183. Adrenal Cortex Physiology Flashcards
What are the steps in synthesis of DHEA, cortisol, and aldosterone?
What are the 4 steroid converting enzymes?
- StAR: transports chol into mito.
- P450SCC: chol side chain cleavage –> pregnenolone
3MC. 3-beta-HSD: pregnenolone -> progesterone (MC path)
4MC. 21: progesterone -> 11-DOC (active MC)
5MC. 11AS: corticosterone -> aldosterone
3A. 17: pregnenolone -> 17-OH pregnenolone
4A. 17: 17-OH pregnenolone -> DHEA
3GC. 17: pregnenolone -> 17-OH pregnenolone
4GC. 21: 17-OH pregnenolone -> 11-deoxycortisol
5GC. 11: 11-deoxycortisol -> cortisol
- 11bDH type I and II: convert cortisol to cortisone (inactivate cortisol)
- 17bDH III: convert androstenedione to testosterone
- 5a-reductase: convert testosterone to 5-DHT (more active)
- Aromatase: T -> E (bone health and controls fb)
What is the precursor for ACTH? How is ACTH synthesized - what is important about byproduct?
What receptors does ACTH bind?
What are the stimuli for aldosterone release?
POMC - ACTH prohormone
Cleavage byproduct: MSH - stimulates skin to proliferate melanocytes (why addison’s disease - high ACTH = hyperpigmentation)
Menalocortin Receptors: MCR1 (skin - MSH/ACTH), MCR2 (adrenal cortex - ACTH), MCR4 (hypothalamus - MSH = satiety, mutations cause AD genetic obesity)
Aldo released by Ang II (low BP, low osmotic pressure, direct renal SNS input), hyperkalemia (sensed by adrenal cortex), ACTH
What is the receptor for steroid hormones?
Effects of GC?
Effects of Androgens? How to test for androgens in men and women?
Effects of MCs?
Why don’t GCs stimulate MCs usually?
Nuclear Receptors = activate target gene transcription
GC: Catabolic (less protein synthesis, less AA uptake, AA diverted to gluconeogenesis in liver, less GH secretion/activation)
Hyperglycemic (more gluconeogenesis, more glycogen deposition, insulin antagonism in peripheral tissue)
Electrolytes (Na retention, K excretion)
Adipose (fat redistribution)
RBC: increase RBC mass
Lymphocytes: decrease immune response
Anti-inflammatory
CNS: increase appetite, modulate mood (euphoria, depression)
Androgens: hair growth (beard, pubic, axillary, body), central/temporal balding, acne (sebum production), penile/clitoral growth, erythropoietic (increase oxygen carrying capacity), anabolic (increase muscle mass), anti-estrogen, voice changes
Women: check DHEAS, adrostenedione, testosterone
Men: check T only
warning: SHBG binds T (low SHBG = lower total T)
MC: Na retention, K excretion (minor H excretion)
GCs activate both MC and GC receptors with varying affinity!
11bDH type I (in liver, lungs, fat): converts cortisone to active cortisol
11bDH type II (in kidney): converts cortisol to inactive cortisone (why cortisol has less MC crossover/effects)
What are the clinical features of cortisol, aldo, adrenal androgen deficiency?
What are signs of excess ACTH (with addison’s disease)?
When does cortisol and ACTH peak?
Low Cortisol: anorexia, nausea, weakness, Na craving, hypoglycemia, hypoNa, hyperK, dehydration, death
Low Aldo: hypoNa, hyperK, dehydration, hypotension
Low Adrenal Androgen: axillary/pubic hair loss, loss of libido in women
Excess ACTH: PIGMENTATION (ACTH/MSH stim of MCR1) - not seen in ACTH deficient!
1st peak: ACTH before wakening in morning, cortisol at wakening
2nd peak: afternoon
if don’t sleep well at night hard to predict peaks
Isolated hypoaldosteronism
- causes
Tx for adrenal hypofx
Cause: most common - hyporeninemic hypo-aldo (type 4 renal tubule acidosis) - benign course complication of DM
Other: rare genetic mutations in aldo synthase, drug-induced (heparin, CCBs, ACEi, BBlocker, cyclosporine), removal of aldo-producing tumor
Tx: replacement tx
- hydrocortisone = cortisol
- 9a-fluorocortisol (fludrocortisone) = synthetic MC
- adrenal androgen replacement not generally necessary
Cushing’s Syndrome
- sx: chronic vs. acute
- etiologies
- hallmark
- biochemical tests
- best localization procedure for location
GC EXCESS
Chronic - centripetal obesity, hyperphagia, buffalo hump, purple striae, ruddy complexion, HTN, acne, hirsutism, echymoses, hyperglycemia/DM, myopathy, osteoporosis
ACUTE - weight loss, psychosis, pigmentation, HTN, acne, hypok alkalosis, hyperglycemia, weakness (hypoK), polyuria-polydipsia (hyperglycemia)
Etiologies: Cushing’s Disease (ACTH-secreting pit adenoma)
Adrenal Tumor (adenoma common, ca rare + large)
Nodular Adrenal hyperplasia (macronodular - abberant receptor expression - GIP, AVP, LH, IL1; micronodular - Carney Complex)
Ectopic ACTH Syndrome (LUNG CA, CA of PANCREAS)
Exogenous steroid administration (most common in US)
Ectopic CRH producing tumor (rare)
HALLMARK: non-suppressibility of excess hormone production
Biochemical: loss of diurnal rhythm of plasma cortisol (MOST SENSITIVE TEST - MIDNIGHT SALIVARY FREE CORTISOL - should be low)
loss of suppressibility of steroid secretion (fails Dexamethasone suppression Test)
excessive steroid production (24hr urine free cortisol excretion, AM cortisol, AM ACTH)
Pit: see on MRI, sample via inferior petrosal
Adrenal: MRI/CT, sample via Adrenal vein
Ectopic: obvious primary cancer source
Selective MC Excess
- etiology (primary vs. secondary)
- Dx tests
Primary: aldo-producing adenoma, bilateral nodular hyperplasia (sx: HTN, hypoK, alkalosis)
Secondary: high renin (due to hypovolemia, sx: hypoK, alkalosis)
HYPO-K IS NOT REQUIRED to consider dx of hyperaldo
Dx Tests: plasma renin + aldo (urinary aldo)
Primary hyperaldo: high aldo suppresses low renin (renin not stimulatable, aldo not suppressible)
Secondary hyperaldo: renin + aldo high (renin and aldo suppressible)
Tx for adrenal hyperfx (4)
- remove responsible tumor (surgery, radio/chemo-tx)
- STOP/MINIMIZE exogenous steroids
- block steroidogenesis with enzyme blocker (ketoconazole, metyrapone)
- Block hormone action with receptor antagonist
GC antagonist - mifepristone
MC antagonist - spironolactone, eplerenone
Androgen antagonist - flutamide, finasteride, spironolactone
Congenital Adrenal Hyperplasia
- what it is
- 21-hydroxylase deficiency (sx, tx)
- Nonclassical CAH (what it is, sx)
- 11-hydroxylase deficiency (sx, tx)
CAH: gene deficiency in steroidogenic enzyme causing cortisol deficiency (loss of -fb = high ACTH = adrenal hyperplasia) and excess production of precursors
21HD: no cortisol and no MCs
girls - ambiguous genitalia (mixed phenotype), hypo-amenorrhea (too much androgen)
sx: Na wasting, shock, short stature, hirsutism
tx: GC/MC replacement
Nonclassical CAH: most common in Ashkenazi Jews and Hispanics
20-50% of 21-H activity preserved = less severe phenotype
Main sx: androgen excess (phenotype like PCOS)
SCREEN ALL PTS WITH SX, and screen parents with high prevalence background before pregnancy
11HD: no cortisol (high 11-DOC - active MC)
girls: ambiguous genitalia
sx: Na retention, HTN (high MC), short stature, hirsutism, hypo/amenorrhea
