Week 4

• Cortisol

  • Excess leads to Cushing’s, oligo/amenorrhoea, T2DM and hypertension.
  • Along with bruising, striae, acne, hirsutism, central adiposity and, in children, growth failure.
  • Deficiency leads to weight loss, hypotension and fatigue.
• The adrenal gland lies immediately superior to the kidney
• The adrenal cortex produces steroid hormones, so binds to intracellular receptors and the medulla produces catecholamines, which binds to cell surface receptors
• The adrenal cortex undergoes self-renewal throughout life
• The adrenal cortex is arranged in three concentric zones: zona glomerulosa, zona fasciculata, and zona reticularis
• Glucocorticoids (GCs) increase blood glucose levels and are involved in the stress response.

  
  

  They increase hepatic gluconeogenesis via stimulation of phosphoenolpyruvate carboxykinase and glucose 6-phosphate.

  
  

  They increase hepatic responsiveness to glucagon and inhibit peripheral glucose uptake in muscle and adipose tissue.

  
  

  They increase lipolysis with release of glycerol and free fatty acids in adipose tissue.
• The effects of GCs are minimal on the fed state and during fasting, they contribute to the maintenance of plasma glucose by increasing gluconeogenesis.

  
  

  The effects on muscle are catabolic by decreasing glucose uptake, protein synthesis, releasing of amino acids.

  
  

  During a stress response, GCs increase blood glucose and are needed to maintain vascular sensitivity to catecholamines while mineralocorticoid actions maintain blood volume
• Aldosterone is released under conditions of low blood pressure and binds weakly to CBP.

  
  

  Its synthesis and release is stimulated by AgII (ZG cells).

  
  

  Aldosterone increases sodium reabsorption, fluid volume, blood pressure, and potassium secretion.
• Cortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor, but in vivo only aldosterone acts as a physiologic agonist of the receptor.
• Liquorice contains inhibitors of 11β-HSD2 and chronic ingestion can cause a mineralocorticoid excess syndrome.
• ACTH is secreted by the anterior pituitary under the control of the hypothalamus and stimulates cortisol secretion.
• Glucocorticoids contribute to the maintenance of plasma glucose during fasting by increasing gluconeogenesis.
• Mineralocorticoids, specifically aldosterone, regulate blood pressure and blood volume.
• The cortisol-cortisone shunt involves the enzymes 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2).
• Topical corticosteroids, such as hydrocortisone, can be converted to cortisol by 11β-HSD1 in the skin.
• • The adrenal cortex secretes different steroids with distinct functions due to differential enzyme expression.
  • Functional zonation in the adrenal cortex corresponds to this differential expression
• • Adrenal glands weigh around 4 grams each and are located close to the kidneys.
  • The adrenal gland consists of a cortex (about 90% of its mass) and an inner medulla.
  • The cortex is divided into three layers: glomerulosa (aldosterone production), fasciculata (cortisol production), and reticularis (androgen production).
  • The adrenal medulla (10-20% of the gland) secretes catecholamines, known as adrenaline and noradrenaline.
• • Adrenal gland development involves two cell types, with outer layers moving inward, and Blood flow contributes to its structural and functional zonation.
  • The absence of the enzyme 17α-hydroxylase in the outer cortex prevents cortisol and androgen synthesis.
  • Steroids released into the adrenal circulation inhibit enzymes in subsequent layers.
  • High cortisol levels in the adrenal medulla stimulate the synthesis of phenylethanolamine-N-methyltransferase, which converts norepinephrine to epinephrine.
• • Cortisol has permissive actions, meaning it doesn't always initiate processes but facilitates them by increasing enzyme activity, inducing enzymes, and influencing other hormones.
  • Glucocorticoid Receptors (GRs) are intracellular, mainly located in the cytoplasm, and associated with heat shock proteins. Cortisol binding displaces these proteins.
  • Phosphorylation of GRs allows them to move into the nucleus, where they form homo- or heterodimers with other hormone-receptor complexes.
• Renin is secreted by Juxtaglomerular cells located in the walls of the afferent arterioles of kidney glomeruli.

  Renin is released in response to a drop in blood pressure or blood volume
• ACE is a central component of the renin-angiotensin-aldosterone axis, and ACE inhibitors are widely used drugs to treat hypertension.

  These drugs lower Ang-II levels resulting in less vasoconstriction and aldosterone secretion
• The adrenal cortex originates from the adrenal primordium (mesoderm) and the medulla from migrating neural crest-derived cells (ectoderm).
• Diseases of the adrenal cortex include disorders of cortisol production such as hypersecretion (Hypercortisolism) and hyposecretion (Hyporcortisolism), leading to adrenal insufficiency.
• Physiological demand for steroids varies considerably throughout the day and increases during periods of stress.
• Alternative and curative treatment modalities are needed, such as cell-based regenerative medicine and gene therapy.
• Hypersecretion of cortisol can be caused by ACTH-dependent conditions like pituitary adenoma secreting ACTH (Cushing's disease) and ectopic tumor secreting ACTH (Cushing's syndrome).
• Non-ACTH-dependent causes of hypersecretion include adrenal adenoma secreting cortisol (Cushing's syndrome) and iatrogenic (chronic use of glucocorticoid drugs) (Cushing's syndrome).
• Cushing's syndrome presents with a classical phenotype that comprises central obesity, prominence of dorsal, temporal, and supraclavicular fat pads, abdominal striae, hypertension, and edema.
• Disorders of cortisol production can also result in hyposecretion, leading to adrenal insufficiency, such as Addison's disease.
• Addison's disease can be autoimmune (mainly anti 21 - hydroxylases) or due to metastasis, haemorrhage, infections (especially TB).
• Adrenal Dysgenesis refers to the gland not forming adequately during development, with genetic causes and mutations in SF-1 and DAX-1.
• Congenital adrenal hyperplasia (CAH) is a condition where increased adrenal androgen output (adrenal hyperandrogenism) is a hallmark, usually reflecting loss-of-function mutations in CYP21A2 or CYP11B1 which prevent cells of the zona fasciculata from synthesizing cortisol.
• Congenital adrenal hyperplasia causes an elevation in ACTH that stimulates adrenal hyperplasia with increased synthesis of dehydroepiandrosterone (DHEA) in utero.
• Late onset (nonclassical) CAH is a milder form with symptoms that might develop anytime after birth, including symptoms of androgen excess such as acne, premature development of pubic hair, accelerated growth, advanced bone age, and reduced adult height.
• Later in life, signs and symptoms of Congenital adrenal hyperplasia (CAH) can vary but may include hirsutism, frontal baldness, delayed menarche, menstrual irregularities, and infertility.
• Cholesterol is converted to pregnenelone by CYP11A1.
• In late onset (nonclassical) CAH, women are generally born with normal female genitalia.
• CAH can lead to early onset (severe) symptoms such as extreme Na+ loss, hyperkalemia, metabolic acidosis, circulatory collapse by the second-third week if not treated, and XX with ambiguous genitalia at birth.
• CYP21A2 mutations cause early onset (severe) CAH, characterised by extreme Na+ loss, hyperkalemia, metabolic acidosis, circulatory collapse by the second-third week if not treated, and XX with ambiguous genitalia at birth.
• Progesterone is converted to 11-deoxycorticosterone by CYP21A2.