ERM2 - Adrenal Pathology

• -at 4-5 weeks gonadal ridge develops
• -gonadal ridge develops into cells of the gonads and the adrenals
• -4-5 weeks germ cells and neural crest cells migrate to gonadal ridge
• -9-14 weeks fetus is capable of steroidgenesis

***lots of conditions affect both gonads and adrenal glands

-Male Gonad: AMH dissolves Mullerian Duct, Testosterone stabilizes Wolffian Duct

-Female Gonad: lack of AMH allows Mullerian Duct to persist, Lack of testosterone allwas Wolffian to dissolve

At 8 weeks external genitalia looks the same in male and female. Increased androgen at this stage --> male genitalia by 10 weeks

• Male
• -increased male hormone causes development of male external genitalia

• Female
• -male hormone is absent, female external genitalia develops

• 1. Fetal Adrenal Androgen Overproduction (CAH)
• 2. Maternal Androgen Overproduction
• 3. Placental Aromatase Deficiency (androgens normally inactivated by placental aromatases into estrogen)

• -decreased cortisol --> excess ACTH (due to lack of negative feedback)
• -excess ACTH causes hyperplastic hypertrophy of the adrenal gland

• CRH: increased
• ACTH: increased
• Cortisol: decreased

• 1. 21-hydroxylase deficiency (most common)
• 2. 11b-hydroxylase deficiency
• 3. 3b-hydroxysteroid dehydrogenase II (rare)

• -causes 90% of CAH
• -autosomal recessive
• -caucasians 1/15,000
• -African Americans 1/42,000
• -Eskimos 1/280

• -excess production of adrenal androgens
• -reduction in cortisol and aldosterone

• 
• Aldosterone pathway: can't progress past progesterone
• Cortisol pathway: can't progress past 17 OH progesterone

More precursors are shunted to the androgen pathway

Chromosome 6 has both a real gene and a non functional pseudogene

Crossing over can cause mutations that inactivate the real gene

Compound heterozygotes are common

• -sexual ambiguity
• -salt wasting

• -chemistry panel
• -17 OH Progesterone
• -plasma renin activity (should be elevated)
• -androgens

-newborn screening (12hrs - 6 days)

• 1. Classic Salt Wasting
• 2. Classic Simple Virilizing
• 3. Non-Classic

• -female genitalia: ambiguous
• -male genitalia: normal
• -incidence: 1/20000
• -decreased cortisol
• -decreased aldosterone

0% enzyme activity

• -female genitalia: +/-ambiguous
• -male genitalia: Normal
• -Incidence: 1/60000
• -decreased cortisol
• -normal aldosterone

1-2% enzyme activity

• * can present at any age from child to adult
• -female genitalia: +/- clitoromegaly
• -male genitalia: normal
• -Incidence: 1/1000
• -normal cortisol
• -normal aldosterone

20-50% enzyme activity

• 1. Correct glucocorticoid deficiency (late at night)
• 2. Replace mineralocorticoid (maintain Na balance)
• 3. Ensure adequate suppression of sex steroids (prevent virilization of females and advancement of skeletal age)

• -second most common form (5-8%)
• -causes Hypertension

• 
• Aldosterone Pathway: DOC builds up (has mineralocorticoid activity --> salt and water retention), decreased aldosterone

Cortisol Pathway: can't progress pass deoxycortisol

More precursors are shunted to the androgen pathway

-Hypertension (DOC build up has mineralocorticoid activity)

-decreased aldosterone

-decreased cortisol

-increased DHEA

1. Replace Glucocorticoids (suppresses ACTH, turns off sex steroid production)

2. Surgery for virilization

3. HTN therapy

-high Delta5:Delta4???

-high DHEA, increased peripheral conversion to stronger androgens causes variable clitoromegaly in females

-low androgen production in testes causes undervirilization in males

• -defect in mineralocorticoid synthesis results in salt wasting
• 

• 1. General
• -central obesity
• -proximal muscle weakness
• -HTN
• -HAs
• -psychiatric disorders

• 2. Skin
• -wide, purpler striae
• -spontaneous ecchymoses
• -facial plethora
• -hyperpigmentation
• -acne
• -hirsutism
• -fungal skin infections

• 3. Endocrine and Metabolic
• -hypokalemic alkalosis
• -osteopenia
• -delayed bone age in children
• -menstrual disorders (decreased libido, impotence)
• -glucose intolerance, DM
• -kidney stones
• -polyuria
• -increase WBC

• 1. ACTH-Dependent (80%)
• 2. ACTH-Independent (20%)

1. pituitary corticotroph adenoma (Cushing's Disease: 85%)

• 2. ectopic ACTH Syndrome (15%)
•      -small cell lung cancer (50%)
•      -foregut tumor
•      -bronchial carcinoid
•      -MTC
•      -Pheo

• 1. Adrenal tumors
•      -adrenal adenoma (>50%)
•      -adrenal carcinoma (<50%)
•      -macronodular hyperplasia (rare)

2. Exogenous Glucocorticoids (common)

• -24 hour urine collection to measure cortisol
• -1 mg dexamethasone stim overnight
• -venous sampling (after stim with CRH)

• -increased ACTH causes hypertrophy of the adrenal cortex
• -large cells with pale cytoplasm, lose column structure
• -expansion of Zona Fasciculata and Reticularis
• -Zona Glomerulas is normal (aldo under different regulation)

• 1. Pituitary Adenoma (resection, radiation, meds, bilateral adrenalectomy)
• 2. Adrenal adenoma/Macronodular Hyperplasia (resection)
• 3. Bronchial Carcinoid (resection)
• 4. SCLCa (chemo)
• 5. Adrenal carcinoma (poor prognosis)

-primary Aldosteronism (elevated Aldosterone)

• Causes:
• 1. Idiopathic Hyperaldosteronism (70%)
• 2. Aldosterone producing Adenoma (30%)

Aldosterone: increases Na reabsorption, increases K and H secretion

• 1. HTN (chronic, difficult to control)
• 2. Hypokalemia
• 3. Metabolic Alkalosis

• Labs
• -suppressed renin activity
• -elevated aldosterone
• -PAC:PRA >20

• -confirm increased aldo and decreased renin
• -CT adrenal gland for tumor
• -venous sampling of adrenal veins for tumor

-Addison's disease

Primary: adrenal gland can be destroyed or absent (elevated ACTH)

Secondary: hypothalamus or more likley pituitary (decreased ACTH)

• -autoimmune adrenalitis (Addison's)
• -metastatic cancer (lung, breast, stomach, colon)
• -infections (TB)
• -amyloidosis
• -Menigiococcymal sepsis

• -hypothalamic disease
• -pituitary disease
• -exogenous corticosteroid use and withdrawal (decreased negative feedback to HPA --> decreased CRH and ACTH --> adrenal atrophy, takes time to recover)

• -weakness, fatigue
• -wt loss, anorexia
• -abdominal pain, N/V
• -depression
• -hyperpigmentation
• -hypotension
• -hypoglycemia

***non-specific

• -give synthetic ACTH and watch for cortisol response
• -should see no change

-insulin induced hypoglycemia test: stress (ie: hypoglycemia) stimulates CRH and ACTH release, if cortisol doesn't rise have problem with ACTH production

-Metyrapone test: blocks 11 deoxycortisol conversion to cortisol, decreased cortisol levels should increase ACTH, leading to increased 11 deoxycortisol, if there is no increase there's a problem with ACTH secretion

• -usually found incidentally on imaging
• -found on 5% of abdominal CTs
• -found on 35% of autopsy
• -increased prevalence with age

• -non-functional benign (76%)
• -fxnl benign: Cushing's (15%)
• -primary adrenal cancer (1-4%)
• -Pheochromocytoma (4%)
• -Mets (5%)

• Imaging
• 1. CT (contrast washes out)
• 2. MRI

• -Hormonally active: resect tumor
• -Hormonally inactive: resect > 4cm, tumors >4cm are much more likely to be malignant