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Endocrine Physiology – Transport, Mechanism of Action, and Regulation of Hormone Signalling

Transport of Hormones in Blood

  • Two broad chemical classes
    • Water-soluble hormones (peptides, most amines)
    • Lipid-soluble hormones (steroids, thyroid hormones, nitric oxide)

Water-Soluble Hormones

  • Are hydrophilic; circulate freely in the aqueous plasma.
  • No carrier required, therefore no delay between secretion and availability.

Lipid-Soluble Hormones & Transport (Binding) Proteins

  • Plasma is largely water; “oil (lipid) and water do not mix.”
  • Require specific transport (binding) proteins synthesized mainly by the liver.
  • Functions of transport proteins:
    • Temporarily convert the hormone into a water-compatible form.
    • Prevent filtration at the renal glomerulus, reducing urinary loss.
    • Provide a readily accessible circulating reserve so the endocrine gland does not have to synthesize hormone de novo for every demand.
    • Prolong plasma half-life of both lipid-soluble and certain water-soluble hormones (binding protein ≈ “protective coat”).

Free vs. Bound Hormone Fraction

  • Immediately after secretion, ≈ 0.1\%\;\text{to}\;10\% of a lipid-soluble hormone remains unbound (“free fraction”).
  • Free hormone = biologically active form; only this fraction can leave capillaries, penetrate tissues, bind receptors, and trigger a response.
    • Example: clinical lab value “free T4” = free thyroxine able to diffuse into cells.
  • Bound fraction is hormonally inactive until it dissociates from its carrier.

Mechanism of Action – Lipid-Soluble Hormones

  • Sequence of events
    1. Free hormone diffuses from plasma → interstitial fluid → across the phospholipid bilayer.
    2. Intracellular receptor located in cytosol or nucleus binds hormone.
    3. Hormone–receptor complex acts as a transcription factor: binds DNA, alters gene expression.
    4. mRNA is transcribed, exits nucleus, and is translated on ribosomes.
    5. Newly synthesized proteins modify cell activity (structural proteins, enzymes, transporters, etc.).
  • Latency is longer (minutes–hours) but effect is sustained because new protein must be degraded to terminate signal.

Mechanism of Action – Water-Soluble Hormones

  • Cannot diffuse across lipid bilayer; receptors are integral membrane proteins.

Classic cAMP Second-Messenger Cascade

  1. Hormone = “first messenger.” Binds extracellular domain of its receptor.
  2. Receptor conformational change activates a coupled G-protein (Gα subunit swaps GDP→GTP).
  3. Gα•GTP stimulates adenylyl cyclase (AC).
  4. AC converts
    \text{ATP} \xrightarrow{\text{adenylyl\ cyclase}} \text{cAMP} + \text{PP}_i
    producing the second messenger cAMP.
  5. cAMP activates protein kinase A (PKA).
  6. PKA phosphorylates numerous target proteins → functional alterations:
    • Enzyme activation/inhibition (e.g., glycogen synthesis, lipid degradation).
    • Opening/closing ion channels.
    • Phosphorylation of transcription factors → indirect changes in gene expression.

Signal Amplification (Cascade Effect)

  • One hormone molecule can trigger exponential multiplication of the signal:
    • 1 hormone → ~100 G-proteins → many AC enzymes → hundreds of cAMP → thousands of PKA molecules → millions of phosphorylated proteins.
  • Hence very low plasma concentrations suffice to elicit large physiological responses.

Hormone Interactions at a Target Cell

Determinants of Responsiveness

  • Plasma hormone concentration.
  • Number of receptors (up- or down-regulation).
  • Simultaneous influence of other hormones.

Types of Hormone–Hormone Interactions

  1. Synergistic

    • Two hormones reinforce each other; combined effect > additive.
    • Example: \text{Estrogen} + \text{Progesterone} produce a ~50-fold response vs. ~5-fold individually.

  2. Permissive

    • Activity of one hormone requires prior or simultaneous presence of another.
    • Example: Oxytocin (milk ejection) needs Prolactin (milk production) to be effective.

  3. Antagonistic

    • One hormone opposes the action of another.
    • Example: Insulin (↓ blood glucose) vs. Glucagon (↑ blood glucose).

Control of Hormone Secretion – Three Primary Stimuli

  1. Hormonal Stimulation

    • A hormone triggers secretion of a second hormone, often governed by feedback loops.
    • Example: \text{TSH}{(anterior\ pituitary)} \rightarrow \text{Thyroid\ gland} \rightarrow \text{T3/T4}; rising T3/T_4 feedback inhibits TSH release.

  2. Humoral (Blood-Borne) Stimulation

    • Changes in ion or nutrient levels provoke hormone release.
    • Example: ↑ blood glucose → pancreatic β-cells secrete insulin.

  3. Nervous System Stimulation

    • Autonomic neurons synapse on endocrine tissue.
    • Example: Sympathetic pre-ganglionic fibers → adrenal medulla → release of epinephrine & norepinephrine during fight-or-flight.
  • Endocrine glands often secrete in short pulsatile bursts; stimulus intensity modulates burst frequency and amplitude.