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

Cells of the Anterior Pituitary

• Somatotropes produce GH (Growth Hormone).
• Lactotropes produce PRL (Prolactin).
• Thyrotropes produce TSH (Thyroid Stimulating Hormone).
• Corticotropes produce ACTH (Adrenocorticotropic Hormone).
• Gonadotropes produce FSH (Follicle Stimulating Hormone) and LH (Luteinizing Hormone).
• Chromophils are further subdivided into acidophils and basophils, depending on whether they have an affinity for acid or basic dyes.
• Acidophils stain pink.
• Basophils stain purple.
• Somatotropes and lactotropes are acidophils
• Thyrotropes, corticotropes, and gonadotropes are basophils.

Layers of the Adrenal Cortex

• The adrenal cortex has three layers; zona glomerulosa, zona fasciculata, and zona reticularis.
• The zona glomerulosa is a thin, outer layer where cells are arranged in rounded clusters. Here mineralocorticoids are secreted, which regulate electrolyte balance.
• The zona fasciculata is a thick, middle layer where cells are arranged in fascicles (parallel cords) separated by capillaries. It comprises 3/4 of the adrenal cortex. Abundant cytosolic lipid droplets give cells a foamy appearance, turning them into spongiocytes. Glucocorticoids, which regulate fuel metabolism, and androgens are secreted here.
• The zona reticularis is a narrow, inner layer composed of cells in a branching network. Glucocorticoids and androgens are secreted here.

Glucocorticoids

• They are corticosteroids produced in two layers of the adrenal cortex; zona fasciculata and zona reticularis.
• They are involved in the metabolism of carbohydrates, protein, and fat.
• Glucocorticoids increase hemoglobin (Hb) concentration.
• They facilitate stress response and tissue repair.
• Glucocorticoids are anti-inflammatory.
• Hydrocortisone is widely used in ointments to relieve swelling and other signs of inflammation.
• Excessive glucocorticoid secretion or medical use suppresses the immune system.
• Examples include cortisol and corticosterone.
• Cortisol is the most potent and corticosterone being weaker.
• Glucocorticoids facilitate fat and protein catabolism, gluconeogenesis, and the release of fatty acids and glucose into the blood.
• They stimulate fat and protein catabolism (breakdown).
• Glucocorticoids trigger gluconeogenesis (glucose production from non-carbohydrate sources).
• They are also involved in the release of fatty acids and glucose into the blood.
• Glucocorticoids stimulate the production of RBCs and enhance the release of hemoglobin (Hb).
• This becomes important during times of stress or inflammation when the body requires more oxygen.

Neural and Hormonal Stimuli

• In short-term stress, nerve impulses lead to the adrenal medulla secreting amino acid-based hormones (catecholamines like epinephrine and norepinephrine).
• This results in; increased heart rate and blood pressure, the liver converting glycogen to glucose and releasing it into the blood, dilation of bronchioles, changes in blood flow patterns leading to decreased digestive system activity and reduced urine output, and increased metabolic rate.
• More prolonged stress is a hormonal stimuli.
• The hypothalamus releases CRH (corticotropin-releasing hormone).
• ACTH is secreted, stimulating the adrenal cortex to secrete steroid hormones (mineralocorticoids and glucocorticoids).
• This results in; the retention of sodium and water by the kidneys, increased blood volume and blood pressure, the conversion of proteins and fats to glucose or the breakdown of them for energy, increased blood glucose, and suppression of the immune system.

Cortisol in a Coordinated Response

• As part of a coordinated response, cortisol counteracts insulin and raises blood glucose levels.
• Cortisol triggers the breakdown of fat in adipose tissue, promotes the generation of glucose in the liver, and reduces bone formation.
• In muscles it decreases amino acid uptake leading to muscle protein breakdown.

Fat-Soluble Hormones

• Ex: Cholesterol, Progesterone, Cortisol (hydrocortisone), Aldosterone, Estradiol, Testosterone
• Fat-soluble hormones enter the cell and directly affect genes.

Water-Soluble Hormones

• Water-soluble hormones bind to the cell surface and 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.
• Cortisol binds to receptors in liver cells, activating specific genes.
• This activation changes how the liver handles sugars.
• Fat creation increases (lipogenesis).
• Glucose production is increased (gluconeogenesis).
• Breakdown of glycogen is increased (glycogenolysis).
• Glycogenesis decreases.

Gluconeogenesis

• It means 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.
• It's crucial 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.
• Peripheral insulin resistance happens because signaling and glucose uptake is impaired.
• Excess GCs lead to muscle atrophy, elevated plasma fatty acids and triglycerides, altered hepatic carbohydrate and lipid metabolism, and impaired pancreatic β-cell function.
• GCs also reduce bone destiny by increasing bone resorption while inhibiting bone formation.
• Skin manifestations can also result from having too many GCs.
• The current review explores GC regulation of body composition and metabolism.
• While 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 are corticosteroids that influence salt and water homeostasis as it relates to electrolyte and fluid balance.
• It is produced from the adrenal cortex, particularly in the zona glomerulosa.
• An example is aldosterone, which 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.
• This is crucial for maintaining blood pressure.

Renin-Angiotensin System

• This system is a hormone cascade that regulates blood pressure and fluid balance.
• The 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: 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

• It is the main adrenal estrogen produced by the adrenal cortex, 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.
• Estradiol 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 occurs in the AP.
• Mitosis and cell differentiation are targets.
• It facilitates tissue growth.
• Plays a role in the growth of bone, cartilage, and muscle. -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

• GH is involved in protein synthesis; boosting transcription and translation.
• It stimulates fat metabolism.
• Growth requires energy
• Adipocytes release fatty acids & glycerol resulting in protein-sparing effect
• It facilitates carbohydrate metabolism: reduced glucose uptake from diet, but the brain relies on glucose. So, it 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.
• The increased lipolysis caused by GH leads to elevated fatty free 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, which has downstream consequences.
• 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 (secreted by the stomach when empty) stimulates GH secretion.
• Interactions with the hypothalamus cause hunger and GHRH release, thus readying target organs for nutrient usage.

Prolactin

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

Insulin

• Is a peptide produced by Beta cells of pancreatic islets
• Insulin 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. In turn, blood glucose is reduced.
• Low blood glucose stimulates glucagon secretion by certain pancreatic cells stimulating glycogen breakdown. Subsequently blood glucose is increased.

Somatostatin

• It is 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. -It causes dysregulation of glucose homeostasis, and leads to excessive insulin & severe hypoglycemia.