Hormones: Endocrine Function and Action

• A hormone acts as a chemical messenger secreted into the blood by specialized cells like endocrine glands
• These messengers regulate long-term body functions such as growth, metabolism, internal environment regulation, and reproduction

How Hormones Act

• Hormones bind to specific receptors on or inside target cells
• This regulates key cellular processes:
  • Enzyme Activity: Hormones activate or inhibit enzymes for biochemical reactions
  • Ion Transport: Hormones control ion movement like sodium, potassium, and calcium
  • Gene Expression: Hormones influence protein production

Endogenous vs. Exogenous Hormones

• Endogenous hormones are naturally produced in the body
• Exogenous hormones come from external sources like medications or hormone therapy

Exocrine vs. Endocrine Glands

• Glands are classified into exocrine and endocrine
• Endocrine glands secrete hormones directly into the bloodstream
  • These hormones travel to distant target organs
  • Examples are the thyroid, adrenal gland, and pancreas (for insulin)
• Exocrine glands secrete substances through ducts to specific locations
  • The secretions do not go into the bloodstream
  • Examples are sweat glands, salivary glands, and the pancreas (for digestive enzymes)

Experimental Endocrinology Approaches

• Ablation (Removal): Removing a gland to see what happens without it
• Replacement: Adding back a gland or hormone extract to see how it works
• Excess Production: Introducing extra hormone amounts to study effects
• Chemical Isolation: Extracting and characterizing active substances

Biological Assays in Endocrinology

• Biological assays (bioassays) test hormones on biological systems like animals or cell cultures to observe responses

Arnold Adolph Berthold's Experiment

• Arnold Adolph Berthold (1803-1861) removed testes from male chickens and observed a loss of masculine traits
• When he reimplanted the testes, normal male traits returned
• Effects are due to hormones released into the bloodstream, and not direct neural connections

Classic vs. Non-Classic Hormones

• Classic hormones are secreted by cells in endocrine glands
  • They travel in the blood to distant organs and act at low concentrations
• Non-classic hormones are not produced by distinct endocrine glands
  • They are secreted by neurons, immune cells, and gut endocrine cells
  • They act locally via diffusion and can function as both hormones and CNS neurotransmitters

Hormone Action via Receptors

• Cells respond to hormones through specific receptors
• Receptor location (cell membrane or inside the cell) adapts to the hormone’s chemical properties
• Hormone binding triggers an intracellular signaling cascade, leading to physiological responses
• Cells can modulate their sensitivity by upregulating or downregulating receptor expression

Hormone Inactivation and Termination

• Hormonal signals must be terminated
• Ways of inactivation include:
  • Hormone Metabolism: Liver & kidney break down hormones, determining their half-life
  • Extracellular Breakdown: Nonspecific proteases degrade peptide hormones in the extracellular fluid
  • Receptor-Hormone Complex Internalization: Hormone-receptor complexes are internalized, stopping the signal

Ways to Classify Hormones

• Hormones are classified by source, mechanism of action, or chemical structure

Source of Hormone Production

• Gastrointestinal (GI) Tract: Hormones such as gastrin, secretin, and cholecystokinin (CCK)
• Gonads (Ovaries/Testes): Sex hormones such as estrogen, progesterone, and testosterone
• Anterior Pituitary Gland: Hormones such as growth hormone (GH), prolactin (PRL), and luteinizing hormone (LH)

Hormone Mechanism of Action

• G-Protein Coupled Receptors (GPCRs): Common for peptide and amine hormones, activating intracellular signaling cascades
• Receptor Tyrosine Kinases (RTKs): Used by insulin and growth factors to trigger phosphorylation
• Intracellular Receptors: Steroid hormones (e.g., cortisol, estrogen) pass through cell membranes and bind to intracellular receptors to influence gene expression

Chemical Classification of Hormones

• Peptide/Protein Hormones: A large category ranging from short peptides (3 amino acids) to large glycoproteins (e.g., insulin, LH)
• Amine Hormones: Derived from tyrosine (e.g., epinephrine, dopamine) or tryptophan (e.g., melatonin)
• Steroid Hormones: Derived from cholesterol (e.g., cortisol, aldosterone, testosterone)

Peptide/Protein Hormones

• This is the largest class of hormones
  • They are composed of 3 amino acids to large proteins (e.g., insulin, growth hormone)
  • They are hydrophilic (water-soluble) and cannot cross cell membranes and so they bind to membrane receptors
  • They have a short half-life (seconds to minutes) in ECF, and require continuous secretion

Peptide Hormone Synthesis and Secretion

• Peptide hormones are secreted with several processing steps
• Preprohormone Synthesis: The hormone synthesizes as a large, inactive preprohormone in the ribosome
  • A signal sequence directs it into the rough endoplasmic reticulum (ER)
• Prohormone Formation: The signal sequence removal creates prohormone
• Processing in Golgi Apparatus: Prohormone transported through the Golgi complex, packaged into secretory vesicles with enzymes
• Final Activation & Storage: Enzymes cleave the prohormone into active hormone and additional peptide fragments within vesicles
• Hormone Secretion: Upon a signal, secretory vesicles release contents via exocytosis, and the hormone enters the bloodstream

Peptide Hormone Localization

• Peptide hormone-producing cells are identified using immunohistochemistry
• Insulin stored in pancreatic beta cells
• Luteinizing Hormone (LH) localized in anterior pituitary cells

Peptide Hormone Signal Transduction

• Responses are rapid
  • Binding to Membrane Receptor (GPCR or RTK)
  • Activation of intracellular signaling cascades
  • Modification of existing proteins
• Key Signaling Components include:
  • G-Proteins (G)
  • Amplifier Enzymes (AE)
  • Tyrosine Kinases (TK)
  • Ion Channels

Amine Hormones

• Amine hormones derive from either tryptophan or tyrosine

Tryptophan-Derived Hormone

• Melatonin is produced by the pineal gland and regulates sleep-wake cycles

Tyrosine-Derived Hormones

• Tyrosine gives rise to catecholamines and thyroid hormones
• Catecholamines (Neurohormones):
  • Act via membrane receptors
  • Includes dopamine, norepinephrine, and epinephrine
• Thyroid Hormones:
  • Produced by epithelial-derived cells in the thyroid gland
  • Act via intracellular receptors
  • Includes thyroxine (T4) and triiodothyronine (T3)

Steroid Hormones

• They are derived from cholesterol
• They are produced in specialized organs like the adrenal cortex (e.g., cortisol, aldosterone), gonads (e.g., testosterone, estradiol, progesterone) and the placenta (during pregnancy)
• Chemically, they are small and stable
• The half-life ranges from minutes to days

Steroid Hormone Synthesis and Release

• Cholesterol Source: Imported or synthesized within cells
  • Cholesterol itself has little hormonal activity
• Enzymatic Conversion: Enzymes in the smooth endoplasmic reticulum (SER) or inner mitochondrial membrane convert cholesterol into different steroid hormones
  • Only the active enzymes determine the exact type of steroid
• No Storage: Steroids are not stored in vesicles
  • They are synthesized on demand by increasing enzyme activity
  • They are released via simple diffusion across cell membranes
• Transport in Blood: Steroids circulate bound to protein carriers (albumin)
  • Only unbound (free) steroids can diffuse into cells

Steroidogenic Pathway

• Cholesterol is a precursor for multiple steroid hormones
  • Gonadal Hormones: Testes → Testosterone (converted to DHT) and Ovaries → Estradiol, Progesterone
  • Adrenal Cortex Hormones: Glucocorticoids (Cortisol) and Mineralocorticoids (Aldosterone)

Steroid Hormone Mechanism of Action

• In blood, steroids circulate bound to protein carriers
• Intracellular Action: Steroid receptors are cytoplasmic or nuclear
  • The hormone-receptor complex binds to DNA at steroid response elements (SREs)
  • This regulates gene expression, leading to mRNA and protein synthesis
• Rapid vs. Slow Responses: Steroid hormones primarily regulate gene transcription, leading to long-term effects
  • Some steroids can also act via membrane receptors for quicker effects

Steroid Hormone Function

• They act as ligand-activated transcription factors, regulating gene expression by binding to steroid response elements
• Newly synthesized proteins function as additional transcription factors
• Steroid hormones facilitate long-term physiological regulation including metabolism, the immune system and reproduction

Hypothalamic-Pituitary Axis

• The axis operates through a hierarchical control system
• It has multiple feedback loops to regulate hormone secretion

Integrating Centers in the Hypothalamic-Pituitary Axis

• Hypothalamus: The first tier, producing neurohormones that stimulate or inhibit the anterior pituitary gland
• Anterior Pituitary Gland: Releasing trophic (trop(h)ic) hormones in response to hypothalamic signals
• Endocrine Target Glands: The third tier, producing hormones in specific organs (e.g., thyroid gland, adrenal cortex, gonads)

Feedback Loops in the Hypothalamic-Pituitary Axis

• Hormones as feedback signals regulate the hypothalamic-pituitary system.
• Long-loop negative feedback: The target endocrine gland hormone inhibits secretion of both the anterior pituitary hormone and the hypothalamic-releasing hormone.
  • The hypothalamus releases corticotropin-releasing hormone (CRH) which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH)
  • ACTH stimulates the adrenal cortex to release cortisol and provides negative feedback by inhibiting both CRH and ACTH secretion
• Short-loop negative feedback: The anterior pituitary hormone inhibits its hypothalamic-releasing hormone.
  • The anterior pituitary releases adrenocorticotropic hormone (ACTH). ACTH acts directly on the hypothalamus to suppress corticotropin-releasing hormone (CRH) secretion.
• Ultra-short-loop feedback: Hypothalamic neurohormones regulate their own secretion.
  • Gonadotropin-releasing hormone (GnRH) released by the hypothalamus inhibits its own further release.

Why Hormones Are Used as Feedback Signals

• The hypothalamic-pituitary system controls multiple organ systems via hormonal signals
• Hormones have systemic effects such as influencing growth, reproduction, and stress
• Hormonal feedback allows for fine-tuning and adaptability in response to internal and external stimuli.

Hormone Interactions

• Hormones do not act alone but interact to regulate processes
• These interactions include:
  • Synergism: When combined effect is greater than the sum of individual effects
    • An example is when glucagon, epinephrine, and cortisol acting together increasing blood glucose
  • Permissiveness: One hormone allows another to exert its full effect, but does not cause the effect itself
    • Example: Thyroid hormone and reproductive hormones triggering puberty
  • Antagonism: One hormone opposes the action of another
    • Example: Insulin lowers blood glucose and glucagon raises it

Endocrine Pathologies

• Hormonal disorders can result from excess or deficient secretion, or abnormal responsiveness
• Hypersecretion (Excess Hormone Production):
  • Caused by tumors (adenomas) or dysfunction in feedback regulation
    • An example is Cushing's syndrome from excess cortisol
• Hyposecretion (Deficient Hormone Production): Caused by genetic mutations, gland atrophy, or nutrient deficiency - An example is hypothyroidism (low thyroid hormone)
• Abnormal Target Tissue Responsiveness:
  • Caused by down-regulation of receptors or genetic mutations
    • An example is Type 2 diabetes mellitus (insulin resistance)

Hormonal Control

• Hormone levels are regulated by negative feedback loops
• In cortisol regulation, stress or low blood glucose causes the hypothalamus to release corticotropin-releasing hormone (CRH)
  • The anterior pituitary releases adrenocorticotropic hormone (ACTH)
  • The adrenal cortex releases cortisol, increasing blood glucose and suppressing immune function
• Cortisol inhibits CRH and ACTH release to prevent excessive production