Cortisol Production and Function

• Glucocorticoids are produced and secreted by the zona fasciculata, with cortisol being the most important.

Cortisol Production Control

• The hypothalamus secretes corticotropin releasing hormone (CRH), which travels to the anterior pituitary gland.
• CRH binds to corticotroph cells, stimulating the release of adrenocorticotropic hormone (ACTH) into the bloodstream.
• ACTH stimulates cells of the adrenal cortex to take up cholesterol, which zona fasciculata cells convert to cortisol.

Pattern of Cortisol Release

• Cortisol is secreted as it is produced, not stored.
• Secretion is pulsatile, peaking in the morning around 6 am.
• Stressful stimuli like hypoglycemia, infections, caffeine, sleep deprivation, and stress also trigger cortisol secretion.

Cortisol Receptors

• Cortisol receptors exist in nearly every cell and are intracellular.

Functions of Cortisol - Immune Response

• Cortisol promotes an anti-inflammatory state by inhibiting interleukin-2 production by white blood cells, as well as other inflammatory products.

Functions of Cortisol - Cellular Metabolism in Adipose Tissue, Liver and Muscles

• In adipose tissue, it triggers lipolysis, which is the breakdown of fats for energy
• In the liver, it triggers gluconeogenesis and increased glycogen storage
• In muscles, it stimulates proteolysis, generating amino acids for gluconeogenesis

Functions of Cortisol - Other Tissues

• In general tissues, it increases insulin resistance, leading to increased blood glucose levels.
• In blood vessels, it up-regulates alpha1 adrenergic receptors, causing vasoconstriction and increased blood pressure.
• In bone, it inhibits osteoblasts, decreasing bone formation, suppresses calcium absorption, and decreases type I collagen production.

Cortisol Negative Feedback

• Cortisol signals the hypothalamus to stop secreting corticotropin releasing hormone (CRH), decreasing anterior pituitary secretion of adrenocorticotropic hormone (ACTH)
• Cortisol signals directly into the anterior pituitary to stop the release of adrenocorticotropic hormone (ACTH)

Antidiuretic Hormone (ADH)

• Antidiuretic hormone, or ADH, is a peptide hormone that is anti- or against -diuresis which is excessive urine production
• ADH is produced in the paraventricular and supraoptic nuclei in the hypothalamus and released into the posterior pituitary, then into the bloodstream.

Triggers of ADH Release - Osmolarity

• Supraoptic nuclei in the anterior hypothalamus detect elevated blood osmolarity via osmoreceptors.
• Increases past the normal set point cause the nuclei to fire action potentials, creating a thirst response and increasing ADH production.

Triggers of ADH Release - Baroreceptors

• Baroreceptors in the carotid artery and arch of the aorta detect low blood pressure
• Low blood pressure triggers the hypothalamus to increase ADH secretion.

Target Cells of ADH

• Kidneys: ADH targets principal cells in the distal convoluted tubule and collecting duct cells, which have Vasopressin receptor 2 (AVPR2).
• Arteries: ADH targets smooth muscle cells

Actions of ADH on AVPR2 Receptors

• AVPR2 receptors cause the kidneys to retain more water
• G protein activation signals ATP to cAMP, increasing cAMP:
• Cell produces water channel proteins (aquaporin 2)
• Aquaporin 2 proteins insert themselves into the apical surface of the cells which triggers water to leave the lumen and enter the cells of the kidney and then enter the bloodstream → blood osmolarity decreases

Actions of ADH on Smooth Muscle Cells in Arteries

• ADH constricts smooth muscle cells, increasing peripheral vascular resistance and blood pressure.
• Increased blood pressure is detected by baroreceptors, which send inhibitory signals to the hypothalamus to stop ADH secretion.

Glucagon

• Glucagon is a hormone that raises blood glucose levels when fasting.
• Glucagon is produced by alpha cells in the Langerhans islets of the pancreas
• Preproglucagon is converted to proglucagon, then to glucagon, and stored inside granules in the alpha cells.

Regulators of Glucagon Release (Triggers)

• Low blood glucose (detected by the alpha cells)
• Adrenaline (from the sympathetic nervous system)
• Cholecystokinin (from intestinal cells)

Regulators of Glucagon Release (Inhibitors)

• High blood glucose (detected by the alpha cells)
• Insulin (secreted by beta cells)
• Somatostatin (inhibits excessive hormone release)
• Growth hormone

Effects of Glucagon

• Glucagon is a catabolic hormone that promotes breakdown of large storage molecules (glycogen, fat) into smaller energy molecules (glucose, fatty acids).

Glucagon Receptor

• Glucagon Receptor
• Transmembrane
• Activates intracellular proteins

Glucagon Target Cells

• Liver: Causes breakdown of glycogen into glucose, glucose production (gluconeogenesis), which are both released into the blood, and fat breakdown (lipolysis).
• Adipose tissue: Causes fat breakdown (lipolysis), releasing fatty acids into the blood.

Interplay of Glucagon and Insulin

• During fasting, alpha cells secrete glucagon.
• After a meal, glycemia rises, beta cells secrete insulin, and insulin inhibits glucagon secretion.
• As glycemia drops, insulin production drops, and glucagon is secreted again.

Growth Hormone

• Growth hormone regulates body growth and is controlled by the hypothalamic-pituitary axis.
• The hypothalamus secretes growth hormone-releasing hormone (GHRH) into the hypophyseal-portal system
• GHRH binds to receptors on somatotroph cells, stimulating growth hormone release.

Control of Growth Hormone Release (Increased)

• Stimuli to hypothalamus to release GHRH
• Hypoglycemia
• Epinephrine (From adrenal glands)
• Estrogen and Testosterone which during puberty
• Creates the pubertal growth spurt!

Control of Growth Hormone Release (decreased)

• Increased GHRH in blood, which signals hypothalamus to stop making more
• Somatomedins are hormones made by liver, muscle and bone
• Somatomedins signal the anterior pituitary cells to stop making growth hormone .
• Growth hormone and somatomedins signal the hypothalamus to make somatostatin
• Somatostatin is also called growth hormone inhibiting hormone

Targets and Effects of Somatostatin

• Pituitary: Blocks GHRH from acting on somatotroph cells
• Pancreas: Somatostatin is made by the delta cells of the pancreas.
• Somatostatin blocks release of insulin, glucagon, gastrin, and vasoactive intestinal peptides

Effects of Growth Hormone

• Growth hormone has direct and indirect effects

Direct Effects of Growth Hormone

• Stimulation of cellular metabolism → tissue growth
• Adipose tissue: Triggers lipolysis, providing substrates for metabolism in other cells
• Liver: Triggers gluconeogenesis and glycogenolysis, releasing glucose
• Tissues: Increases insulin resistance, increasing blood glucose levels

Indirect Effects of Growth Hormone via IGF-1

• Binds to insulin-like growth factor 1 receptors and insulin receptors
• Promotes cellular metabolism
• Prevents cell death
• Increases rate of cell division and differentiation
• Muscles: Stimulates amino acid uptake into the muscle cells, increasing protein production and muscle growth
• Bones: Acts on growth plates of long bones and stimulates activity of osteoblasts and chondrocytes, boosting bone growth

Insulin

• Source: Pancreas
• Islets of Langerhans - Beta cells
• Insulin control of release
• Glucose levels ↑ → beta cells secrete insulin into the blood
• Indirect = they increase blood glucose, fatty acid, and amino acid levels
• Stimulates insulin secretion
• Norepinephrine (sympathetic nervous system)
• Somatostatin (hormone)

Insulin Target Cells and Effects

• Insulin is an anabolic hormone that promotes the conversion of small molecules (glucose, fatty acids, amino acids) into large storage molecules (glycogen, fat/adipose tissue, proteins) inside target cells.

Insulin Target Cells Effects

• Liver: Insulin converts glucose to glycogen and inhibits gluconeogenesis.
• Extra glucose is sent to adipose tissue to be stored as fat.
• If glycogen storage capacity is reached, insulin prompts the liver to convert glucose into fatty acids for storage in adipose tissue.
• Adipose Tissue: Fatty acids → fat
• Skeletal muscle
• Amino acids and glucose uptake into muscle cells
• Amino acids → protein → muscle growth

Types of Extracellular Calcium

• Most of the extracellular calcium, the calcium in the blood and interstitium, is split almost equally into calcium that’s diffusible and calcium that’s not diffusible
• Two categories
• Free-ionized calcium and Complexed calcium
• Non-diffusible calcium
• Bound to large negatively charged proteins
• i.e. albumin!
• Too large and charged to cross membranes
• Not involved in cellular processes

Free Ionized Calcium

• Involved in cellular processes
• Neuronal action potentials
• Contraction of skeletal, smooth, and cardiac muscle
• Hormone secretion
• Blood coagulation

Source of Parathyroid Hormone and Control

• Parathyroid glands
• Chief cells
• Normal-high calcium → inhibits PTH release
• Low calcium → stimulates PTH release

Parathyroid Hormone

• Parathyroid hormone works to increase extracellular calcium in three ways.
• Bones
• Kidneys
• Activates an enzyme called 1-alpha-hydroxylase This enzyme converts calcidiol (inactive form of vitamin D) into calcitriol (also called 1,25-dihydroxycholecalciferol), which is the active form of vitamin D! Active vitamin D travels to the gastrointestinal tract and enters the enterocytes of the small intestine → increase the activities of the calcium channels on the cell membrane → cells absorb more calcium from food = increases serum calcium

Parathyroid Hormone - Bones

• PTH binds to receptors on osteoblasts → they release cytokines
• Cytokines get multiple macrophage precursors to fuse together and form an osteoclast
• The osteoclasts break down the bone → calcium and phosphate are released into the blood
• In the blood, phosphate binds to calcium → forms a complex → calcium can’t be used in cellular processes

Parathyroid Hormone - Kidneys

• Proximal convoluted tubules: PTH binds to receptors → stop sodium and phosphate cotransporters on the apical surface of the tubular cells → Phosphate is NOT re-absorbed into the bloodstream → phosphate leaves the body in the urine
• Principal cells of the distal convoluted tubules : Increases serum calcium PTH binds to receptors → cells start making more sodium-calcium channels → embed on the apical surface → more calcium is taken out of the forming urine and it put back into the bloodstream

Parathyroid Hormone - Vitamin D Activation

• Proximal tubular cells
• Activates an enzyme called 1-alpha-hydroxylase
• This enzyme converts calcidiol (inactive form of vitamin D) into calcitriol (also called 1,25-dihydroxycholecalciferol), which is the active form of vitamin D!
• Active vitamin D travels to the gastrointestinal tract and enters the enterocytes of the small intestine → increase the activities of the calcium channels on the cell membrane → cells absorb more calcium from food

Thyroid Hormones

• Two versions
• Triiodothyronine – T3
• Highly active form
• Half-life = 1-2 days
• Thyroxine/ tetraiodothyronine - T4
• Less active form
• Half-life = 6-8 days
• Source of Thyroid Hormones
• Follicular cells in the thyroid gland endocytose thyroglobulin
• Endocytose thyroglobulin into a vesicle → fuses with the lysosome → thyroglobulin is cleaved by proteases → T3 and T4 are released into the bloodstream
• Through the monocarboxylate transporter (MCT)

Control of Thyroid Hormone Release

• Hypothalamus-Pituitary Axis
• Low levels of thyroid hormone in the bloodstream → hypothalamus secretes thyrotropin releasing hormone (ΤRH) into the hypothalamo- hypophyseal portal system → TRH binds to a surface protein on thyrotroph cells in the anterior pituitary → they release the hormone thyroid stimulating hormone (TSH; also known as thyrotropin) into bloodstream
• TSH travels to the thyroid gland → binds to the TSH receptors on membrane of the follicular cells → T3 and T4 are produced and then released
• Negative Feedback
• High levels of thyroid hormones
• Inhibits hypothalamus production of TRH
• Inhibits anterior pituitary gland production of TSH
• Acts to lower thyroid hormone secretion from the thyroid gland

Transport of Thyroid Hormone in the Bloodstream

• T3 and T4 bind to circulating plasma proteins:
• Thyroxine binding globulin (TBG)
• Albumin
• Transthyretin
• Bound T3 and T4 are not active = act as a reservoir of hormone
• Unbound T3 and T4 are active Targets of Thyroid Hormone
• Thyroid hormone targets almost every cell of the body!
• Effects of Thyroid Hormone

General Effects of Thyroid Hormone

• All tissues except brain, spleen and gonads
• Increases activity of the Na-K ATPase → increases oxygen consumption → increases metabolic rate
• Catabolic Effects
• Increases proteolysis, lipolysis and gluconeogenesis
• Does this by increasing catecholamine, glucagon and growth hormone activity
• Cardiovascular System
• Increases β1 adrenergic receptors → increases contractility of heart and heart rate → increases cardiac output
• Growth and Development
• Crucial for development of the central nervous system
• Increases bone formation and maturation