General Endocrinology

• Body functions are controlled by nervous and endocrine (hormonal) systems to maintain homeostatic mechanisms.

Nervous System

• The effector response is fast, short, and targeted.
• Primarily regulates muscle activity, sensation, cognition, or excretion.
• Communication to target cells via neurotransmitters.

Endocrine System

• The effector response is slower in onset, longer-lasting, and more diffused compared to the nervous system.
• Regulates metabolic functions, membrane transport, secretion, reproduction, growth, development, and behavior.
• Made up of a system of glands without external ducts and specialized cells that secrete hormones directly into the blood (found in GIT, CNS, kidney etc.)

Endocrine Signaling

• Endocrine cells release a chemical signal = hormone = first messenger.
• This diffuses into the blood/ECF and is transported to more or less distant target tissues equipped with specific receptors.

Hormone Overview

• A chemical substance and signaling molecule is produced and secreted by specific cells.
• Hormones are transported by blood (10⁻⁶ – 10⁻¹² M) to target structures.
• Target cells have specific receptors.
• A hormone (H) causes a specific response in distant target tissue.
• Ernest Starling (1866 – 1927) was a British physiologist.
• In 1902, Starling isolated secretin, released into blood from the epithelial cells of the duodenum, which stimulates secretion of pancreatic digestive juice.
• In 1905, Starling coined the term "hormone" (Greek: hormōn – stir up, impulse).

Endocrine Glands and Hormones

• Hypothalamus: Releasing and inhibitory hormones
• Anterior pituitary gland: Growth hormone, Adrenocorticotropin, Thyroid-stimulating hormone, Luteinizing hormone, Follicle-stimulating hormone, Prolactin
• Posterior pituitary gland: Vasopressin (ADH), Oxytocin
• Thyroid gland: Thyroxine (T₄), Triiodothyronine (T₃)
• Parathyroid gland: Parathyroid hormone (PTH)
• Endocrine pancreas: Insulin, Glucagon
• Adrenal cortex: Glucocorticoids (cortisol, corticosterone), Mineralocorticoids (aldosterone), Androgens
• Adrenal medulla: Catecholamines (epinephrine, norepinephrine, dopamine)
• Testes: Testosterone
• Ovaries: Estrogens, Progesterone
• Placenta: Human chorionic gonadotropin (HCG), Human somatomammotropin, Estrogens, Progesterone
• Kidney, heart, GIT, pineal gland, adipocytes

Chemical Nature of Hormones

• Steroid hormones are derived from cholesterol, are lipid-soluble, and include hormones of the adrenal cortex, testes (testosterone), ovaries (estrogen, progesterone), placenta (estrogen, progesterone), and vitamin D.
• Amine hormones are derived from tyrosine, include hormones of the thyroid gland (lipid-soluble) and adrenal medulla (water-soluble).
• Peptide and proteins are all remaining hormones and are water-soluble.

Steroid Hormone Secretion

• Steroid hormones are synthesized from cholesterol in mitochondria, smooth endoplasmic reticulum, and cytoplasm.
• There is very little storage of the final hormone in endocrine cells.
• Large storage of precursor molecules (cholesterol and cholesterol esters) occurs in the cytoplasm.
• Stimulus for secretion → activation of synthesizing enzymes → production and secretion of H→ diffusion across cell membrane → ISF → blood.
• Most cholesterol comes from plasmatic lipoproteins, less de novo synthesis of cholesterol in endocrine cells.

Amine Hormone Secretion

• Amine hormones are derived from tyrosine.
• They are formed by enzymes in the cytoplasm of endocrine cells.
• Catecholamines are stored in vesicles and are released by exocytosis.
• Thyroid hormones are incorporated into the big protein thyroglobulin.
• Thyroid hormones are stored in colloid in follicles outside the cells bound to thyroglobulin.
• During secretion, T₃ and T₄ are cleaved from thyroglobulin and released into capillaries.

Polypeptide and Protein Hormone Secretion

• Formed in endoplasmic reticulum of endocrine cells.
• Hormones are stored in secretory vesicles in cytoplasm until a specific signal causes secretion.
• Released by exocytosis (due to ↑ Ca²⁺ or ↑ cAMP in cytoplasm).

Control of Hormone Secretion: Negative Feedback

• Negative feedback is the most common.
• The activity of a gland is influenced by the effects of hormone it produces or by hormone itself.
• Responses to the feedback signal oppose the original signal.
• Prevents overactivity of gland.

Control of Hormone Secretion: Positive Feedback

• Responses to the feedback signal amplify the original signal.
• Positive feedback does not lead to stability (regulation), rather to a progressive change in one direction.

Control of Hormone Secretion: Simple Feedback Loop

• Gland -> Hormone -> Effect

Control of Hormone Secretion: Hierarchical Control

• Cerebral cortex -> Hypothalamus (+ Hormone) -> Anterior pituitary gland (+ Hormone) -> Peripheral gland -> Hormone -> Target tissue.

Transport in Blood: Water-Soluble

• Peptides and catecholamines are transported in blood.
• They are dissolved in plasma.
• Transported in free form (unbound) → diffusion across capillary wall → diffusion to target cells.
• Fast onset of action.

Transport in Blood: Lipid-Soluble

• Steroid and thyroid hormones are transported in blood.
• They are mainly bound to plasma proteins (reservoir).
• Small fraction in free form (biologically active form).
• Slower onset of action.
• Dynamic equilibrium: Protein-bound hormone ↔ Free hormone

Concentration of Hormone in Blood

• Depends on the rate of hormone secretion.
• Depends on the rate of hormone elimination.
• Mechanisms of elimination:
  • Endocytosis of the hormone-receptor complex and its intracellular catabolism (peptides)
  • Metabolic destruction by enzymes (the metabolism in the target tissues sometimes activates the hormone, e.g. T₄ → more active T₃, testosterone → dihydrotestosterone)
  • Excretion by liver to bile
  • Excretion by kidney to urine
• Peptides and catecholamines (in plasma mainly free) are relatively more susceptible to the actions of enzymes in blood and tissues → short half-time of their circulation (minutes – hours).
• Steroid and thyroid hormones (in plasma mainly bound to proteins) are more resistant → removal lasts hours – days.

Hormone Action

• A hormone is able to influence only target cells via specific receptors (large proteins).
• Complex hormone-receptor → cascade of reactions → effect (growth, metabolism, development...)
• Actions can be stimulatory, inhibitory, or permissive.
  • Permissive action: no direct effect, necessary for full effect of another hormone (one hormone potentiates the effect of another hormone)
  • Pleiotropic: producing more than one effect
  • Multiplicity: one process is regulated by more than one hormone

Receptors

• Large proteins that are highly specific for a single hormone
• Location:
  • Cell membrane: peptides and catecholamines (water-soluble hormones)
  • Cytoplasm: steroids (lipid-soluble hormones)
  • Cell nucleus: T-hormones (lipid-soluble hormones)

Receptors Properties

• Specificity: RC binds only one type of hormone (or structurally related)
• Affinity: strength with which hormone binds to RC
• Saturation: degree to which RC is occupied by hormone
• Competition: ability of molecule to compete with hormone (agonist or antagonist)

Down- and Up-Regulation

• Down-regulation:
  • ↓ total number of RC for given hormone
  • causes inactivation of RC or signalling pathway, destruction of RC, or decreased production of RC
  • response to chronic ↑ concentration of hormone
• Up-regulation:
  • ↑ total number of RC for given hormone
  • response to chronic ↓ concentration of hormone
  • target cell is more sensitive to hormone

Signal Transduction Pathways of Water-Soluble Messengers

Hormone -> Binding to EC portion of membrane receptor (RC)

• Ionotropic RC (Ligand-gated channel) to enact Change in MP
• Enzymatic activity of RC (Catalytic RC) to enact a Cellular Response
• G-protein coupled RC -> Second messenger Activation of protein kinase -> Protein phosphorylation -> Cellular Response

Channel-Coupled Receptors: Ligand-Gated Channels

• Binding of messenger to RC causes a conformational change of RC.
• Opening of channel →Ions diffusion → Change in MP → Cellular Response

Catalytic Receptors

• Membrane RC with enzymatic activity on the cytoplasmic side of membrane
• Membrane RC activates the IC enzyme closely associated with RC
  • Receptor guanylyl cyclase = Natriuretic peptides
  • Receptor tyrosine kinase = Insulin, Growth factors
  • Leptin RC

Receptor Tyrosine Kinase

• RC phosphorylates itself on tyrosine residue.
• Binding of hormone to RC (EC) → Stimulation of tyrosine kinase → Autophosphorylation of RC (IC) → Phosphorylation of proteins → Intracellular signal systems → EFFECTS

G-Protein Coupled RCs

• The largest family of RCs (hundreds).
• Signal molecules = hormones, neurotransmitters, vasoactive peptides, odorants
• Effectors = enzymes, channels, transporters, contractile proteins.
• Display GTP-ase activity, regulate synthesis of the second messenger.
• Heterotrimeric G proteins have 3 subunits: α, β, and γ.

G-Protein Coupled Receptors Process

• Hormone binds to its receptor.
• R-H binds to G-protein.
• G-protein exchanges GDP for GTP.
• G-protein with GTP dissociates into subunits α and βγ.
• Subunit α activates enzyme producing 2nd messenger
• After GTP splitting by α subunit, complex α-GDP dissociates from the enzyme.
• Second messenger is degraded by enzyme.

Second Messengers

• Extracellular message should be transferred into the intracellular environment.
• Small, diffusible molecules.
• Mediates a variety of immediate intracellular events or induces long-term changes.
• Most are mediated by kinases phosphorylating target proteins (pumps, enzymes, channels, transcription factors).
  • Adenylyl cyclase and cyclic AMP
  • Diacylglycerol and inositol triphosphate
  • Ca²⁺

Adenylyl Cyclase and cAMP

• Adenylyl cyclase and cyclic AMP -> Protein kinase A creates cAMP-dependent protein kinase -> Proteins phosphorylation --> Cellular response
  • NE, EPI, ADH, glucagon, pituitary hormones.

Diacylglycerol and Inositol Triphosphate

-PIP2 to activate Phospholipase C -> IP3 and DAG - IP3 -> Ca²⁺ release from ER - DAG -> PKC - Protien Phosphorylation - Cellular Response -NE, EPI, ACh, ADH

Calcium

• Sources of Ca²⁺: ECF (ligand or voltage-gated channels), Endoplasmic reticulum
• Cell response to ↑ Ca²⁺:
  • Calmodulin → calmodulin-dependent protein kinases
  • Direct effect of Ca²+ on target protein

Signal Amplification

• Binding of hormone to RC → hundreds of second messenger molecules → thousands of effector molecules

Cytoplasmic Receptors

Steroid hormones, vitamin D process:

• Hormone diffusion across the membrane -> Binding of hormone to cytoplasmic receptor -> Dissociation of accompanying protein (chaperon) -> Dimerization of complexes R-H -> Transport of complex R-H to the nucleus -> Binding of R-H on HRE sequence of DNA (hormone response element) together with coactivators and RNA-polymerase -> Activation of transcription → synthesis of mRNA -> mRNA diffusion into the cytoplasm -> Translation activation -> Protein synthesis

Nuclear Receptors

• Hormone diffusion across the membrane
• Binding of T hormone to its nuclear receptor in heterodimer with RXR (retinoid X receptor) – bound to HRE
• Release of corepressor and binding of coactivator and RNA-polymerase on the complex
• Activation of transcription → synthesis of mRNA
• mRNA diffusion into the cytoplasm
• Initiation of translation
• Protein synthesis