adrenal

• Adrenal gland


  Two endocrine organs, one surrounding the other

  
• Main secretions of the adrenal medulla


  • Epinephrine
  • Norepinephrine
  • Dopamine

  
• Secretions of the adrenal cortex


  • Glucocorticoids
  • Mineralocorticoids
  • Androgens

  
• Glucocorticoids


  Steroids with widespread effects on the metabolism of carbohydrate and protein
• Mineralocorticoids


  Essential to the maintenance of Na+ balance and extracellular fluid (ECF) volume
• Adrenal medulla


  Constitutes 28% of the mass of the adrenal gland, contains two cell types: epinephrine-secreting and norepinephrine-secreting

  
• Zones of the adrenal cortex


  • Zona glomerulosa
  • Zona fasciculate
  • Zona reticularis
• Zona glomerulosa


  Contains the enzymatic mechanism for aldosterone biosynthesis

  
• Zona fasciculate and zona reticularis


  Contain the enzymatic mechanisms for forming cortisol and sex hormones

  
• All three cortical zones secrete corticosterone

  
• Norepinephrine, epinephrine, and small amounts of dopamine are synthesized by the adrenal medulla

  
• Norepinephrine formation


  Hydroxylation and decarboxylation of tyrosine
• Epinephrine formation


  Methylation of norepinephrine
• Catecholamines in plasma


  About 95% of the dopamine and 70% of the norepinephrine and epinephrine are conjugated to sulfate
• Catecholamines half-life


  About 2 min in the circulation
• Effects of epinephrine and norepinephrine


  • Glycogenolysis in liver and skeletal muscle
  • Mobilization of free fatty acids (FFA)
  • Increased plasma lactate
  • Stimulation of the metabolic rate

  
• Adrenergic receptors


  α- and β-adrenergic receptors

  
• Catecholamines increase the secretion of insulin and glucagon


  • Via β-adrenergic mechanisms
  • Via α-adrenergic mechanisms

  
• Norepinephrine and epinephrine


  Increase the force and rate of contraction of the isolated heart (mediated by β1-receptors)

  
• Norepinephrine


  Produces vasoconstriction in most organs via α1-receptors
• Epinephrine


  Dilates the blood vessels in skeletal muscle and the liver via β2-receptors

  
• Dopamine


  • Produces renal vasodilation, probably by acting on a specific dopaminergic receptor
  • Produces vasoconstriction, probably by releasing norepinephrine
  • Has a positive inotropic effect on the heart by an action on β1-adrenergic receptors

  
• Dopamine in the renal cortex


  Causes natriuresis, may exert this effect by inhibiting renal Na, K, ATPase

  
• Catecholamine secretion is low in basal states, but the secretion of epinephrine and, to a lesser extent, that of norepinephrine is reduced even further during sleep

  
• Increased adrenal medullary secretion is part of the diffuse sympathetic discharge provoked in emergency situations, which Cannon called the "emergency function of the sympathoadrenal system"

  
• Adrenal cortex hormones


  Derivatives of cholesterol, contain the cyclopentanoperhydrophenanthrene nucleus

  
• Steroids normally secreted in physiologically significant amounts by the adrenal cortex


  • Aldosterone
  • Cortisol
  • Corticosterone
  • Dehydroepiandrosterone (DHEA)
  • Androstenedione

  
• Deoxycorticosterone


  A mineralocorticoid that is normally secreted in about the same amount as aldosterone but has only 3% of the mineralocorticoid activity of aldosterone
• Steroid biosynthesis


  1. Cholesterol is the precursor

  2. Some cholesterol is synthesized from acetate, but most is taken up from LDL in the circulation

  3. Cholesterol ester hydrolase catalyzes the formation of free cholesterol in the lipid droplets

  4. Cholesterol is transported to mitochondria by a sterol carrier protein

  5. In the mitochondria, it is converted to pregnenolone

  6. Pregnenolone moves to the smooth endoplasmic reticulum, where some is dehydrogenated to form progesterone

  7. ACTH binds to high-affinity receptors on the plasma membrane of adrenocortical cells, activating adenylyl cyclase via Gs, leading to a prompt increase in the formation of pregnenolone and its derivatives

  8. Over longer periods, ACTH also increases the synthesis of the P450s involved in the synthesis of glucocorticoids

  
• Cortisol binding

  • Bound to an α globulin called transcortin or corticosteroid-binding globulin (CBG) in the circulation
  • CBG is synthesized in the liver and its production is increased by estrogen
  • CBG levels are elevated during pregnancy and depressed in cirrhosis, nephrosis, and multiple myeloma
  • When the CBG level rises, more cortisol is bound, and initially the free cortisol level drops, stimulating ACTH secretion and more cortisol secretion
  • Changes in the opposite direction occur when the CBG level falls

  
• Cortisol binding to albumin

  A minor degree of binding also takes place, increasing the half-life of cortisol in the circulation to about 60–90 min

  
• Bound steroids


  Physiologically inactive, but function as a circulating reservoir of hormone that keeps a supply of free cortisol available to the tissue

  
• Cortisol metabolism and excretion


  1. Metabolized in the liver, the principal site of glucocorticoid catabolism

  2. Most cortisol is reduced to dihydrocortisol and then to tetrahydrocortisol, which is conjugated to glucuronic acid

  3. Cortisone is an active glucocorticoid because it is converted to cortisol, but it is not secreted in appreciable quantities by the adrenal glands

  4. Little, if any, of the cortisone formed in the liver enters the circulation, because it is promptly reduced and conjugated to form tetrahydrocortisone glucuronides

  
• Aldosterone


  • Bound to protein to only a slight extent, half-life is short (about 20 min)
  • Much is converted in the liver to the tetrahydroglucuronide derivative, some is changed in the liver and in the kidneys to an 18-glucuronide

  
• 17-Ketosteroids


  • The major adrenal androgen is dehydroepiandrosterone, although androstenedione is also secreted
  • 11-Hydroxy derivative of androstenedione and the 17-ketosteroids formed from cortisol and cortisone by side chain cleavage in the liver
  • Testosterone is also converted to a 17-ketosteroid
  • In normal adults, about two-thirds of the urinary ketosteroids in men are secreted by the adrenal or formed from cortisol in the liver, and about one-third are of testicular origin

  
• Adrenal androgens


  • Promote protein anabolism and growth, but have less than 20% of the activity of testosterone from the testes
  • Secretion is controlled acutely by ACTH and not by gonadotropins
  • In normal males, exert very little masculinizing effect when secreted in normal amounts, but can produce appreciable masculinization when secreted in excessive amounts

  
• Adrenal androgen androstenedione


  Converted to testosterone and to estrogens (aromatized) in fat and other peripheral tissues, an important source of estrogens in men and postmenopausal women

  
• Glucocorticoid mechanism of action


  Multiple effects triggered by binding to glucocorticoid receptors, the steroid–receptor complexes act as transcription factors that promote the transcription of certain segments of DNA

  
• Effects of glucocorticoids


  • Increased protein catabolism
  • Increased hepatic glycogenesis and gluconeogenesis
  • Increased glucose-6-phosphatase activity, raising plasma glucose level
  • Anti-insulin action in peripheral tissues, worsening diabetes
  • Increased plasma lipid levels and ketone body formation in diabetics

  
• Glucocorticoids


  Inhibit ACTH secretion, a negative feedback response on the pituitary