INTERNAL MEDICINE – ADRENAL GLAND DISORDERS
ADRENAL GLAND/SUPRARENAL GLAND
ADRENAL CORTEX – outer
- Mineralocorticoid: aldosterone
- Glucocorticoid: cortisol
- Androgens: DHEA
EMBRYOLOGY
- Adrenal originates from UROGENITAL RIDGE
→ separate from gonads and kidneys (6wk
AOG)
- 7-9th wk AOG: sexual differentiation →
adrenal cortex starts to produce cortisol and
DHEA
Most common cause of congenital ambiguous
genitalia? 21-HYDROXYLASE DEFICIENCY
Adrenal medulla is farthest from blood supply – it is
prone to ischemia/infarct
- Shock, adrenal hemorrhage + severe
meningococcemia = WATERHOUSE
FRIEDRICHSEN SYNDROME
Venous drainage:
- Right suprarenal → vena cava
- Left suprarenal → left renal vein
o LONGER: Left renal vein
NUTCRACKER SYNDROME
- Left renal vein is compressed by Superior
Mesenteric Artery + abdominal aorta
VARICOCELE
- Testicular vein (Pampiniform plexus) = dilated
+ varicosed
- Left testicular vein drains to left renal vein at a
right angle or perpendicular
- Left-sided varicocele caused by: RENAL CELL
CARCINOMA
o Mcc type of renal cell Ca: CLEAR CELL
o TRIAD: Hematuria + mass + flank pain
REGULATORY CONTORL OF STEROIDOGENESIS
HPA Axis – Glucocorticoids + Androgens
- Stress can stimulate hypothalamus
- Corticotropic hormones = released
circadian rhythm
RAAS – Mineralocorticoids
GLUCOCORTICOID SYNTHESIS is under inhibitory
feedback control by hypothalamus and pituitary
- Hypothalamic release of CRH occurs in
response to stress
- CRH stimulates the cleavage of
proopiomelanocortin (POMC) by pituitary-
specific prohormone convertase 1 (PC1) →
yields ACTH
o ACTH is released by corticotrope cells
of the anterior PG → regulator of
adrenal cortisol synthesis
CRH, ACTH
- Pulsatile; follows circadian rhythm
- Hypothalamic control
- SUPRACHIASMATIC NUCLEUS
- Arises early in the morning: 8am; peak levels
in the morning, low in evening
Glucocorticoid excess/deficiency diagnosed by
Dexamethasone Suppression Test
- Excess glucocorticoid test
- Dexamethasone: synthetic → suppress
CRH/ACTH → downregulation of endogenous
cortisol
- Diagnosis of Cushing’s disease: ↑cortisol
o vs. ADDISON’S DISEASE: ↓ cortisol
ACTH Stimulation Test/COSYNTROPIN
- assess glucocorticoid deficiency
- Administration of cosyntropin, collection of
blood 0, 30, 60 mins
- NORMAL response: cortisol >20ug/dL
(>500nmol/L) after 30-60mins
Growth Hormone Tests:
Insulin Tolerance Test (ITT)
- Inject insulin to induce hypoglycemia
- NORMAL response: cortisol >20ug/dL
o GH >5.1ug/L
- Contraindications:
o Seizure, severe hypoglycemia,
electrolyte abnormalities, stroke
Juxtaglomerular Apparatus = JG cells + Macula Densa
RAAS
- JG cells (in kidneys) → release RENIN →
cleavage of angiotensinogen → ANGIOTENSIN
I (liver)
in - In LUNGS: pulmonary capillaries → ACE
cleaves AI → ANGIOTENSIN II → binds and
activates AII receptor type 1
- ↑Aldosterone production and
vasoconstriction
o Enhances SODIUM RETENTION
o POTASSIUM EXCRETION
- Macula densa: Na sensor
 - Stimulus: HYPOVOLEMIA or HYPOTENSION
CUSHING’S SYNDROME
STEROID HORMONE SYNTHESIS ACTH- Ectopic secretion of ACTH by non-
- ACTH stimulation is required for initiation dependent pituitary tumor
- Melanocortin-2-rcp (MC2R): ACTH rcp Pituitary corticotrope adenoma
o Interacts with MRAP → forms ACTH- Adrenocortical carcinoma (ACC)
complex → transported to cell independen Adrenocortical adenoma
t Nodular adrenal hyperplasia
membrane and binds to ACTH
- ACTH binding activates adenylate cyclase → Iatrogenic Exogenous glucocorticoids
↑cAMP → protein kinase (pKA) signaling
pathway Management:
o ↑ import of cholesterol esters - 24hour urinary cortisol excretion
o ↑ activity of hormone-sensitive lipase - Dexamethasone test
- Recommended surgical approach for
→ cleaves cholesterol esters to
Cushing’s disease: TRANSPHENOIDAL
cholesterol – inhibited by ORLISTAT
PITUITARY SRUGERY
o ↑ availability of CREB: enhances
- ORAL AGENTS:
transcription of CYP11A1 – for
o METYRAPONE: inhibits cortisol
glucocorticoid synthesis
synthesis at the level of 11B-
hydroxylase
All steroidogenic pathways require cholesterol import
into mitochondria – requires steroidogenic acute METYRAPONE STIMULATION TEST
regulatory protein (StAR) → shuttles cholesterol to Based on the principle that
inner mitochondria decreasing serum cortisol
- Pregnenolone: precursor of steroid hormones concentrations normally produces
increase in ACTH secretion due to
ENaC: Epithelial Na channels decrease in glucocorticoid negative
Cortisol is inactivated → cortisone by 11B- feedback
hydroxysteroid dehydrogenase To detect partial defects in pituitary
- Occurs in kidney (DCT), colon, salivary glands ACTH secretion
o KETOCONAZOLE: inhibits early steps
ALDOSTERONE SYNTHESIS of steroidogenesis; S/E: gynecomastia
- Zona Glomerulosa: ALDOSTERONE SYNTHASE in males
(CYP11B2)
ETOMIDATE
CLINICAL DISORDERS - Short-acting intravenous anesthetic agent
Adrenal cortex disorders (in general) - Indication: severe cases of cortisol excess
- Clinical manifestations: - Potently blocks 11B-HYRDOXYLASE and
o Diastolic hypertension aldosterone synthase, used to lower
o ↑ gluconeogenesis cortisol
o Lipolysis
o Protein catabolism ECTOPIC ACTH SYNDROME
o Edema - more frequently identified in men
- Notorious for causing ectopic ACTH
o Hypokalemia
production: SMALL CELL LUNG CARCINOMA
(SCLCA)/OAT CELL CA
CUSHING’S SYNDROME
o From NEUROENDOCRINE CELL/
- Chronic exposure to excess glucocorticoids of
KULCHITSKI CELL
any etiology – constellation of features
o SCLCA produces ACTH and ADH
CUSHING’S DISEASE - Predominantly caused by occult carcinoid
- Refers specifically to Cushing’s syndrome tumors
caused by a pituitary corticotrope adenoma o Lung: most frequently
- More frequently affects women except during o Thymus
prepubertal cases (boys) o pancreas
- Most common cause: ACTH-producing
pituitary adenoma
McCune-Albright Syndrome SMITH-LEMLI OPTIZ SYNDROME
- Rare cause of ACTH-independent Cushing’s - Cholesterol synthesis disorder
- polycystic fibrous dysplasia - 7-dehydrocholesterol reductase deficiency
- unilateral café-au-lait spots - Mental retardation
- precocious puberty - Craniofacial malformations
- PATHOGENESIS: Mutations in GNAS-1 - Growth failure
- Syndactyly
MINERALOCORTICOID EXCESS - Ambiguous genitalia
- PRIMARY ALDOSTERONISM: most common
cause of mineralocorticoid excess
- Reflecting excess production of aldosterone - Progressive external ophthalmoplegia
by the adrenal zona glomerulosa - Pigmentary retinal degeneration
- Bilateral micronodular hyperplasia is more - Cardiac conduction defects
common than unilateral adrenal adenomas - Gonadal failure
- CLINICAL HALLMARK: HYPOKALEMIC - Hypoparathyroidism
HYPERTENSION - DM type 1
Clinical manifestation:
- Potassium depletion and increased Na
retention
- Metabolic alkalosis
- Aldosterone excess → direct damage to
myocardium and kidney glomeruli
- Severe hypokalemia → muscle weakness,
overt proximal myopathy, hypokalemic
paralysis
- Severe alkalosis → muscle cramps and tetany
- Increased rate of osteoporosis, DM2,
cognitive dysfunction

PRIMARY ALDOSTERONISM: CONN’S SYNDROME

LIDDLE SYNDROME
- Excess mineralocorticoid activity
- Mutation in ENaC (beta and gamma subunits)
- Decreasing receptor internalization and
degradation
- Hypokalemic hypertension

ASSIGNMENT: GITELMAN’S SYNDROME

BARTTER SYNDROME

CONNSHING SYNDROME
- Concurrent mild autonomous cortisol excess
(MACE)

Others:
AUTOIMMUNE POLYGLANDULAR SYNDROME 1 (APS1)
- Hypoparathyroidism
- Chronic mucocutaneous candidiasis
- AI disorder (thyroid AI, vitiligo, premature
ovarian failure)
- Rarely lymphomas

TRIPLE A SYNDROME (ALLGROVE)

- Alacrima, achalasia, neurologic impairment
- Addison’s disease