• The adrenal glands are pyramidal organs located in the retroperitoneum, one above each kidney
• cortex – outer region; yellow due to cholesterol storage; derived from mesoderm; it produces steroids
• medulla – center region; maroon in color; derived from neural crest; it produces catecholamines
• Blood Supply – from the inferior phrenic arteries, renal arteries, and branches directly off the aorta
• a portal system drains the cortex into the medulla, carrying corticoids which Ý enzymatic conversion of NE Þ Epi
• primary venous drainage is the inferior vena cava on the right and the left renal vein on the left

• Three Zones – transition between these zones is gradual; they regulate salt, sugar, and sex
• (1) zona glomerulosa – outer subcapsular layer of small lipid-poor columnar cells arranged in irregular clusters
• controls salt – makes mineralocorticoids that use Na⁺⁺ homeostasis to regulate blood volume
• (2) zona fasciculata – wide zone of uniform large lipid-laden cuboidal cells arranged in radiating cords around sinusoids
• controls sugar – makes glucocorticoids, which Ý Ý blood glucose
• (3) zona reticularis – inner layer, compact cells arranged in a network
• controls sex – makes adrenal androgens; also serves as reservoir for zona fasciculata

Steroid Hormones – made in adrenal cortex

• Adrenal cells have abundant mitochondria and smooth ER for steroid production from membrane-bound lipid droplets
• SER and mitochondria Þ steroid hormones; RER and Golgi Þ peptide hormones
• steroids are never stored, so biosynthesis and secretion are closely coordinated
• Steroid Synthesis – begins with cholesterol (27 carbons); Carbons are taken off via Redox Reactions (hydroxylation/dehydroxylation)
• requires many enzymes in both cytoplasm and mitochondria; different steroids have different sets of enzymes
• because of the number of enzymes involved, ectopic steroid production almost never occurs; by contrast, ectopic production of peptide (e.g. ACTH) may require de-repression of single gene, and is a common event
• first step (rate limiting) makes pregnenolone, a 21-carbon steroid – two potential pathways:
• (1) progesterone Þ hydroxylated at C-21 Þ aldosterone
• (2) 17-OH progesterone Þ hydroxylated at C-21 Þ cortisol
• 21-hydroxylase deficiency – results in inability to produce aldosterone and cortisol from progesterone
• loss of cortisol Þ Ý Ý ACTH (no feedback inhib.) Þ Ý Ý pregnenolone Þ Ý Ý other steroids, esp. androgens
• causes early development of secondary sexual characteristics, early growth spurt followed by premature epiphyseal closure due to androgens; in girls this may also cause virilization at birth thus confusing gender
• Regulation
• glucocorticoid – hypothalamic CRH Þ pituitary ACTH Þ zona fasciculata hypertrophy
• mineralocorticoid – renin-angiotensin system Þ angiotensin II Þ zona glomerulosa hypertrophy
• pituitary problems affect cortisol but not aldosterone; adrenal problems affect both
• Steroid Receptor – similar to the thyroid hormone receptor – bind gene regulatory element to affect transcription
• no spare receptors so receptor binding and action of hormone curves are superimposable
• Ý cortisol receptors Þ Ý survival of acute lymphoblastic leukemia patients, suggesting cortisol has critical function in life
• Receptor Specificity – mineralocorticoid and glucocorticoid receptors are not specific; both can bind cortisol and aldosterone
• aldosterone Þ cortisol receptors – not a problem, since systemic levels of aldosterone are very low
• cortisol Þ aldosterone receptors–prevented in cells that respond to aldosterone by intracellular modification of cortisol
• 11-hydroxysteroid dehydrogenase (11-HSD) – produces 11-dehydrocortisol – ß affinity of cortisol for mineralocorticoid receptors
• glycerotinic acid (in licorice) inhibits 11-HSD Þ licorice causes symptoms of Ý Ý mineralocorticoid, cortisol in urine
• Steroid Catabolism – free steroids are glucuronidated in liver and excreted from kidney; some free steroid is also excreted
• liver disease can ß catabolism Þ Ý level of steady state unbound active steroid

Glucocorticoid – cortisol

• Cortisol secretion from zona fasciculata is regulated by ACTH along the Hypothalamic/Pituitary/Adrenal Axis
• ACTH also plays some role in androgen secretion (which usually parallels ACTH secretion)
• there are multiple interactions between immune system and hypothalamic/pituitary/adrenal endocrine axis
• e.g., IL-1 from macrophages Þ Ý CRH Þ Ý cortisol Þ ß IL-1 synthesis
• Control of Release
• negative feedback by cortisol – serum concentrations of cortisol and ACTH are thus inversely proportional
• circadian (diurnal) rhythm – ACTH is high in the morning and low at night (due to suprachiasmic input to hypothal.)
• secreted episodically (like all hormones)
• stress – increases ACTH
• Protein Binding – 92% protein bound (75% by corticosteroid binding protein (CBG), 17% by Albumin)
• only free, unbound form is active and can inhibit ACTH secretion
• estrogen Ý cortisol secretion by Ý concentration of CBG Þ less free cortisol to inhibit ACTH secretion
• Action of Glucocorticoids
• Glucose Homeostasis and Metabolism – anabolic in the liver, catabolic everywhere else
• release amino acids from skeletal muscle (50% ala and glu) for gluconeogenesis, also from skin and bone
• counterregulates insulin (Ý glycogen, Ý gluconeogenesis, ß glucose uptake in adipose tissue, Ý a.a. release)
• Immune Effects – anti-inflammatory, immunosuppressive
• ß capillary permeability and blood flow, ß endothelial swelling, ß immune complex membrane passage
• ß eosinophils, Ý neutrophils (number, function, and responsiveness)
• ß function of monocytes and macrophages: ß cytokine production (IL-1), ß phagocytosis Þ Ý infection
• Kills lymphocytes (T>B), ß response to Ag; greater effect on cell mediated; redistribution to Lymphoid tissue
• Other Effects – necessary for blood vessels to respond to catacholamines
• Therapeutic uses of Glucocorticoids – treatment of serum sickness, urticaria, hemolytic anemia, hematologic malignancies, collagen vascular disorders (lupus, RA), infections that cause serious immune response, transplants

Mineralocorticoid – aldosterone

• Secretion from zona glomerulosa is regulated by the Renin-Angiotensin System (for adaptive blood pressure response)
• renin is a small peptide made in juxtaglomerular cells of afferent renal arterioles
• renin is regulated by renal baroreceptors, adrenergic nerves, and circulating factors (hormones)
• renin cleaves proangiotensinogen to Angiotensin I
• Angiotensin Converting Enzyme (ACE) in lung capillaries cleaves off 2 amino acids from angiotensin I to form Angiotensin II, the most potent vasoconstrictor known
• angiotensin II stimulates aldosterone secretion at low levels (even at levels too low to Ý BP by vasoconstriction)
• angiotensin II stimulates cortisol secretion at very high levels
• Atrial Natriuretic Factor (ANF), made in heart, opposes renin-angiotensin-aldosterone system
• ß action of aldosterone, ß renin secretion, ß A-II vasoconstriction, blocks A-II stimulation of aldosterone
• Action of Mineralocorticoids – Retention of Na⁺ and Excretion of K⁺ and H⁺ in renal tubules
• results in hypernatremia, hypokalemia, alkalosis, hypertension

• interpretation of ACTH and cortisol levels (works for all pituitary trophic hormone–target organ axes):
• ACTH high:
• cortisol high – Autonomous secretion of ACTH or resistance to cortisol action
• cortisol low – primary cortisol insufficiency (pathology of adrenal gland itself)
• ACTH low:
• cortisol high – Autonomous secretion by adrenal gland
• cortisol low – Pituitary Failure = secondary insufficiency (pathology of pituitary gland)
• Secondary Adrenal Insufficiency: if the Cortisol is low, the ACTH should be high; so if it ain’t high it's low, even if it is in the normal range, because the normal range is normal for a healthy, adult, ambulatory volunteers drawn from 8-10 in the morning
• Recall that cortisol secretion is highly variable because of the four factors mentioned above (Hypo-pit-adrenal axis, diurnal rhythm, episodic secretion, stress). All must be considered when trying to evaluate adrenal function.
• Basal Adrenal Function Test – levels are generally unreliable due to diurnal rhythm and huge cortisol response to stress
• the issue is not, "can one generate basal levels (10mg/d)?" but, "can one respond to stress (200mg/d), i.e. shock?"
• has most value in looking at cortisol excess
• Dynamic Testing – used to evaluate cortisol deficiency
• ACTH Stimulation Test ("cosyntropin stim") – asses cortisol reserve in adrenal by stimulating the adrenal with cosyntropin, the active (C-terminal) part of ACTH; it this works, then the problem is with the pituitary (ACTH production) and not the adrenal (ACTH response)
• Metyrapone Test – inhibits steroid synthesis Þ Ý ACTH Þ stimulation of Cortisol secretion
• Insulin Tolerance Test – induce hypoglycemia and asses whole system: CRH, ACTH, Cortisol
• Plasma ACTH Level – measure directly; if it ain't high it's low
• CRF (CRH) Stimulation Test – asses ACTH reserve in pituitary
• If you suspect Hyperfunction Þ Do a Suppression Test
• If you suspect Hypofunction Þ Do a Stimulation Test