Introduction to Endocrinology – Unit 5 Lecture #1

Introduction to Endocrinology

• Endocrinology = science of hormone-producing glands and the actions of their products in maintaining the chemical integrity of the body’s internal environment.
• Both endocrine and nervous systems serve communication functions.
  • Nervous: electrical + chemical signaling.
  • Endocrine: purely chemical signaling.
• Shared/overlapping molecules:
  • Neurotransmitters that are also hormones: norepinephrine, thyrotropin-releasing hormone (TRH), antidiuretic hormone (ADH).
  • Neuroendocrine secretions (neurons → ECF): oxytocin, catecholamines.
• Overlapping physiological effects: e.g. norepinephrine & glucagon both trigger glycogen hydrolysis in hepatocytes.

Definitions

• Hormone: endogenous substance produced by specialized cells, transported to target tissue(s) to elicit a physiological response.
• Endocrinology: study of hormones, their production, regulation, action, & removal.
• “Tropic” hormone: produced by adenohypophysis; stimulates another gland/organ (“turning/changing”).
• “Trophic” hormone: promotes growth/nourishment of tissues (often steroids) (“nurturing”).

Functional Categories of Hormone Actions

1. Growth, development, maturation.
2. Control of systemic homeostasis, energy balance, integrated metabolism.
3. Regulation of reproduction.

Chemical Classes of Hormones

• Protein/Polypeptide Hormones
  • Examples: ACTH, insulin, parathyroid hormone (PTH).
  • Water-soluble; circulate mainly free.
  • Short half-life: <10\text{–}30\ \text{min}.
  • Bind surface receptors → intracellular second-messenger cascades.
• Aromatic Amine Hormones (AA-derived)
  • Examples: thyroid hormones (thyroxine/T4), catecholamines.
  • Derived from tyrosine.
  • Water-soluble; circulate free & protein-bound.
  • Catecholamines → second-messenger pathways; thyroid hormones cross membrane directly, act predominantly at nucleus.
• Steroid Hormones
  • Examples: cortisol, estrogen, testosterone.
  • Non-polar; circulate mainly protein-bound (reversible).
  • Half-life: 30\text{–}90\ \text{min}.
  • Enter cells by passive diffusion → bind intracellular (cytoplasmic/nuclear) receptors.

Transport, Protein Binding & Half-Life

• Equilibrium forms immediately between free and protein-bound fractions once in plasma.
• Free fraction = biologically active.
• General half-life patterns
  • Protein-bound hormones: T_{1/2} \approx 60\text{–}100\ \text{min}.
  • Non-protein-bound (hydrophilic) hormones: T_{1/2} \approx 5\text{–}60\ \text{min}.
  • Epinephrine: unique hydrophilic hormone with T_{1/2} < 1\ \text{min}.

Hormone Signaling Pathways

• Interaction = hormone + specific receptor → receptor activation → intracellular signaling → physiological change.
• Circulating concentrations often picomolar/nanomolar, yet high specificity/response.
• Cell may express hundreds of receptor types simultaneously.

Cell-Surface Receptors

1. G-Protein-Coupled Receptors (GPCRs)
   • Polypeptide hormones frequently use GPCRs.
   • Activation often couples to adenylate cyclase → \uparrow cAMP (classic second messenger).
2. Enzyme-Coupled Receptors
   • Six subfamilies; major = Receptor Tyrosine Kinases (RTKs).
   • Ligands: insulin, IGF-1, EGF, FGF, etc.
   • Trigger kinase cascades regulating growth & metabolism; common oncogenic targets.

Intracellular/Nuclear Receptors

• Steroids & thyroid hormones diffuse through membrane.
• Bind cytoplasmic or nuclear receptors → hormone-receptor complex acts as transcription factor.
• Example: thyroid hormones bind directly to chromatin to modulate mRNA synthesis.

Mechanisms of Second-Messenger Action (Protein Hormones)

1. Hormone binds extracellular receptor.
2. Conformational change activates effector (e.g. G-protein).
3. Effector (adenylate cyclase, phospholipase C, etc.) generates second messenger (cAMP, IP$_3$, DAG, Ca$^{2+}$).
4. Second messenger activates protein kinases → phosphorylation cascade → cellular response (enzyme regulation, gene expression, secretion, etc.).

Hypothalamus–Pituitary Axis

• Pituitary (hypophysis) suspended from hypothalamus by stalk.
• Two portions:
  • Adenohypophysis (anterior) – glandular; receives hypothalamic releasing hormones via portal vessels.
  • Neurohypophysis (posterior) – neural tissue; stores/releases hormones made in hypothalamic neurons.

Hypothalamus

• Regulates primitive functions: water balance → sex drive.
• Produces releasing hormones:
  • Corticotropin-releasing hormone (CRH).
  • Growth hormone-releasing hormone (GHRH).
  • Gonadotropin-releasing hormone (GRH/GnRH).
  • Prolactin-releasing hormone (PRH).
  • Thyrotropin-releasing hormone (TRH).
• Produces inhibiting hormones, e.g. prolactin-inhibiting hormone (dopamine).

Adenohypophysis (Anterior Pituitary)

• No direct neural connection; linked by hypophyseal portal blood system.
• Secretes “tropic” hormones that regulate other endocrine glands.

Neurohypophysis (Posterior Pituitary)

• Not a true gland; mass of axons + neuroglia.
• Hormones (e.g., ADH, oxytocin) synthesized in hypothalamic nuclei → transported along axons → stored/released upon neural signal.

Classification of Endocrine Disorders

• Primary: pathology in the target endocrine gland itself.
• Secondary: pathology in adenohypophysis (defective stimulating hormone).
• Tertiary: pathology in hypothalamus (defective releasing hormone).

Biosynthesis & Structure–Function Relationship

• Many hormones made in specialized endocrine cells (e.g., insulin in pancreatic β-cells).
• Some require complex enzymatic cascades (e.g., aldosterone from cholesterol in adrenal zona glomerulosa).
• Minor structural modifications can inactivate a hormone:
  • Estradiol $\xrightarrow[hydroxylation]{}$ estriol (addition of one -OH → loss of potent estrogenic activity).

Hormone Release Dynamics

• Stimulus → release may occur within seconds or take days.
• Termination of action can also be delayed (days–weeks) after stimulus cessation.
• Hormones can act locally (paracrine/autocrine) as well as systemically via bloodstream (e.g., pancreatic somatostatin on neighboring α/β cells).

Regulation via Feedback Systems

• Negative feedback = dominant mechanism.
  • Rise in target gland hormone inhibits hypothalamic releasing hormone and/or pituitary tropic hormone, stabilizing levels.
• Ensures potent hormones remain tightly controlled.

Mechanistic Summary by Solubility

• Water-soluble (protein/peptide, catecholamines):
  • Receptors on cell membrane.
  • Use second messengers.
  • Shorter T_{1/2}.
• Lipid-soluble (steroids, thyroid):
  • Diffuse through membrane.
  • Intracellular/nuclear receptors.
  • Act at DNA level to alter transcription.
  • Longer T_{1/2} (if protein-bound).

Clinical Implications & Disorders

• Endocrine disease categories:
  1. Hormone deficiency (congenital or acquired).
  2. Hormone excess (overproduction, iatrogenic/medication).
  3. Hormone resistance (receptor-mediated, post-receptor, or at target tissue level).
• Manifestations depend on hormone(s) & level of abnormality.
• Example: Diabetes mellitus = most prevalent endocrine metabolic disorder in Western countries.
• Genetic defects in biosynthetic pathways (e.g., congenital adrenal hyperplasia) → loss of end-product hormones, build-up of intermediates → cardiovascular/reproductive dysfunction, gender ambiguity.

Numerical/Statistical References

• Circulating hormone concentrations: picomolar–nanomolar range.
• Half-life values reiterated:
  • Protein hormones: <10\text{–}30\ \text{min}.
  • Steroids: 30\text{–}90\ \text{min}.
  • Strongly protein-bound fraction: T_{1/2}\approx 60\text{–}100\ \text{min}.
  • Epinephrine: T_{1/2}<1\ \text{min}.

Connections to Nervous System

• Bidirectional regulation: endocrine hormones can modulate neural activity; neural inputs (stress, circadian cues) modulate hormone release.
• Several glands (e.g., adrenal medulla) derived from neural tissue, illustrating evolutionary link.

Practical Takeaways

• Comprehensive knowledge of hormone classes, transport, receptor types, and feedback loops is foundational for diagnosing & managing endocrine disorders.
• Distinguishing primary vs secondary vs tertiary pathology is critical for targeted therapeutic intervention.

Recommended Reading

• Bishop, 9th ed., Chapter 13, pp. 371–391 (corresponding to Unit 5 material).