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Genital and Adrenal Embryology
- -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
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Differentiation of Internal Genitalia
-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
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Differentiation of External Genitalia
At 8 weeks external genitalia looks the same in male and female. Increased androgen at this stage --> male genitalia by 10 weeks
- -increased male hormone causes development of male external genitalia
- Female
- -male hormone is absent, female external genitalia develops
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Most Common Causes of Androgen Excess
- 1. Fetal Adrenal Androgen Overproduction (CAH)
- 2. Maternal Androgen Overproduction
- 3. Placental Aromatase Deficiency (androgens normally inactivated by placental aromatases into estrogen)
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Hypothalamic-Pituitary-Adrenal Axis
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Adrenal Hyperplasia Results from decreased Cortisol Secretion
- -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
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Forms of CAH
- 1. 21-hydroxylase deficiency (most common)
- 2. 11b-hydroxylase deficiency
- 3. 3b-hydroxysteroid dehydrogenase II (rare)
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21 Hydroxylase Deficiency: Epidemiology
- -causes 90% of CAH
- -autosomal recessive
- -caucasians 1/15,000
- -African Americans 1/42,000
- -Eskimos 1/280
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21 Hydroxylase Deficiency: Pathophysiology
- -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
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21 Hydroxylase Deficiency: Genetics
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
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21 Hydroxylase Deficiency: Clinical Features
- -sexual ambiguity
- -salt wasting
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21 Hydroxylase Deficiency: Diagnostic Tests
- -chemistry panel
- -17 OH Progesterone
- -plasma renin activity (should be elevated)
- -androgens
-newborn screening (12hrs - 6 days)
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21 Hydroxylase Deficiency: Subtypes
- 1. Classic Salt Wasting
- 2. Classic Simple Virilizing
- 3. Non-Classic
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Classic Salt Wasting
- -female genitalia: ambiguous
- -male genitalia: normal
- -incidence: 1/20000
- -decreased cortisol
- -decreased aldosterone
0% enzyme activity
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Classic Simple Virilizing
- -female genitalia: +/-ambiguous
- -male genitalia: Normal
- -Incidence: 1/60000
- -decreased cortisol
- -normal aldosterone
1-2% enzyme activity
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Non-Classic
- * 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
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21 Hydroxylase Deficiency: Treatment
- 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)
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11 Hydroxylase Deficiency: Epidemiology
- -second most common form (5-8%)
- -causes Hypertension
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11 Hydroxylase Deficiency: Pathophysiology
- 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
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11 Hydroxylase Deficiency: Clinical Features
-Hypertension (DOC build up has mineralocorticoid activity)
-decreased aldosterone
-decreased cortisol
-increased DHEA
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11 Hydroxylase Deficiency: Treatment
1. Replace Glucocorticoids (suppresses ACTH, turns off sex steroid production)
2. Surgery for virilization
3. HTN therapy
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3b-Hydroxysteroid Dehydrogenase Deficiency: Pathophysiology
-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
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Clinical Sx of Cushing's Syndrome
- 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
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Cushing's Syndrome: Types
- 1. ACTH-Dependent (80%)
- 2. ACTH-Independent (20%)
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ACTH-Dependent Cushing's
1. pituitary corticotroph adenoma (Cushing's Disease: 85%)
- 2. ectopic ACTH Syndrome (15%)
- -small cell lung cancer (50%)
- -foregut tumor
- -bronchial carcinoid
- -MTC
- -Pheo
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ACTH-Independent Cushing's
- 1. Adrenal tumors
- -adrenal adenoma (>50%)
- -adrenal carcinoma (<50%)
- -macronodular hyperplasia (rare)
2. Exogenous Glucocorticoids (common)
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Cushing's Syndrome: Diagnosis
- -24 hour urine collection to measure cortisol
- -1 mg dexamethasone stim overnight
- -venous sampling (after stim with CRH)
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Cushing's Syndrome: Adrenal Pathology
- -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)
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Cushing's Syndrome: Treatment
- 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)
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Conn's Syndrome: Background and Causes
-primary Aldosteronism (elevated Aldosterone)
- Causes:
- 1. Idiopathic Hyperaldosteronism (70%)
- 2. Aldosterone producing Adenoma (30%)
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Conn's Syndrome: Clinical Features
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
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Conn's Syndrome: Diagnosis
- -confirm increased aldo and decreased renin
- -CT adrenal gland for tumor
- -venous sampling of adrenal veins for tumor
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Adrenal Insufficiency: Background
-Addison's disease
Primary: adrenal gland can be destroyed or absent (elevated ACTH)
Secondary: hypothalamus or more likley pituitary (decreased ACTH)
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Adrenal Insufficiency: Causes of Primary
- -autoimmune adrenalitis (Addison's)
- -metastatic cancer (lung, breast, stomach, colon)
- -infections (TB)
- -amyloidosis
- -Menigiococcymal sepsis
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Adrenal Insufficiency: Causes of Secondary
- -hypothalamic disease
- -pituitary disease
- -exogenous corticosteroid use and withdrawal (decreased negative feedback to HPA --> decreased CRH and ACTH --> adrenal atrophy, takes time to recover)
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Adrenal Insufficiency: Clinical Features
- -weakness, fatigue
- -wt loss, anorexia
- -abdominal pain, N/V
- -depression
- -hyperpigmentation
- -hypotension
- -hypoglycemia
***non-specific
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Adrenal Insufficiency: Diagnosis
- -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
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Incidental Adrenal Tumor: Epidemiology
- -usually found incidentally on imaging
- -found on 5% of abdominal CTs
- -found on 35% of autopsy
- -increased prevalence with age
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Incidental Adrenal Tumor: Types
- -non-functional benign (76%)
- -fxnl benign: Cushing's (15%)
- -primary adrenal cancer (1-4%)
- -Pheochromocytoma (4%)
- -Mets (5%)
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Incidental Adrenal Tumor: Diagnosis
- Imaging
- 1. CT (contrast washes out)
- 2. MRI
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Incidental Adrenal Tumor: Management
- -Hormonally active: resect tumor
- -Hormonally inactive: resect > 4cm, tumors >4cm are much more likely to be malignant
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