior phrenic artery, aorta, and renal arteries.

The right adrenal vein is short and exits the gland medially to enter the vena cava. The left adrenal vein exits anteriorly and usually drains into the left renal vein. As a result, adrenal venous catheterization is accomplished more easily on the left than the right.

Adrenal Anatomy The adrenal cortex is composed of

three zones histologically. Outer zona glomerulosa, site for

aldosterone synthesis. Central zona fasciculata and

inner zona reticularis produce both cortisol and androgens.

Adrenal Anatomy Most of the blood supply to the

medulla comes from venous blood draining through the cortex. This provides the adrenal chromaffin cells with high concentration of the enzyme phenyethanolamine N- methyltransferase (PNMT) required for conversion of norepinephrine to epinephrine.

The Cortex Three major hormones Cortisol Androgens Aldosterone

The Cortex Zona glomerulosa is the

exclusive site of production of aldosterone because it lacks the enzyme 17 alpha hydroxylase necessary for production of 17 a- progesterone and 17 a-pregnalone, which are the precursors to cortisol and androgens.

The Cortex Zona fasciculata and reticularis

function as a unit to produce cortisol, androgens, and small amounts of estrogen, but it lacks the enzymes necessary to convert 18-hydroxycorticosterone to aldosterone.

Cortex Cholesterol is the precursor from

which all adrenal steroids are synthesized.

Conversion of cholesterol to pregnenolone is the rate limiting step in adrenal steroidogenesis and is the major site of action of ACTH.

SteroidogenesisCholesterol

Pregnenolone

Progesterone

11-Deoxycorticosterone

Corticosterone

Aldosterone

17-Hydroxypregnenolone

17-Hydroxyprogesterone

11-Deoxycortisol

Cortisol

DHEA

Androstenedione

Testosterone

Estradiol

3β hydroxysteroid dehydrogenase

21β-hydroxylase

11β-hydroxylase

Aldosterone synthase

Cholesterol desmolase

17α-hydroxylase 17,20 lyase

Glucocorticoids Regulated by hypothalamus and

pituitary via secretion of CRH and ACTH.

Glucocorticoids Cortisol, like ACTH is secreted in a pulsitile

manner, and plasma levels closely parallel those of ACTH. Superimposed on this is a circadian rhythm that results in peak cortisol levels in the early morning and a nadir in the late evening.

Physical and emotional stress (trauma, surgery, and hypoglycemia) increase cortisol secretion by stimulating release of CRH and ACTH from hypothalamus and pituitary respectively.

Glucocorticoids Normal daily production of cortisol

is 10-30mg. The liver is the main site of

metabolism. Two major metabolites are 17-hydroxycorticosteroids and 17-ketosteroids, excreted in the urine.

Glucocorticoids Metabolic effects are stimulation of

hepatic gluconeogenesis, inhibition of protein synthesis, increased protein catabolism, and lipolysis of adipose tissue.

Glucocorticoids The increased release of AA from muscle

protein and release of glycerol and free fatty acids from fat provide the substrate for hepatic gluconeogenesis.

Also increase glycogen synthesis, peripheral uptake of glucose is inhibited, and may cause hyperglycemia and increased insulin secretion.

Glucocorticoids Loss of collagen, impair wound

healing by inhibition of fibroblasts. Inhibit bone formation, reduce

calcium absorption by gut (steroid induced osteoporosis).

Glucocorticoids Numerous antiinflammatory actions,

which include inhibition of leukocyte mobilization and function, decreased migration of inflammatory cells to sites of injury, decreased production of inflammatory mediators (IL-1, leukotrienes, and bradykinins).

Also essential for cardiovascular stability, as evidenced by the collapse that occurs in patients with adrenal insufficiency.

Androgens Dehydro-3-epiandrosterone (DHEA)

and DHEA sulfate. Minimal direct biologic activity. In periphery they undergo

conversion to androgens, testosterone, and dihydrotestosterone.

Androgens Increased in Cushing syndrome, adrenal

carcinoma, congenital adrenal hyperplasia. In adult men accounts for only 5% of

testosterone, in prepubertal boys, however, increased production may be manifested by the early development of secondary sexual characteristics and penile enlargement.

In females, manifested by acne, hirsuitism, virilization, and amenorrhea.

Aldosterone Maintains extracellular fluid

volume and regulation of sodium and potassium.

Renin-angiotensin system regulates it.

Aldosterone Renin is secreted by

juxtaglomerular cells of the kidney in response to decreased pressure in the renal afferent arterioles.

Decreased sodium concentration sensed by the macula densa promote renin as well.

Aldosterone Renin is also stimulated by

hyperkalemia, and inhibited by potassium depletion.

Angiotensin II is a potent vasoconstrictor, also stimulates zona glomerulosa to secrete aldosterone.

Aldosterone then stimulates reabsorption of sodium in exchange for potassium and hydrogen ion secretion.

Renin-Angiotensin

Cushings Syndrome Constellation of signs and

symptoms that result from chronic glucocorticoid excess.

Most common source is iatrogenic administration of glucocorticoids.

ACTH-secreting tumors of pituitary are the most common cause of spontaneous Cushing syndrome.

Cushing’s Syndrome, CausesEndogenous Pituitary adenoma

(Cushing’s Disease) Ectopic ACTH

production Ectopic CRH

production Adrenal adenoma

Adrenal carcinoma Adrenal hyperplasia

Exogenous Therapeutic steroids

(pills, lotions, creams)

Major depression Alcoholism

Cushings Syndrome Pituitary Cushing, also termed Cushing

disease, accounts for 70% of all cases of Cushing syndrome.

Ectopic ACTH secreting tumors comprise 15% of all cases and associated with small cell cancers of the lung.

Primary adrenal tumors (adenomas, carcinomas) account for 15-20% of cases.

Cushing Syndrome These patients lose diurnal variation in

cortisol levels. Elevated levels of urinary free cortisol

present in 90% of patients. Normally only 1% of cortisol excreted in urine.

Low dose dexamethasone suppression test will suppress pituitary secretion of ACTH and adrenal production of steroids. So, if am plasma cortisol is suppressed then Cushing is ruled out.

Cushing Syndrome Plasma ACTH levels are used to

differentiate ACTH-dependent (pituitary and ectopic ACTH secreting tumors) from adrenal causes of Cushing syndrome.

With primary adrenal tumors, ACTH should be suppressed (<5pg/ml).

With pituitary causes, it will be normal or slightly elevated (15-200pg/ml).

With ectopic ACTH secreting tumors, it will be markedly elevated.

Cushing Syndrome High Dose Dexamethasone Test

may be used to distinguish pituitary from non-pituitary causes of ACTH-dependent Cushing syndrome.

Rationale is that the high dose will not suppress cortisol production from a primary adrenal neoplasm or ectopic ACTH secreting tumor.

Suspect Cushing Syndrome

24 hour urine free Cortisol X 3 days 100mg/24 hr.

Cushing’s Syndrome

Low dose Dexamethasone suppression test

Equivocal (possible pseudo-Cushing’s)

No suppressionof plasma cortisol

SuppressesPlasma cortisol(<5 ng/ml)

Cushing’s Syndrome No cushing’s

Cushing’s Syndrome

Late-afternoon/midnight measurement of plasma cortisol + ACTH

Plasma cortisol >50ng/mlPlasma ACTH <5 pg/ml

ACTH-independentCushing’s

Adrenal tumor orhyperplasia

Adrenal CT/MRI

Surgical removal

No Cushing’s

Plasma cortisol >50 ng/ml, ACTH >50 pg/ml

ACTH-dependant Cushings Syndrome

High dose dexamethasone suppression test? Metyrapone stim. Test, ?inferior petrosal

Sinus sampling

>50%reduction in cortisol

Pituitary tumor (Cushing’s disease)

Pituitary CT/MRI

Pituitary surgery

cure FailurePituitary irradiation or

Bilateral adrenalectomy

<50% reduction in cortisol

Ectopic ACTH

Thoracic/abdominal CT/MRI

Treatment of primary lesionBilateral adrenalectomyNecessary occasionally

Adrenal Insufficiency, Addisons Weight loss, anorexia 90% Nausea, vomiting 66% Weakness, tiredness, fatigue 94% GI complaints 61% abdominal pain 28% Diarrhea 18% Muscle pain 16% Salt craving 14% Hypotension, dizziness, syncope 14% Lethargy, disorientation 12%

Adrenal Insufficiency, Causes Autoimmune Steroid withdrawal Adrenal atrophy (lymphocytic adenitis

with fibrosis) Malignant infiltration Hemorrhage Sepsis Iatrogenic (post op) Sarcoidosis, Tuberculosis

Adrenal Insufficiency, Diagnosis Hyponatremia Hyperkalemia Azotemia Hypercalcemia 10-30% associated with other endocrine

disorders AM cortisol level, ACTH level Rapid ACTH test

0.25 mg IV cosyntropin Measure cortisol before and 60 min after Cortisol level should be >18mcg/dl at 60 min

Adrenal Insufficiency, Treatment Acute – stress dose

dexamethasone Chronic – hydrocortisone (200-

300mg) plus fludrocortisone (.05-1.0mg/day)

ACTH stim test to establish diagnosis

Hyperaldosteronism Primary (suppressed renin)1. Adrenal adenoma2. Adrenal carcinoma3. Bilateral hyperplasia Secondary1. Renal artery stenosis2. Edematous states (cirrhosis, renal

failure)

Hyperaldosteronism, Diagnosis CT scan Adrenal vein sampling Urinary 18-hydroxycortisol –

elevated in adenoma. plasma hydroxycorticosterone

(overnight recumbent)- > 100 in adenoma

Hyperaldosteronism, Diagnosis Serum K < 3.6 mEq/L Plasma renin activity (PRA) < 1

ng/ml Plasma aldosterone >22 ng/dL Urine aldosterone > 14 mcg/24hrs Urine K > 40 mEq/24 hrs Plasma aldosterone:PRA ratio > 50:1

Hyperaldosteronism, Treatment Bilateral hyperplasia-medical,

spironolactone, amiloride. Unilateral adenoma-

adrenalectomy.

Adrenal Medulla L-Tyrosine converted to L-DOPA converted to Dopamine converted to L-Norepinephine converted to L-Epinephrine Degrades to VMA, metanephrine,

normetanephrine

Catecholamines Exert their effect by interaction will

cell-specific receptors. The principle physiologic effect of

alpha receptor stimulation is vasoconstriction.

Catecholamines Two types of Beta receptors exist. Beta-1 receptors mediate inotropic

and chronotropic stimulation of cardiac muscle, whereas Beta-2 receptors induce relaxation of smooth muscle in non-cardiac tissues, including blood vessels, the bronchi, uterus, and adipose tissue.

Pheochromocytoma 10% extraadrenal 10% bilateral 10%familial 10%children 10% malignant 10% assoc with MEN 10% present with a stroke

Pheochromocytoma Pounding in chest (from B-1

receptor mediated increase in CO). Headaches Hands and feet become moist,

cool, and pale (from A-receptor induced peripheral constriction).

10% present in “pheocrisis” 50% found as incidentaloma.

Pheochromocytoma Elevated BP, fever, flushing,

sweating, anxiety, feeling of doom. Most attacks are short-lived

(15min). May be precipitated by position,

stress, physical activity….

Pheochromocytoma, Diagnosis 24hr urinary catecholamines (NE, Epi,

Dop) and metabolites (metanephrine, normetanephrine, VMA).

Plasma catecholamine or metabolites during episode.

Elevated serum epinephrine suggests pheo in medulla or Organ of Zukerkandl

NO FNA! (can precipitate hypertensive crisis).

Pheochromocytoma, Diagnosis Localizing studies: CT, MRI, MIBG scan

Thin cut CT detects most lesions: 97% intraabdominal.

MRI: 90% pheos bright on T2 weighted scan MIBG: used for extraadrenal, recurrent,

multifocal, malignant disease. Malignant disease

Local invasion, disease outside of adrenal/paraganglionic tissue.

No histological or clinical criteria can differentiate malignant disease.

Pheochromocytoma, Treatment Treatment is surgery Must medically optimize prior to surgery

Treat HTN Expand intravascular volume Control cardiac arrhythmias

Phenoxybenzamine (α-adrenergic antagonist) most commonly given 1-3 wks prior to OR. Other α-adrenergic antagonists, CCB, ACEI used

Pheochromocytoma, Treatment PO salt and fluid repletion. May need β-blocker as

antiarrhythmic. Do not start until after pt α-blocked.

Metyrosine – decreases catecholamine synthesis.

Incidentaloma Found on work up for another cause, not

on cancer workup US 0.1% CT 0.4 to 4.4% MRI

70-94% are benign and nonfunctional >3cm more likely to be functional Up to 20% may be subclinically active Increase with age, no change in sex 5-25% will increase in size by at least 1cm

Incidentaloma Increased risk of adrenocortical

carcinoma with increasing size<4cm 2%

4.1-6cm 6% >6cm 25%

No change with age or sex

Incidentaloma, Workup Bioclinical examination

Dexamethasone suppression test Urinary/plasma catecholamine/metanephrines Serum potassium, plasma aldosterone

concentration-plasma renin activity ratio (if hypertensive)

Rule out other malignancy Stool for occult blood CXR Mammogram

Incidentaloma, Who Gets Surgery? Unilateral, functioning tumors. >6cm; 4-6 cm is a grey area. Rapid growth rate. Imaging not c/w benign adenoma. No surgery if workup reveals metastasis. ?Younger patients (increased lifetime

cancer risk, longer f/u, lower incidence of adrenal masses).

Incidentaloma, Watchful Waiting <4cm, nonfunctioning tumors. CT in 3 and 12 months. If no

increase in size, no data to support further imaging.

? Periodic hormonal testing. If a tumor will start to hyperfunction, this will most likely happen in 3-4 yrs.

Functioning mass Nonfunctioning mass

adrenalectomy >4.5 cmAtypical CTappearance

<4.5 cmBenign

appearance

History ofExtraadrenalmalignancy

adrenalectomyRepeat CT/MRI3 and 12 months

ConsiderFNA

+ FNA - FNA

adrenalectomy observeAdapted from Camerons, Current Surgical Therapy 7th ed. Pg 635