unit 5, lesson 5, Cortisteroids hormones

• Steroids are synthesized within the adrenal cortex
• Steroids include corticosteroids (glucocorticoids like cortisol, and mineralocorticoids like aldosterone) and androgens

Anatomy of Adrenal Glands

• Adrenal glands are located above the kidneys
• Adrenal glands consist of the outer cortex and inner medulla

Adrenal Gland Zones

• Steroids are synthesized in the adrenal cortex (80%)
• Catecholamines (noradrenaline and adrenaline) are synthesized in the adrenal medulla (20%)
• Zona glomerulosa cells secrete aldosterone (lack 17-a-hydroxylase)
• Zona fasciculata is the widest region and it contains cells with many lipid droplets
• Zona fasciculata cells secrete glucocorticoids and some sex steroids
• Zona reticularis contains small epithelial cells with fewer lipid droplets
• Zona reticularis cells secrete glucocorticoids and some sex steroids

Synthesis of Corticosteroids

• Glucocorticoid pathway involves 17-hydroxylated corticosteroids (i.e., pregnenolone to cortisol/hydrocortisone)
• Mineralocorticoid pathway involves 17-deoxy corticosteroids (i.e., pregnenolone to corticosterone)
• Steroid hormones have a 21-carbon skeleton, cyclohexane rings A, B & C in 'chair' conformation ('boat' unstable), and a cyclopentane ring D
• The adrenal cortex produces steroids only as required, sufficient for only a few minutes' secretion under normal conditions
• 60-80% of cholesterol comes from the blood via low-density lipoprotein (LDL)
• Adrenocorticotrophin hormone (ACTH) stimulates the transport of cholesterol into cells
• Cholesterol stored in the adrenal cortex is an increasingly important precursor when corticosteroid production is stimulated
• Cholesterol can also be made in cells from acetate and acetylcoenzyme A

Biosynthetic Pathways

• Mineralocorticoid Pathway: Cholesterol → Pregnenolone → Progesterone → 11-Deoxy-corticosterone → Corticosterone → Aldosterone
• Glucocorticoid Pathway: Cholesterol → 17α-Hydroxy-pregnenolone → 17-Hydroxy-progesterone → 11β-Deoxycortisol → Cortisol
• Androgen/Oestrogen Pathway: Cholesterol → Dehydroepiandrosterone (DHEA) → Androstene-3,17-dione → Testosterone → Oestradiol

Transport of Corticosteroids

• Cortisol accounts for 90% of corticosteroid output in man (15-30 mg per day, plasma level 5-20µg/100ml, therapeutic levels >100µg/100ml)
• Corticosteroid-binding globulin/transcortin, together with albumin, binds approximately 90% of plasma glucocorticoids
• Transcortin has low capacity and high affinity, while albumin has high capacity and low affinity
• Usually, the majority of corticosteroids are bound to transcortin
• 10% free plasma glucocorticoids are biologically active
• Changes in free cortisol concentration influence pituitary modulation of adrenal cortex function

Metabolism of Corticosteroids

• Cortisol, corticosterone, and aldosterone are metabolized in the liver
• Reduction of the 4,5 double bond and the C3 and C20 keto groups occurs during the metabolism
• Resultant derivatives are conjugated with glucuronic acid or sulphate at the C3 hydroxyl group
• Excretion occurs in urine

Regulation of Corticosteroid Biosynthesis

• Neural input stimulates the hypothalamus to release corticotrophin-releasing hormone (CRH)
• CRH stimulates the anterior pituitary to release Corticotrophin (ACTH)
• ACTH stimulates the adrenal cortex to produce glucocorticoids (in ZF and ZR) and mineralocorticoids (in ZG)
• Glucocorticoids in ZF and ZR and mineralocorticoids in ZG affect long negative feedback loop
• Anterior pituitary affects short negative feedback loop
• Renin-angiotensin system also regulates corticosteroid

CRH

• CRH is corticotrophin releasing hormone and is composed of a 41 amino acid peptide
• Released into the portal circulation of the pituitary
• CRH levels are controlled mainly by glucocorticoids, also by ACTH and CNS input
• Released from the hypothalamus in response to emotional (fear, anxiety) or traumatic (pain, injury, hypoglycaemia, infection, excess heat or cold) stress and the sleep-wake cycle
• Release is also potentiated by vasopressin, oxytocin, adrenaline, and cytokines
• Acts on pituitary corticotroph cells

ACTH

• ACTH is adrenocorticotrophic hormone or corticotrophin
• It is a 39 amino acid peptide
• Release is regulated both by CRH and glucocorticoids
• Secretion is stimulated by vasopressin
• Complex control includes sleep-wake cycle, stress, psychiatric disturbances, neurotransmitters, and peptides
• Direct effect on corticosteroid production in ZF and ZR, and stimulates production of steroidogenic enzymes

Diurnal Variation

• In the absence of stress, there is a diurnal rhythm in ACTH and glucocorticoid release
• This adapts to changes in sleep/wake patterns
• The rhythm is controlled by CRH

Molecular Mechanism of Action

• Steroid receptors are intracellular and belong to a gene superfamily of nuclear receptors
• Glucocorticoid and mineralocorticoid receptors are located in the cytoplasm
• Androgen, oestrogen, and progesterone receptors are located in the nucleus
• All steroid receptors interact with nuclear DNA to modulate transcription of specific genes
• They can increase or decrease protein expression
• Glucocorticoid receptors are found in most tissues, 10,000-70,000 per cell

Physiological Actions of Corticosteroids

• Affects carbohydrate and protein metabolism
• Affects fat metabolism
• Affects central nervous system
• Affects bone
• Mineralocorticoid effects
• Permissive effects
• Anti-inflammatory and immunosuppressive effects

Carbohydrate & Protein Metabolism Effects

• Increases production of glycogen and glucose
• Antagonizes the action of insulin on glucose uptake, increasing blood glucose
• In the absence of glucocorticoids, individuals subjected to shortage of food or extensive exercise may have hypoglycaemic episodes
• Increases protein breakdown and reduces protein synthesis
• Prolonged high doses of glucocorticoids lead to high blood glucose (hyperglycaemia) with wasting of muscle, thinning of skin and capillary walls, and loss of bone matrix

Fat Metabolism

• Stimulates fat breakdown (lipolysis) and inhibits fat synthesis
• Produces more glucose
• Large doses lead to redistribution of body fat to neck and shoulder regions and cheeks with loss of fat from limbs

Central Nervous System Effects

• Involved in neuronal development in the foetal and neonatal brain.
• May be involved in the development of the CRH-ACTH axis

Effects on Bone

• Regulates calcium metabolism, leading to a net decrease in plasma calcium
• Prolonged doses of glucocorticoids can lead to osteoporosis

Mineralocorticoid Effects

• Increases Na⁺ reabsorption in exchange for K⁺ excretion
• Increases water retention

Permissive Effects

• Allows other hormones to exert effects (e.g., catecholamine-stimulated fat mobilization)
• Helps the body to maintain its temperature and respond to stress
• Stress leads to increased cortisol, preventing stress-induced defense reactions from getting out of control

Anti-inflammatory and Immunosuppressive Effects

• Decreases vasodilation and fluid exudation by vasoconstricting small blood vessels directly
• Decreases the action of T helper cells
• Reduces clonal proliferation of T cells due to decreased IL-1, IL-2, and TNF-α production
• Reduces the number of circulating T- and B-lymphocytes and antibody production
• Impairs recognition responses in antigen presentation
• Decreases leukocyte accumulation in the inflamed area and macrophage release
• Increases neutrophil release from bone marrow
• Reduces the generation of toxic oxygen radicals from neutrophils and macrophages
• Reduces the phagocytic activity of macrophages
• Decreases fibroblast function, resulting in less collagen and glycosaminoglycans accumulation in chronic inflammation
• Decreases production of prostanoids and leukotrienes, suppressing PLA₂ activity
• Decreases generation of pro-inflammatory mediators (IL-1, IL-1β, IL-2, IL-3, IL-6, IL-8, INF-α, INF-y, TNF-a, collagenase, IL-2 receptor, COX-2, INOS)
• Increases production of anti-inflammatory mediators (I-kB, IL-4, IL-10, IL-13, TGFβ, lipocortin-1)
• Reduces complement component concentrations in plasma
• Stabilizes mast cell and lysosomal membranes

Aldosterone

• Mineralocorticoid
• Deoxycortisone also has some activity as do glucocorticoids.
• <0.2mg/day produced, free active concentration 100pmol/l
• Secretion controlled mainly by renin-angiotensin system via angiotensin II
• ACTH and hyperkalaemia also increase release
• Intracellular mineralocorticoid receptors found in epithelial cells
• Receptors only found in distal and convoluted tubules and collecting duct in the kidney, bladder, colon, sweat and salivary glands.
• Cells expressing these receptors also contain 11-ẞ-hydroxysteroid dehydrogenase that inactivates glucocorticoids to reduce mineralocorticoid action

Mechanism of Action of Aldosterone

• Delayed onset (1-2 hrs)
• Increased production of Na+ transporter in the luminal membrane, pumps Na⁺ out of luminal fluid into tubular cells
• Probably increases synthesis of Na⁺/K⁺ ATPase in the basolateral membrane, pumps Na⁺ out of tubular cells into plasma
• Non-genomic mechanism involving spironolactone-insensitive receptors on the basolateral membrane: Stimulation activates Na⁺/H⁺ anti-porter in the luminal membrane, pumps Na⁺ out of lumen into cells

Clinical Disorder of Corticosteroids

• Hypersecretion of corticosteroids causes Cushing's disease or Cushing's syndrome
• Cushing's is caused by over-production of ACTH, ACTH-independent factors, CRH, or prolonged glucocorticoid therapy
• Symptoms include muscle weakness and wasting, back pain (osteoporosis), easy bruising, purple striae in the skin, redistribution of body fat (rounded/moon face, prominent abdomen, buffalo hump, thin legs), virilisation of women, hyperglycaemia, polyuria, polydipsia, diabetes mellitus, and psychological disturbances
• Elevated plasma and urine cortisol levels (loss of diurnal variation)
• Treatment includes surgery, drug treatment, or stopping glucocorticoids

Summary

• The adrenal cortex produces 2 types of steroid from cholesterol
• These steroids corticosteroids (glucocorticoids and mineralocorticoids)
• Glucocorticoid release is controlled by ACTH, which has a negative feedback loop
• Mineralocorticoid release is controlled by the renin-angiotensin system
• Corticosteroids act on intracellular receptors, regulating gene transcription
• Corticosteroids exhibit many physiological effects on carbohydrate, protein, and fat metabolism, CNS, bone, Na⁺/H₂O absorption, permissive effects, anti-inflammatory effects, and immunosuppressive effects