Cortisol & Glucocorticoids

BCH 120 — Metabolic & Endocrine Biochemistry · Dr. Radi

build Jul 17 · 11:11 · CC BY-NC-SA 4.0 · owned figures (RDKit / matplotlib / PyMOL)
Dr. Radi

By the end of this unit, you can…

  • Explain cortisol's stress response (gluconeogenesis, fuel mobilization, immune suppression), its synthesis in the zona fasciculata, and control by the HPA axis with negative feedback
  • Describe cortisol's metabolic effects (catabolic, anti-insulin) and its anti-inflammatory mechanism (NF-κB blockade) with the glucocorticoid drugs
  • Analyze the adrenal cortisol disorders — Cushing's syndrome, Addison's disease, and congenital adrenal hyperplasia
Dr. Radi

Today's route 🗺️

  1. Cortisol, Stress & the HPA Axis
  2. Cortisol's Effects & Anti-Inflammatory Power
  3. Cushing's, Addison's & CAH
Dr. Radi

1 · Cortisol, Stress & the HPA Axis

"Cortisol is the hormone that gets you through a crisis — it raises blood sugar, mobilizes fuel, and quiets non-urgent systems. It's made in the adrenal fasciculata on command from the brain, through a feedback loop you should know cold."

Dr. Radi

Cortisol: the stress hormone

Cortisol is your body's response to stress — trauma, infection, cold, pain, low blood sugar, even emotion. Its whole job is to get you through the crisis: it raises blood glucose (gluconeogenesis, and it counteracts insulin by pulling GLUT4 off the membrane), it breaks down stores (muscle protein → amino acids, fat → fatty acids, all shipped to the liver), and it suppresses the immune system. Brilliant for a short emergency — but chronically high cortisol wastes muscle, weakens bone, and impairs memory.

Dr. Radi

The HPA axis and its feedback

Cortisol is controlled by the hypothalamic-pituitary-adrenal (HPA) axis — the same three-tier logic as the thyroid. The hypothalamus sends CRH, which tells the pituitary to release ACTH, which drives the adrenal cortex (zona fasciculata) to make cortisol. Then the control knob: cortisol feeds back negatively on both the pituitary and hypothalamus to shut its own axis off. ACTH works the fasciculata cell through cAMP → StAR → more cholesterol to P450scc — exactly the steroidogenesis you learned last unit.

Dr. Radi

Making cortisol in the fasciculata

The cortisol pathway uses the same P450 hydroxylation toolkit as aldosterone, with one key branch. Starting from pregnenolone, the enzyme 17α-hydroxylase adds a 17-OH (this is the step that steers toward cortisol and the sex steroids, away from aldosterone). Then 3β-HSD, 21-hydroxylase, and 11β-hydroxylase finish the job: pregnenolone → 17-OH-pregnenolone → 17-OH-progesterone → 11-deoxycortisol → cortisol. Remember those enzyme names — a block at 21- or 11-hydroxylase starves cortisol and causes CAH.

Dr. Radi

2 · Cortisol's Effects & Anti-Inflammatory Power

"Cortisol has two claims to fame: it's a catabolic fuel-mobilizer that raises blood sugar by robbing the periphery, and it's the most powerful anti-inflammatory the body makes — which is why glucocorticoid drugs are everywhere in medicine."

Dr. Radi

The fuel strategy: rob the body to feed the brain

Cortisol is catabolic and anti-insulin — it strips the periphery to keep glucose flowing. In muscle, it breaks down protein to free amino acids; in adipose, it releases fatty acids; both are shipped to the liver, which runs gluconeogenesis and packs away glycogen, raising blood glucose. At the same time it blocks glucose uptake in muscle (fewer GLUT4 transporters), so more sugar stays in the blood. Perfect for surviving a fast or a fight — but sustained, it causes the muscle-wasting, thin skin, and "steroid diabetes" of cortisol excess. (Spent cortisol is later inactivated by 11β-HSD to cortisone and cleared by the liver.)

Dr. Radi

The ultimate anti-inflammatory

This is cortisol's blockbuster role. It shuts down inflammation mostly by blocking NF-κB — the master switch of the inflammatory response. Cortisol's receptor (GR) induces IκB (which traps NF-κB outside the nucleus) and directly interferes with NF-κB, so the cell stops making COX-2, PLA₂, iNOS and the cytokines TNF, IL-1, IL-6 — and immune cells even undergo apoptosis. That's why glucocorticoid drugs — hydrocortisone (a WHO essential medicine) and the stronger synthetics prednisolone (~4×) and dexamethasone (~40×) — treat allergy, autoimmune disease, asthma, and transplants.

Dr. Radi

3 · Cushing's, Addison's & CAH

"Cortisol disease comes in two directions and one clever detour. Too much is Cushing's; too little is Addison's; and a synthesis block gives congenital adrenal hyperplasia — where a missing enzyme reroutes the whole gland into making androgens."

Dr. Radi

Too much vs too little cortisol

Two mirror-image diseases. Cushing's = too much cortisol (an ACTH/adrenal tumor, ectopic ACTH, or — most often — steroid drugs): central obesity, moon face, hyperglycemia, hypertension, osteoporosis. Addison's = too little (the adrenal cortex destroyed, autoimmune or TB), so both cortisol and aldosterone fall: fatigue, low BP, skin darkening (high ACTH/MSH); JFK had it. Diagnose with the dexamethasone-suppression and ACTH-stimulation tests; treat by removing the tumor or replacing the hormones.

Dr. Radi

CAH: a block that makes androgens

Here's an elegant piece of pathophysiology. In CAH, an enzyme in the cortisol pathway is missing — usually 21-hydroxylase (~90% of cases). Low cortisol means no feedback, so ACTH stays sky-high — but since it can't finish cortisol, precursors are shunted into androgens, causing virilization of newborn girls and early puberty in boys. (An 11-hydroxylase block adds hypertension, as deoxycorticosterone builds up.) The fix is logical: give glucocorticoids to restore feedback and switch off the androgens.

Dr. Radi

Can you…?

  • ☐ explain cortisol's stress response (gluconeogenesis, fuel mobilization, immune suppression), its synthesis in the zona fasciculata, and control by the HPA axis with negative feedback?
  • ☐ describe cortisol's metabolic effects (catabolic, anti-insulin) and its anti-inflammatory mechanism (NF-κB blockade) with the glucocorticoid drugs?
  • ☐ analyze the adrenal cortisol disorders — Cushing's syndrome, Addison's disease, and congenital adrenal hyperplasia?

If any box stays empty, the practice site has a drill for it. 🧪

Dr. Radi