Chapter 11 – Endocrine Glands: Secretion & Action of Hormones

Overview

• Chapter focuses on secretion, transport, receptor binding and physiological effects of hormones produced by the major endocrine glands.
• Key anatomical structures: hypothalamus, pituitary (anterior & posterior), adrenal cortex & medulla, thyroid, parathyroid, and pancreatic Islets of Langerhans.
• Core themes
  • Chemical diversity of hormones → determines solubility, transport, receptor location, speed of action.
  • Signal transduction → genomic vs. non-genomic, second-messenger pathways.
  • Hormone–hormone interactions (synergistic, permissive, antagonistic).
  • Hierarchical control (hypothalamus → pituitary → peripheral gland) with predominantly negative feedback.

Endocrine Glands: General Concepts

• Glands are ductless; secrete hormones directly into bloodstream.
• Target cells must possess specific, high-affinity, low-capacity receptors.
• Specialized neurons release neurohormones (e.g., hypothalamic releasing factors, oxytocin, ADH).
• Hormones regulate metabolism, growth, reproduction, homeostasis.

Chemical Classification of Hormones

• Amine hormones (derived from tyrosine/tryptophan)
  • Norepinephrine (NE), epinephrine (Epi), thyroxine (T4), melatonin.
• Polypeptide / protein hormones (short to long AA chains)
  • ADH, GH, insulin, oxytocin, glucagon, ACTH, PTH.
• Glycoproteins (protein + carbohydrate)
  • LH, FSH, TSH.
• Steroids (cholesterol-derived lipids)
  • Testosterone, estrogen, progesterone, cortisol.
• Physical property split
  • Lipophilic (steroid + thyroid) → diffuse through membranes, nuclear/cytoplasmic receptors.
  • Hydrophilic (all others) → membrane receptors, second messengers.

Hormonal Actions & Interactions

• A single tissue usually exposed to multiple hormones simultaneously.
• Synergism: combined effect > additive (e.g., Epi + NE on heart rate).
• Permissiveness: hormone A primes tissue → enhances response to hormone B (e.g., estrogen up-regulates uterine progesterone receptors).
• Antagonism: hormone A opposes hormone B (e.g., insulin ↓ blood glucose vs. glucagon ↑ it).

Mechanisms of Hormone Action

Receptor Location & Speed

• Lipophilic hormones
  • Carried in blood bound to plasma proteins.
  • Receptors in cytoplasm or nucleus → alter gene transcription ("genomic"), latency ≥ 30\;\text{min}.
  • Some steroids also have rapid "nongenomic" membrane actions.
• Hydrophilic hormones
  • Receptors on plasma membrane.
  • Rely on intracellular second messengers for rapid effects (seconds–minutes).

Nuclear Hormone Receptors (Superfamily)

• Have two functional domains: ligand-binding + DNA-binding.
• After binding, receptor–hormone complex translocates to nucleus, binds hormone-response element (HRE) on DNA.
• HRE architecture
  • Steroid HRE = two identical half-sites; requires receptor dimerization (homodimer).
  • Thyroid HRE = heterodimer (T3-receptor + retinoic acid receptor) occupying adjacent half-sites.

Thyroid Hormone Particulars

• Thyroid releases 90\% T4 (thyroxine) & 10\% T3; 99.96\% of circulating T4 bound to TBG → acts as reservoir.
• Inside target cells: T4 de-iodinated → T3 (active form) → binds nuclear receptor.

Second-Messenger Systems (Membrane-Receptor Hormones)

Adenylate Cyclase – cAMP Pathway

1. Hormone binds receptor → G-protein α-subunit (Gs) dissociates.
2. Gs activates adenylate cyclase → converts ATP \rightarrow cAMP.
3. cAMP binds regulatory subunit of protein kinase A (PKA) → catalytic subunit phosphorylates target enzymes.
4. Termination: phosphodiesterase converts cAMP \rightarrow 5'!\text{AMP}.

Phospholipase C – IP3 / DAG – Ca^{2+} Pathway

1. Hormone → receptor → Gq protein → activates phospholipase C.
2. PLC cleaves membrane phospholipid → IP_3 + DAG.
3. IP_3 diffuses to ER → opens Ca^{2+} channels → cytosolic Ca^{2+} rises.
4. Ca^{2+} + calmodulin → activates kinases; DAG can activate PKC → phosphorylation cascades.

Tyrosine Kinase Receptor Pathway (Insulin, growth factors)

1. Hormone binds extracellular α-subunits, causing β-subunits to dimerize & autophosphorylate.
2. Tyrosine-phosphorylated receptor phosphorylates downstream signaling proteins.
3. Insulin specifically triggers vesicular insertion of GLUT-4 transporters → ↑ glucose uptake.

Dual Messenger Example: Epinephrine

• β-adrenergic → cAMP; α-adrenergic → IP_3/Ca^{2+}.

Pituitary Gland

General Anatomy

• Suspended from hypothalamus via infundibulum.
• Two lobes: anterior (adenohypophysis) & posterior (neurohypophysis).

Posterior Pituitary (Neurohypophysis)

• Stores/releases hormones synthesized in hypothalamic nuclei.
  • Antidiuretic hormone (ADH/vasopressin): kidneys reabsorb H$_2$O → water conservation.
  • Oxytocin: uterine contractions (parturition) & milk-ejection (let-down) reflex.
• Axonal transport along hypothalamo-hypophyseal tract; release triggered by neuroendocrine reflexes (e.g., suckling, osmoreceptors).

Anterior Pituitary (Adenohypophysis)

• Produces six trophic hormones; maintain size & function of targets.
  • Growth Hormone (GH / somatotropin) – protein synthesis, AA uptake, tissue growth.
  • Thyroid-Stimulating Hormone (TSH) – thyroid T3/T4 secretion.
  • Adrenocorticotropic Hormone (ACTH) – adrenal cortex cortisol & aldosterone.
  • Follicle-Stimulating Hormone (FSH) – ovarian follicle growth, spermatogenesis.
  • Luteinizing Hormone (LH) – ovulation, corpus luteum, testosterone production.
  • Prolactin (PRL) – milk synthesis in mammary glands.
• Hypothalamic regulation via releasing/inhibiting hormones delivered through hypothalamo-hypophyseal portal system (median eminence → anterior pituitary capillary bed).

Feedback Control

• Short loop: anterior pituitary hormones retrograde to hypothalamus ↓ releasing hormone.
• Long loop: peripheral gland hormones (e.g., cortisol, T3/T4) ↓ pituitary + hypothalamus.
• Positive feedback exists but rare (e.g., pre-ovulatory estrogen → LH surge).
• Higher brain input: stress, emotion, circadian rhythms modulate hypothalamic signals.

Adrenal Glands

Structure

• Sit atop kidneys; outer cortex (mesoderm) & inner medulla (neural crest).

Adrenal Medulla (Chromaffin cells)

• Sympathetic post-ganglionic analogue; secretes 80\% Epi, 20\% NE.
• "Fight or flight": ↑ respiratory rate, heart rate & CO, generalized vasoconstriction (↑ venous return), glycogenolysis, lipolysis.
• Epi hormonal effects last \approx10× longer than direct NE neurotransmission.

Adrenal Cortex (Three zones under ACTH)

• Zona glomerulosa → Aldosterone (mineralocorticoid): kidneys ↑ Na^{+} reabsorption, ↑ K^{+} secretion.
• Zona fasciculata/reticularis → Cortisol (glucocorticoid): inhibits glucose utilization, stimulates gluconeogenesis → ↑ blood glucose.
• Also secretes small amounts of sex steroids (androgens).

Thyroid Gland

Anatomy & Histology

• Inferior to larynx; composed of spherical follicles.
• Follicular cells → T3 & T4; lumen colloid rich in thyroglobulin.

Hormone Synthesis

1. I^{-} actively transported into follicular cells → released into colloid.
2. Oxidized to I_{2}; iodination of tyrosine residues in thyroglobulin → MIT/DIT.
3. Coupling: DIT + DIT → T4; DIT + MIT → T3 (still within thyroglobulin).
4. Under TSH stimulation, thyroglobulin endocytosed → proteolysis releases free T3/T4 into blood.

Goiter Pathophysiology (Iodine Deficiency)

• ↓ dietary I^{-} → ↓ T3/T4 → no negative feedback → ↑ TSH.
• TSH trophic effect enlarges gland → goiter.

Parathyroid Hormone (PTH)

• Released when blood Ca^{2+} falls.
• Targets bone (resorption), kidney (↑ Ca^{2+} reabsorption, ↑ 1,25-D calcitriol), intestine (indirect ↑ absorption) → restore Ca^{2+}.

Pancreas – Islets of Langerhans

• Endocrine clusters scattered within exocrine pancreas.
• Alpha (α) cells: secrete glucagon (low glucose trigger).
  • Promotes glycogenolysis & lipolysis → ↑ blood glucose.
• Beta (β) cells: secrete insulin (high glucose trigger).
  • Facilitates cellular glucose uptake (GLUT-4), glycogenesis, lipogenesis → ↓ blood glucose.

General & Specific Hormone Actions (Systems Level)

• Gene expression modulation → developmental & differentiation roles (fetal sex determination, CNS maturation).
• Enzyme cascade modulation → metabolic control (anabolism/catabolism balance).
• Cardiovascular: Epi, angiotensin II, aldosterone regulate HR, BP, blood volume.
• Renal: ADH & aldosterone govern water & electrolyte balance.
• Skeletal: PTH, calcitriol, GH influence bone remodeling.
• Reproductive: GnRH → LH/FSH → gonadal steroids; prolactin & oxytocin for lactation.
• Immune: glucocorticoids are immunosuppressive.
• CNS: thyroid hormones crucial for neuronal development; stress hormones modulate mood, cognition.

Feedback Control Principles

• Negative feedback predominant
  • Example: LH \rightarrow \text{testis} \rightarrow \uparrow \text{testosterone} \rightarrow -| LH.
• Positive feedback rare but critical
  • Example: E_2 \uparrow \rightarrow \text{LH surge} \rightarrow \text{ovulation}.
• Hormone half-lives, receptor density, second-messenger degradation (e.g., phosphodiesterase for cAMP) provide additional fine-tuning.

Endocrine Overview Summary

• Hormones are chemical messengers released by specialized glands or neurons.
• Transport mode (blood vs. synapse) and solubility dictate receptor localization & signaling mechanics.
• Body maintains hormonal homeostasis via hierarchical axes and feedback loops.
• Understanding endocrine integration is essential for grasping growth, metabolism, stress responses, and reproduction.