Endocrine system: hypothalamic hormones, growth hormone, prolactin, others (lecture 11)

Glucocorticoids

• Glucocorticoids are anti-inflammatory agents.
• Widely used in ointments as hydrocortisone to relieve swelling and other signs of inflammation.
• Excessive secretion or medical use can suppress the immune system.
• Stimulate RBC production promoting hemoglobin release.
• Involved in carbohydrate, protein, and fat metabolism.
• Increase hemoglobin concentration.
• Facilitate stress response and tissue repair.
• Cortisol is the most potent, while corticosterone is weaker.
• Facilitate fat and protein catabolism, gluconeogenesis, and the release of fatty acids and glucose into the blood.
• Trigger gluconeogenesis.

Neural and Hormonal Stimuli

• In short-term stress, nerve impulses cause the adrenal medulla to secrete catecholamines (epinephrine and norepinephrine).
• Increased heart rate and blood pressure and the liver converts glycogen to glucose.
• Bronchioles dilate, blood flow patterns change, digestive system activity decreases, and urine output reduces.
• Metabolic rate increases.
• With prolonged stress, the hypothalamus releases CRH.
• ACTH is secreted, stimulating the adrenal cortex to secrete mineralocorticoids and glucocorticoids.
• Kidneys retain sodium and water, increasing blood volume and blood pressure.
• Proteins and fats convert to glucose or break down for energy and blood glucose increases, while the immune system is suppressed.

Cortisol in a Coordinated Response

• Cortisol is involved in a coordinated response that counteracts insulin and raises blood glucose levels.
• Triggers fat breakdown in adipose tissue, promotes glucose generation in the liver, and reduces bone formation.
• Decreases amino acid uptake in muscles, leading to muscle protein breakdown.

Fat-Soluble Hormones

• Examples are cholesterol, progesterone, cortisol (hydrocortisone), aldosterone, estradiol, and testosterone.
• Fat-soluble hormones enter the cell.
• Directly affect genes.

Water-Soluble Hormones

• Water-soluble hormones bind to the cell surface.
• Trigger a chain reaction inside the cell.

How Cortisol Affects the Liver

• Cortisol prepares the body for a "fight or flight" response by making more energy available.
• Binds to receptors in liver cells, activating specific genes.
• Fat creation increases (lipogenesis).
• Glucose production is increased (gluconeogenesis).
• Breakdown of glycogen is increased (glycogenolysis).
• Glycogenesis decreases.

Gluconeogenesis

• The generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids.
• Glucocorticoids stimulate the liver to produce glucose from non-carb sources.
• Essential during stress or fasting when glucose levels are low.
• Enzymes are essential for the efficient conversion of substrates into glucose.
• Glucocorticoids promote the breakdown of proteins in muscle and other tissues, releasing AAs into the bloodstream.
• These AAs can serve as building blocks for glucose production in the liver.

Glucocorticoids and Homeostasis

• Glucocorticoids (GCs) are critical in maintaining energy homeostasis.
• Chronic excessive GC exposure, like in Cushing's syndrome (CS), impacts body composition and metabolism by causing whole-body insulin resistance and abdominal adiposity.
• Excess GCs lead to muscle atrophy, elevated plasma fatty acids and triglycerides, altered hepatic carbohydrate and lipid metabolism, and impaired pancreatic β-cell function.
• Peripheral insulin resistance happens because signaling and glucose uptake is impaired.
• GCs also reduce bone destiny by increasing bone resorption while inhibiting bone formation, with skin manifestations also resulting from having too many GCs.
• The current review explores GC regulation of body composition and metabolism.
• Physiological exposure to GCs and a responsive HPA axis are essential for any organism's survival, chronic exposure to even slight GC excess causes excessive abdominal and ectopic adipose tissue, dyslipidemia, cardiovascular disease, and decreased survival.

Mineralocorticoids

• Mineralocorticoids influence salt and water homeostasis related to electrolyte and fluid balance.
• Produced from the adrenal cortex in the zona glomerulosa.
• Aldosterone influences blood pressure.
• Aldosterone acts on Na+ and K+ receptors in the distal convoluted tubule (DCT) and collecting tubules.
• Aldosterone's main function is to increase Na+ reabsorption and K+ excretion in the tubules, which is crucial for maintaining blood pressure.

Renin-Angiotensin System

• This system is a hormone cascade that regulates blood pressure and fluid balance.
• Kidneys detect low blood pressure and high Cl- levels.
• Prorenin in the blood is converted to renin.
• Renin converts angiotensinogen from the liver to angiotensin I.
• Angiotensin I is converted to angiotensin II around pulmonary endothelial cells.
• Angiotensin II travels to the adrenal cortex and stimulates aldosterone production as well as narrows blood vessels.

Renin Release

• Renin release involves secretion of it by granular cells and has three regulatory pathways.
• Renal baroreceptors: a drop in renal perfusion pressure stimulates renin release.
• Macula densa: low Cl- in the DCT triggers renin release.
• Sympathetic nervous system: release triggered by beta adrenergic receptors.

Estradiol

• The main adrenal estrogen is produced by the adrenal cortex and interstitial cells in testes.
• Also produced by ovaries (follicles), zona fasciculata & zona reticularis.
• Estradiol is a steroid involved in the maintenance of female reproductive tissues (eggs, oocytes, endometrium/ uterine lining).
• Interstitial cells in testes can produce estradiol, which prevents sperm cell death.
• Contributes to skeletal and skin growth/maintenance.
• After menopause, the ovaries do not function; only the adrenals secrete estradiol.

Growth Hormone

• GHRH stimulates the anterior pituitary (AP) releases GH.
• The highest production of GH occurs in the AP.
• Mitosis and cell differentiation are targets of GH.
• Facilitates tissue growth.
• Plays a role in the growth of bone, cartilage, and muscle.
• Production decreases with age leading to less bone and muscle, and more fat.
• GH has a short half-life (6-20 min).
• The liver secretes insulin-like growth factors I & II (IGFs) which stimulate other target cells.
• IGF-II is critical in fetal growth.

GH Physiological Effects

• Involves in protein synthesis; boosting transcription and translation.
• It stimulates fat metabolism.
• Growth requires energy
• Adipocytes release fatty acids & glycerol resulting in protein-sparing effect
• Facilitates carbohydrate metabolism; reduces glucose uptake from diet
• The brain relies on glucose.
• GH stimulates gluconeogenesis in the liver which is glucose production.
• Facilitates electrolyte Balance causing retention of electrolytes.

GH Effects on Metabolic Health

• GH is involved in physiological effects on glucose metabolism.
• Directly, by inducing gluconeogenesis, glycogenolysis, and lipolysis.
• Indirectly, via IGF-1 stimulation, facilitating insulin action.
• It inhibits insulin-induced suppression of hepatic gluconeogenesis, thus increasing glucose production.
• Increased lipolysis caused by GH, increases free fatty acids (FFA) which contribute to insulin resistance.
• GH stimulates the liver to produce IGF-I.
• GH and IGF-I increases gluconeogenesis in the liver and reduces glucose uptake in the muscle and adipose tissue.
• It promotes glycogenolysis in the liver, further increasing blood glucose levels.
• The combined effects of increased glucose production, decreased glucose uptake, and insulin resistance results in hyperglycemia.

GH Interaction with Atherosclerosis

• Atherosclerosis is a disease characterized by the buildup of fats & cholesterol in artery walls.
• GH deficiency leads to decreased levels of IGF-1.
• Downstream consequences include impaired glucose metabolism, increased body fat, more difficulty for blood to flow through vessels (increasing BP), and decreased immune function.

Growth Hormone Interactions

• IGF-1 and ghrelin maintain a balance with growth hormone
• IGF-1 inhibits GH secretion, by inhibiting GHRH release and stimulating somatostatin release.
• Ghrelin is secreted by the stomach when empty stimulating GH secretion.
• Interactions with the hypothalamus cause hunger and GHRH release, thus readying target organs for nutrient usage.

Prolactin

• Prolactin-releasing hormone releases Prolactin from the anterior pituitary gland.
• Prolactin is a protein, that stimulates milk production (lactation) due to suckling stimulus and lower progesterone.
• It increases LH receptors in interstitial cells (males), which produce testosterone.
• Plays a role in fetal brain development and immune tolerance.
• Key for pulmonary surfactant synthesis, which reduces surface tension in the alveoli of the lungs.

Insulin

• Insulin is a peptide produced by Beta cells of pancreatic islets
• Stimulates the uptake of glucose from blood into liver, fat & skeletal muscles lowering blood sugar.
• There are two types of diabetes:
  • Type I (insufficient insulin production).
  • Type II (insulin resistance) where the body doesn't respond.
• Type I diabetes is an autoimmune disease where the immune system attacks and destroys beta cells in the pancreas

Glucagon

• Peptide made of Alpha cells of the pancreatic islets
• Increases glucose and FAs in blood
• Catabolic, it breaks down substances to release energy.
• Secreted if blood insulin and/or glucose is low.

Pancreas Regulation

• High blood glucose stimulates insulin secretion by certain pancreatic cells, which stimulates other cells to take up glucose, reducing blood glucose.
• Low blood glucose stimulates glucagon secretion by certain pancreatic cells stimulating glycogen breakdown, increasing blood glucose.

Somatostatin

• A peptide produced in the delta cells of pancreatic islets.
• Acts as a paracrine regulator of alpha and beta cells; stimulated by glucose and AAs.
• Lowers stomach acid secretion.
• Inhibits catecholamine secretion.
• Ablation of somatostatin cells leads to impaired pancreatic islet function resulting in neonatal death in rodents.
• Causes dysregulation of glucose homeostasis, and leads to excessive insulin & severe hypoglycemia.