Adrenal / Cortisol Basics

Question 1

Basic Anatomy (where is ea hormone made)

Answer 1

• 1- Medulla (inner 20%) - from neuroectoderm; makes catecholamines (epi)
• 2- Cortex (outer 80%) - from mesoderm; high fat/cholesterol content b/c makes hormones from cholesterol
• Zona Glomerulosa - outermost; aldosterone production
• Zona Fasiculata - middle and largest; cortisol production
• Zona Reticularis - innermost; DHEA and androstenedione production (sex hormone precursors converted to testosterone and estrogen outside adrenal)

Question 2

Adrenal Blood Supply

Answer 2

• RICH; branches off aorta, inferior phrenic artery and renal artery –> drain into central vein w/ smooth musc
• Flows from outer cortex –> inner medulla so synthesis of cortisol in cortex can regulate synthesis of catecholamines in medulla
• When stress –> ACTH –> inc flow –> more catecholamines produced –> venoconstriction (combo of more flow and dec lumen can cause acute, spontaneous, bilateral hemorrhage in stress esp if underlying thrombotic/anti-thrombotic condition)

Question 3

Adrenal Development (fetus to puberty)

Answer 3

• At 2 mo gestation - outer “definitive” zone that will be future adrenal and inner “fetal zone” that will regress
• By birth - fetal is only 2/3 of total adrenal; cont to regress until gone at about 1 yr
• Zona glomerulosa and fasiculata form by 2-3 yrs while zona reticularis not well formed until 5-6 yrs and fully formed at puberty (makes sense b/c makes sex cell precursors)

Question 4

3 Fetal / Placenta Enzymes

Answer 4

• HSD3beta2 - converts cholesterol to cortisol and aldosterone to androstenedione; initially expresses in both zones but by mid-gestation only expressed in definitive zone; therefore fetal zone only makes DHEA at this point
  
  • Overall peaks at 8-12 wks then low again until 3rd trimester (needed for maturation of organs like lungs)
• HSD11beta2 (placenta) - inactivates cortisol to cortisone to protect fetus from extra cortisol from mom
  
  • NOT dexamethasone
• Placental Aromatase - converts adronergic steroids to estrogenic steroids so that DHEA from fetal zone becomes estrogen estriol (contributes to mom’s high estrogen) AND prevents conversion to testosterone (protect female fetus from developing male external genitalia)

Question 5

DHEA Throughout Life

Answer 5

• High @ birth b/c made by fetal zone; decreases thru 1st yr as fetal zone regresses then inc again at 5-6 yrs when zona reticularis develops
• Peaks at puberty then dec gradually

Question 6

DHEA and obesity

Answer 6

• DHEA –> androstenedione –> estrone (via aromatase enzyme) AND DHEA –> testosterone –> estradiol (via aromatase enzyme)
• More fat - more aromatase
• Obese women have extra testosterone obese men / post-menopausal women have extra estrogen (protective for osteoporosis but in estrogen cancers; gynecomastia in obese men)

Question 7

Which hormone synthesis pathways are unique to adrenals?

Answer 7

• cortisol and aldosterone (adrenals ONLY)
• CYP11beta1 (cortisol) & CYP11beta2 or aldosterone synthase (aldosterone)
• diff forms so respond to diff regulators; ACTH v. angiotensin II

Question 8

2 Types of Steroid Receptors

Answer 8

• Type 1 - Mineralocorticoid
  
  • Potency is not connected to ligand binding affinity; aldosterone and cortisol bind MR w/ same affinity but aldosterone is 400X more potent in kidney
• Type 2 - Glucocorticoid
  
  • Has ligand binding domain and nuclear binding domain
  • Generally, greater affinity for ligand = greater potency (dexamethasone > cortisol > aldosterone)

Question 9

How does cortisol affect metabolism?

Answer 9

• Carbs - maintain glycogen when fed; inc gluconeogenesis; dec glucose uptake by fat and muscle (form of insulin resistance); inhibits insulin secretion by pancreatic islets
• Lipids - acute lipolysis (breakdown to glycogen for gluconeogenesis); chronic inc visceral and facial fat stores
• Proteins - protein loss from muscle, connective tissue in skin and bone by proteolysis and fibroblast growth (stretch marks)

Question 10

Cardio & Renal Effects of Cortisol

Answer 10

• Cardio - maintain normal cardiac output and sensitivity of vessels to catecholamines
• Renal - maintain water clearance by suppressing ADH and AQ2 (maintain BP) and if very high cortisol it can activate MR instead of aldosterone –> Na retention, HTN, K+ excretion
• High cortisol = HTN
• Low cortisol = hypotension (unresponsive to pressors)

Question 11

Other Effects of Cortisol (5)

Answer 11

• Bone - osteopenia by inhibiting osteoblasts
• GI - suppress absorption of Ca by dec sensitivity to 1,25 dihydroxy vit D
• CNS - mood, sleep, cognition, behavior
• Heme - maintain normal erythropoiesis
• Anti-Inflammatory - inhibits NF-kB and dec cytokine production –> dec T cell function and B cell, eosinophil and macrophage function/#