Endocrine Regulation – Chapter 25 Study Notes

Learning Objectives

• Compare endocrine structure & function with nervous structure & function
• Classify hormones in multiple, non-exclusive ways
  • Structural/chemical class
  • Functional/physiologic class
• Contrast mechanisms of action of steroid vs. non-steroid hormones
• Explain endocrine reflexes plus receptor up- & down-regulation
• Detail eicosanoids (prostaglandins, thromboxanes, leukotrienes):
  • Chemical nature (20-C fatty acid w/ 5-C ring)
  • Classification & mechanism of action
• Describe mechanisms and causes of hormone hyper- & hyposecretion

Neuroendocrine System: Organization & General Functions

• Endocrine + nervous systems form a single integrated “neuroendocrine system”
• Shared general functions
  • Communication
  • Integration of body processes
  • Control / regulation
• Endocrine pathway
  • Secreting (ductless) glandular epithelial cells → hormone molecules enter blood → circulate to virtually every tissue → bind only to cells bearing specific receptors (“target cells”)
  • Response time: usually slow, but duration: long-lasting
• Nervous pathway
  • Neuron → neurotransmitter into synaptic cleft → postsynaptic cell
  • Response time: fast, duration: brief

Major Endocrine Glands (illustrated on classic diagram)

• Hypothalamus
• Pineal gland
• Pituitary (anterior & posterior lobes)
• Thyroid
• Parathyroids (posterior thyroid surface)
• Thymus
• Pancreatic islets
• Adrenal cortex & medulla
• Gonads
  • Testes (male)
  • Ovaries (female)

Functional Classes of Hormones

• Tropic hormones – regulate secretion of another endocrine gland
• Sex hormones – reproductive target tissues/functions
• Anabolic hormones – stimulate anabolism (cell/tissue building)
• Overlaps occur; e.g., \text{GH} is anabolic & tropic

Structural / Chemical Classification of Hormones

• Steroid hormones (lipid soluble, derived from cholesterol)
  • Cortisol, Aldosterone, Estrogens, Progesterone, Testosterone
• Non-steroid hormones (primarily amino-acid based)
  1. Proteins: GH, PRL, PTH, CT, ACTH, Insulin, Glucagon
  2. Glycoproteins: FSH, LH, TSH, hCG
  3. Peptides: ADH, OT, MSH, SS, TRH, GnRH, ANH
  4. Amino-acid derivatives (Amines/iodinated AA): NE, Epi, Melatonin, T4, T3

Steroid Hormones

Basic Properties

• Synthesized from cholesterol → lipid soluble → diffuse through plasma membranes
• Circulate largely bound to plasma proteins; only free fraction is active
• Receptors typically intracellular (cytosolic or nuclear)

Representative Ring Structure

• Steroid nucleus = 3 six-carbon rings + 1 five-carbon ring
  • Functional groups (e.g., \ce{OH},\; C=O) determine mineralocorticoid vs. glucocorticoid vs. sex steroid activity

Synthetic Pathway (mitochondria & smooth ER)

• Cholesterol → Pregnenolone → multiple branch points →
  • Mineralocorticoids: 11\text{-Deoxycorticosterone} \to Corticosterone \to Aldosterone
  • Glucocorticoids: 17\alpha\text{-Hydroxyprogesterone} \to 11\text{-Deoxycortisol} \to Cortisol
  • Androgens/Estrogens: Dehydroepiandrosterone \to Androstenedione \to Testosterone \to Estradiol

Non-steroid Hormones

Proteins & Peptides

• Built from chains of amino acids; may contain disulfide bridges (e.g., insulin’s A & B chains linked via S–S)
• Peptides shorter than ~50 aa (e.g., Oxytocin = 9 aa)

Glycoproteins

• Protein backbone + carbohydrate side chains; α-subunit shared, β-subunit confers specificity (e.g., hCG vs. TSH)

Amino-acid derivatives

• Tyrosine/tryptophan modifications; thyroid hormones iodinated (organification) producing T4 and T3

Principles of Hormone Action

• Receptor-mediated “lock-and-key” specificity
• Magnitude of response ∝ [hormone] × [receptor] × receptor affinity
• Multiple hormones may act on a single target:
  • Synergism – combined > sum of individual (e.g., Epi + Glucagon → ↑blood glucose)
  • Permissiveness – one hormone allows full action of another (e.g., T_3 permits Epi-induced lipolysis)
  • Antagonism – opposite effects (e.g., Insulin vs. Glucagon)

Mechanisms of Action

Steroid (Mobile-Receptor / Nuclear-Receptor Model)

1. Free steroid diffuses across plasma membrane
2. Binds cytosolic receptor → hormone–receptor complex
3. Complex translocates to nucleus, binds hormone-response element (HRE) on DNA
4. Initiates or represses transcription → mRNA → protein synthesis
5. Responses are slow onset (hours) but long duration

• Magnitude determined by free [hormone]; no “amplification cascade” inside cell

Non-steroid (Fixed-Membrane / Second-Messenger Models)

• Hormone cannot cross membrane; receptor is integral protein, often a G-protein–coupled receptor (GPCR)
• Binding activates intracellular signals → enzyme cascades → rapid amplification

Calcium–Calmodulin Pathway (illustrated with Oxytocin example)

1. Hormone (first messenger) binds GPCR → activates G-protein + PIP_2 system
2. Voltage- or ligand-gated Ca^{++} channels open; extracellular Ca^{++} floods cytosol (down gradient)
3. Ca^{++} binds calmodulin → conformational change → Ca^{++}-calmodulin complex (second messenger)
4. Complex allosterically activates or inhibits target enzymes → physiological response

• Other pathways (not pictured but implied): cAMP, cGMP, IP_3 / DAG

Regulation of Hormone Secretion

Endocrine Reflexes (Negative Feedback Loops)

• Example: Parathyroid hormone (PTH) control of blood Ca^{++}
  • Sensor-integrator: parathyroid chief cells
  • Controlled variable: [Ca^{++}]_{blood}
  • Effector: Osteoclast activation → bone resorption → ↑Ca^{++}
  • Correction signal stops once variable returns to set-point

Receptor Density Modulation

• Up-regulation: prolonged low [hormone] → ↑number of receptors → ↑sensitivity
• Down-regulation: chronic high [hormone] → receptor internalization/degradation → ↓sensitivity

Eicosanoids

• Unique lipid mediators; do not meet classical endocrine definition (local action)
• Derived from 20-carbon fatty acid (arachidonic acid) w/ 5-carbon ring

Tissue Hormones

• Synthesized & act within same tissue; diffusion distance: paracrine/autocrine

Prostaglandins (PGs)

• Multiple structural series: PGA, PGE, PGF, etc.
• Extremely diverse effects: vascular tone, uterine contraction, inflammation, platelet aggregation, gastric mucosal protection
• Also include thromboxanes, leukotrienes (not detailed in slides but included under “eicosanoids” umbrella)

Endocrine Disorders

Hypersecretion

• Hyperthyroidism (e.g., Graves’ disease)
• Hyperpituitarism (e.g., GH-secreting adenoma → acromegaly)
• Autoimmunity stimulating receptor (e.g., TSH-R antibodies)

Hyposecretion

• Gland destruction, enzyme defects, dietary deficiency, receptor insensitivity
• Iatrogenic: negative feedback suppression after exogenous anabolic steroid abuse

Connections & Clinical / Ethical Implications

• Understanding receptor regulation is essential for drug therapy (e.g., β-blocker tolerance, insulin resistance)
• Eicosanoid pathways are targets of NSAIDs (aspirin inhibits COX → ↓PG synthesis) → benefits & GI side-effects
• Steroid abuse highlights hyposecretion rebound; ethical concern in sports
• Interplay of endocrine & nervous systems important in stress (HPA axis), lactation (neuroendocrine reflex), reproduction, etc.

Quick Reference Equations & Numbers

• Steroid nucleus: C{17}H{28}O_{2} core + side-chains (varies)
• Eicosanoid definition: 20-carbon chain + 5-carbon ring
• Receptor occupancy equation (simplified): \theta = \frac{[H]}{[H]+K_d} (θ = fraction of occupied receptors)