Endocrine System - Basic to Detail Notes (MBBS Biochemistry)

1. INTRODUCTION TO THE ENDOCRINE SYSTEM

2. CLASSIFICATION OF HORMONES

2a. Peptide and Protein Hormones

• Examples: Insulin, glucagon, GH, ACTH, FSH, LH, TSH, PTH, ADH, oxytocin
• Synthesis: Encoded by mRNA; translated as large precursor proteins
• Precursor chain: Gene → pre-prohormone → prohormone → active hormone
  • Pre-prohormone: Contains signal peptide (cleaved in ER)
  • Prohormone: Inactive precursor (cleaved in Golgi/secretory vesicles)
  • Active hormone: Released by exocytosis
• Example - Insulin: Preproinsulin (110 aa) → Proinsulin (86 aa) → Insulin + C-peptide
• Storage: Stored in secretory vesicles - can be released rapidly
• Transport: Travel freely in plasma (hydrophilic)
• Receptor: Cell surface receptors (cannot cross plasma membrane)
• Half-life: Short (minutes)

2b. Steroid Hormones

• Examples: Cortisol, aldosterone, estradiol, progesterone, testosterone, 1,25-dihydroxycholecalciferol (active Vitamin D)
• Origin: Adrenal cortex, gonads, corpus luteum, placenta
• Precursor: ALL steroid hormones are derived from cholesterol
• Synthesis: Modifications include:
  • Removal/addition of side chains
  • Hydroxylation
  • Aromatization of the steroid nucleus
• NOT stored - synthesized on demand
• Transport: Bind to plasma carrier proteins (e.g., corticosteroid-binding globulin, sex hormone-binding globulin), since hydrophobic
• Receptor: Intracellular receptors (cytoplasmic or nuclear) - hormone enters cell
• Half-life: Longer (hours)

2c. Amine Hormones

• Derived from: Tyrosine (single amino acid)
• Two groups:
  1. Catecholamines - Epinephrine, Norepinephrine, Dopamine
     • Synthesized in adrenal medulla and sympathetic neurons
     • Pathway: Tyrosine → DOPA → Dopamine → NE → Epinephrine
     • Act via cell surface receptors (α, β adrenergic receptors)
  2. Thyroid hormones - T3 (triiodothyronine), T4 (thyroxine)
     • Synthesized in thyroid follicles using iodine
     • Highly lipophilic despite being amine-derived → intracellular receptors
     • Travel bound to thyroid-binding globulin (TBG) in plasma

3. KEY ENDOCRINE GLANDS AND THEIR HORMONES

4. REGULATION OF HORMONE SECRETION

4a. Feedback Mechanisms (most important)

Hypothalamus → Releasing hormone
      ↓
Anterior Pituitary → Tropic hormone
      ↓
Peripheral gland → Hormone
      ↓
[Hormone feeds back] → Inhibits hypothalamus & pituitary

• TRH (hypothalamus) → TSH (pituitary) → T3/T4 (thyroid)
• High T3/T4 inhibits TRH and TSH secretion (negative feedback)

• CRH → ACTH → Cortisol
• High cortisol inhibits CRH and ACTH

• Estrogen surge in mid-cycle triggers LH surge → ovulation
• Oxytocin during labor (more contractions → more oxytocin)

4b. Neural Mechanisms

• Preganglionic sympathetic nerves stimulate adrenal medulla → catecholamine release
• Hypothalamus integrates neural and endocrine signals

4c. Direct Metabolic Feedback

• High blood glucose → insulin secretion (no intermediate)
• Low Ca2+ → PTH secretion
• High Ca2+ → calcitonin secretion

5. MECHANISMS OF HORMONE ACTION (Signal Transduction)

5a. G Protein-Coupled Receptor (GPCR) Mechanism

• GDP bound to α subunit → G protein inactive
• GTP bound to α subunit → G protein active
• Gs (stimulatory) and Gi (inhibitory) types exist

• cAMP is degraded by phosphodiesterase (PDE) → 5'-AMP
• Hormones using this pathway: ACTH, TSH, FSH, LH, glucagon, PTH, calcitonin, catecholamines (β-receptors), ADH (V2 receptor), Histamine (H2)

• IP3 (Inositol 1,4,5-trisphosphate) → Releases Ca2+ from ER → activates calmodulin/protein kinase C
• DAG (Diacylglycerol) → Activates Protein Kinase C (PKC)
• Hormones using this pathway: TRH, GnRH, oxytocin, ADH (V1), catecholamines (α1-receptors), Angiotensin II, Histamine (H1)

5b. Tyrosine Kinase Receptor Mechanism

• Insulin and IGF-1 use this pathway
• Hormone binds → receptor undergoes autophosphorylation (tyrosine residues) → activates downstream cascade (Ras-MAPK, PI3K-Akt)
• Key effect of insulin: GLUT4 translocation to membrane → glucose uptake in muscle and fat

5c. Intracellular (Nuclear) Receptor Mechanism - Steroid & Thyroid Hormones

1. Hormone crosses membrane → binds to cytoplasmic receptor (steroids) or nuclear receptor (T3/T4)
2. Hormone-receptor complex enters nucleus
3. Binds to Hormone Response Elements (HREs) on DNA
4. Alters gene transcription → new mRNA → new protein synthesis
5. Effect is slow (hours to days) but long-lasting

• Cortisol, aldosterone, estrogen, progesterone, testosterone → cytoplasmic receptors
• T3/T4 → nuclear receptors (already in nucleus)
• 1,25-(OH)2 Vitamin D → intracellular receptor

Summary Table: Mechanisms of Action

6. MAJOR HORMONAL AXES IN DETAIL

6a. Thyroid Hormones (T3/T4)

1. Iodide (I-) uptake into thyroid follicular cells via Na+/I- symporter
2. I- oxidized to I2 by thyroid peroxidase (TPO) (requires H2O2)
3. Organification: I2 incorporated into tyrosine residues on thyroglobulin → MIT (monoiodotyrosine) and DIT (diiodotyrosine)
4. Coupling reaction (by TPO):
   • MIT + DIT → T3 (triiodothyronine)
   • DIT + DIT → T4 (thyroxine)
5. Thyroglobulin stored in follicular colloid
6. TSH stimulates pinocytosis of colloid → lysosomal proteolysis → releases T3 and T4

• T4 → reverse T3 (rT3, inactive) in illness/fasting

• Increase basal metabolic rate (BMR)
• Stimulate Na+/K+ ATPase → increase O2 consumption
• Promote protein synthesis and bone growth
• Enhance β-adrenergic receptor sensitivity (cardiovascular effects)
• Regulate CNS development in fetus/neonate (critical - deficiency causes cretinism)
• Positive chronotropic and inotropic effects on heart

• PTU (propylthiouracil): Inhibits TPO + blocks T4 → T3 conversion
• Methimazole: Inhibits TPO only
• Wolff-Chaikoff effect: Acute excess iodide temporarily inhibits thyroid hormone synthesis

6b. Adrenal Cortex Hormones

• Metabolic (catabolic): Gluconeogenesis ↑, protein catabolism, lipolysis → hyperglycemia
• Anti-inflammatory: Inhibits PLA2 → reduces arachidonic acid release; reduces cytokines
• Immunosuppressive: Lymphocyte/eosinophil reduction
• Mineralocorticoid effect (weak): Na+ retention, K+ loss at high doses
• CNS: Mood, behavior, cognition (excess → depression/psychosis)
• Permissive effects: Potentiates catecholamine action

• Principal cells of collecting duct: ↑ Na+ reabsorption, ↑ K+ and H+ secretion
• Stimulates synthesis of ENaC (epithelial Na+ channel) and Na+/K+ ATPase
• Net effect: Na+ retention, K+ loss, water retention, BP increase

6c. Insulin and Glucagon (Pancreatic Hormones)

• Secreted by β-cells of islets of Langerhans
• Stimulus for secretion: Glucose (primary), amino acids, GIP, parasympathetic stimulation
• Mechanism: Glucose → glycolysis → ATP ↑ → closes KATP channels → depolarization → Ca2+ influx → exocytosis of insulin granules
• Synthesis: Preproinsulin → Proinsulin → Insulin + C-peptide (C-peptide is marker of endogenous insulin production)
• Receptor: Tyrosine kinase (α2β2 tetramer)

• Secreted by α-cells
• Stimulus: Low blood glucose, amino acids, sympathetic stimulation
• Receptor: GPCR → cAMP → PKA
• Actions (catabolic): ↑ Glycogenolysis, ↑ gluconeogenesis, ↑ ketogenesis; opposes insulin

• High I:G ratio (fed state) → anabolism
• Low I:G ratio (fasted/stress) → catabolism

6d. Growth Hormone (GH)

• Secreted by somatotrophs of anterior pituitary
• Regulation: GHRH (stimulates) and Somatostatin/SRIF (inhibits) from hypothalamus
• Pattern: Pulsatile; peak during deep sleep
• Receptor: JAK-STAT pathway (class I cytokine receptor)

• ↑ Lipolysis → FFA in blood
• ↓ Glucose uptake by muscle (insulin antagonism)
• ↑ Blood glucose → "diabetogenic"

• ↑ Protein synthesis, cell proliferation
• ↑ Linear bone growth (epiphyseal plates)
• ↑ Muscle mass, organ growth

6e. Parathyroid Hormone (PTH) and Calcium Regulation

• Bone: ↑ Osteoclast activity → Ca2+ and PO4 release (bone resorption)
• Kidney: ↑ Ca2+ reabsorption (DCT), ↑ PO4 excretion, ↑ 1-hydroxylase (activates Vit D)
• Intestine (indirect, via Vit D): ↑ Ca2+ and PO4 absorption
• Net: ↑ serum Ca2+, ↓ serum PO4

• Skin: UV → D3 (cholecalciferol)
• Liver: 25-hydroxylation → 25-OH D3
• Kidney: 1α-hydroxylation (stimulated by PTH) → 1,25-(OH)2 D3 (calcitriol - active form)
• Actions: ↑ Ca2+ and PO4 absorption from intestine; acts via nuclear receptor

• Released by high Ca2+
• Inhibits osteoclasts → lowers serum Ca2+
• Clinical use: Bisphosphonate alternative for hypercalcemia

7. HYPOTHALAMIC-PITUITARY AXES

HYPOTHALAMUS              ANTERIOR PITUITARY        TARGET GLAND
    TRH              →         TSH              →     Thyroid → T3/T4
    CRH              →         ACTH             →     Adrenal cortex → Cortisol
    GnRH             →         FSH/LH           →     Gonads → Sex steroids
    GHRH/SRIF        →         GH               →     Liver → IGF-1
    Dopamine (PIF)   ⊣         Prolactin        →     Breast → Milk production
    TRH              →         Prolactin (stimulates)

• Stores and releases hormones made in hypothalamus
• ADH (Vasopressin): Made in supraoptic nucleus → acts on V2 receptors in collecting duct → inserts aquaporin-2 channels → water reabsorption
• Oxytocin: Made in paraventricular nucleus → uterine contractions, milk ejection

8. POMC (Pro-Opiomelanocortin) - Important Biochemistry

POMC
 ├── ACTH → α-MSH + CLIP
 ├── β-Lipotropin → β-Endorphin + γ-Lipotropin
 └── γ-MSH

• ACTH and MSH are all derived from POMC by tissue-specific processing
• In Addison's disease (primary adrenal insufficiency): cortisol falls → ACTH rises → excess POMC processing → excess MSH → hyperpigmentation

9. HORMONE TRANSPORT IN BLOOD

10. CLINICAL CORRELATIONS (MBBS Exam High-Yield)

11. QUICK MNEMONICS

• GFR (adrenal cortex zones from outer to inner): Glomerulosa/Fasciculata/Reticularis = Salt/Sugar/Sex
• FLAT PEG (anterior pituitary hormones): FSH, LH, ACTH, TSH, Prolactin, Endorphins, GH
• POMC products: "ACTH is born from POMC, along with MSH and endorphins"
• Steroid hormone actions are "Slow but Sure" (require new protein synthesis)
• cAMP hormones = PTH, ACTH, TSH, FSH, LH, Glucagon, Calcitonin, β-agonists (mnemonic: FLAT ChAMP)
• IP3/Ca2+ hormones = TRH, GnRH, Oxytocin, ADH(V1), Ang-II (mnemonic: GOAT HAVe calcium)

12. STEROIDOGENESIS PATHWAY (Adrenal + Gonadal)

Cholesterol
    ↓ (StAR - rate-limiting transport into mitochondria)
Pregnenolone  ←  (by P450scc / cholesterol desmolase)
    ↓
Progesterone
    ↓ (17α-hydroxylase)
17-OH Progesterone
    ↓ (21-hydroxylase)   ← deficient in CAH (21-hydroxylase deficiency)
11-Deoxycortisol
    ↓ (11β-hydroxylase)
CORTISOL

Progesterone also goes:
    ↓ (21-hydroxylase)
11-Deoxycorticosterone
    ↓ (11β-hydroxylase → 18-hydroxylase → 18-oxidase)
ALDOSTERONE

17-OH Pregnenolone → DHEA → Androstenedione → Testosterone → Estradiol
                                                          ↑
                                               (aromatase)

• StAR (Steroidogenic Acute Regulatory protein): Rate-limiting step - transports cholesterol into mitochondria
• CYP11A1 (P450scc): Cleaves cholesterol side chain → Pregnenolone
• 17α-hydroxylase (CYP17A1): Needed for cortisol and sex steroids (NOT aldosterone)
• 21-hydroxylase (CYP21A2): Most commonly deficient in CAH; needed for cortisol and aldosterone
• 11β-hydroxylase (CYP11B1): Final step in cortisol synthesis
• Aromatase (CYP19A1): Testosterone → Estradiol; Androstenedione → Estrone

• Costanzo Physiology 7th Edition - Chapters 9
• Lippincott Illustrated Reviews: Biochemistry 8th Edition
• Harper's Illustrated Biochemistry 32nd Edition
• Robbins & Kumar Basic Pathology