Mechanism of Hormone Action

Assignment - BPT 1st Year Physiology

1. Introduction

• Goldman-Cecil Medicine, block 36
• Costanzo Physiology 7th Ed, p. 405

2. Classification of Hormones and Their Receptors

3. G Proteins - The Molecular Switch

• When GDP is bound to the α subunit → G protein is inactive
• When GTP is bound to the α subunit → G protein is active

• Gs (stimulatory) - activates adenylyl cyclase
• Gi (inhibitory) - inhibits adenylyl cyclase
• Gq - activates phospholipase C
• Costanzo Physiology 7th Ed, p. 406

4. Mechanism 1: Adenylyl Cyclase - cAMP Second Messenger System

Steps:

1. Hormone binds to its specific receptor on the cell membrane, causing a conformational change in the receptor.
2. The activated receptor couples to the Gs protein, causing the α subunit to release GDP and bind GTP.
3. The αs-GTP complex dissociates and migrates to activate adenylyl cyclase (a membrane-bound enzyme).
4. Adenylyl cyclase catalyzes the conversion of ATP → cyclic AMP (cAMP) inside the cytoplasm.
5. cAMP activates cAMP-dependent protein kinase A (PKA).
6. PKA phosphorylates specific intracellular proteins on serine/threonine residues.
7. Phosphorylated proteins produce the final physiologic response (e.g., secretion, enzyme activation, muscle contraction).
8. Termination: Phosphodiesterase breaks down cAMP → 5'-AMP, switching off the signal.

Hormones using this mechanism:

• Guyton & Hall Medical Physiology, p. 912
• Costanzo Physiology 7th Ed, p. 406

5. Mechanism 2: Phospholipase C - IP3/Ca2+ Second Messenger System

Steps:

1. Hormone binds to its receptor on the cell membrane.
2. The receptor couples to the Gq protein, activating it (GDP → GTP exchange).
3. The αq-GTP complex activates phospholipase C (PLC), a membrane-bound enzyme.
4. PLC cleaves the membrane phospholipid PIP2 (phosphatidylinositol 4,5-bisphosphate) into two second messengers:
   • IP3 (inositol 1,4,5-triphosphate)
   • DAG (diacylglycerol)
5. IP3 diffuses to the endoplasmic reticulum (ER) and triggers release of Ca2+ into the cytoplasm.
6. DAG remains in the membrane and activates protein kinase C (PKC).
7. Together, Ca2+ and DAG activate PKC, which phosphorylates target proteins to produce the physiologic response.
8. Additionally, the lipid portion of DAG yields arachidonic acid, a precursor for prostaglandins.

Hormones using this mechanism:

• Guyton & Hall Medical Physiology, p. 913
• Costanzo Physiology 7th Ed, p. 407

6. Mechanism 3: Calcium-Calmodulin Second Messenger System

Steps:

1. Ca2+ enters the cytoplasm (from extracellular fluid or ER).
2. Ca2+ binds to calmodulin, a ubiquitous intracellular protein with four Ca2+-binding sites.
3. When 3-4 sites are occupied, calmodulin undergoes a conformational change.
4. The Ca2+-calmodulin complex activates calmodulin-dependent protein kinases (CaM kinases).
5. CaM kinases phosphorylate target proteins, producing the cellular response.

Normal intracellular Ca2+ = 10-8 to 10-7 mol/L (inactive state). The calmodulin system activates when Ca2+ rises to 10-6 to 10-5 mol/L.

• Guyton & Hall Medical Physiology, p. 913

7. Mechanism 4: Tyrosine Kinase Mechanism

Two subtypes:

1. Hormone (e.g., insulin) binds to the extracellular domain of its receptor.
2. Binding activates intrinsic tyrosine kinase in the intracellular domain.
3. The receptor autophosphorylates itself on tyrosine residues.
4. Phosphorylated tyrosines serve as docking sites for intracellular signaling proteins (IRS-1, PI3K, MAPK pathways).
5. These pathways regulate glucose uptake, protein synthesis, and cell growth.

1. Hormone (e.g., GH) binds to its receptor.
2. Binding causes receptor dimerization.
3. The intracellular domain associates with and activates JAK (Janus kinase).
4. JAK phosphorylates STAT proteins (Signal Transducers and Activators of Transcription).
5. Phosphorylated STATs dimerize, translocate to the nucleus, and activate gene transcription → new proteins.

• Costanzo Physiology 7th Ed, p. 408-409

8. Mechanism 5: Guanylate Cyclase - cGMP Mechanism

Two subtypes:

• ANP binds to the extracellular domain of the receptor.
• The intracellular domain has guanylate cyclase activity.
• Binding converts GTP → cGMP.
• cGMP activates cGMP-dependent protein kinase (PKG), causing natriuresis and vasodilation.

• NO synthase (in endothelial cells) cleaves arginine → citrulline + NO.
• NO diffuses into vascular smooth muscle cells.
• NO binds and activates soluble/cytosolic guanylate cyclase.
• GTP → cGMP → PKG → smooth muscle relaxation (vasodilation).
• Costanzo Physiology 7th Ed, p. 408

9. Mechanism 6: Steroid Hormone Mechanism (Intracellular / Nuclear Receptor Mechanism)

Steps:

1. Steroid hormone (e.g., aldosterone, cortisol) diffuses freely across the lipid bilayer of the cell membrane.
2. It binds to a specific cytosolic receptor protein (e.g., mineralocorticoid receptor for aldosterone), forming a hormone-receptor complex.
3. This binding causes a conformational change - the complex sheds heat shock proteins (HSPs) that previously kept the receptor inactive.
4. The activated hormone-receptor complex translocates to the nucleus.
5. The complex binds to specific DNA sequences called Hormone Response Elements (HREs) on promoter regions of target genes.
6. This activates (or represses) gene transcription → formation of mRNA.
7. mRNA moves to the cytoplasm → translation at ribosomes → synthesis of new proteins (enzymes, transport proteins, structural proteins).
8. New proteins bring about the final physiologic response.

Key example:

Thyroid hormones (T3/T4):

• Guyton & Hall Medical Physiology, p. 913-914
• Costanzo Physiology 7th Ed, p. 409-410

10. Comparison of Mechanisms

11. Regulation of Hormone Receptors

• Down-regulation: Prolonged high hormone levels cause a decrease in receptor number (e.g., insulin resistance in Type 2 DM). This reduces cell sensitivity.
• Up-regulation: Low hormone levels or stimulation by another hormone can increase receptor numbers. For example, estrogen up-regulates its own uterine receptors AND up-regulates LH receptors in the ovaries.
• Costanzo Physiology 7th Ed, p. 405

12. Summary

1. Adenylyl cyclase - cAMP (most peptide hormones via Gs protein): Rapid effects via protein kinase A phosphorylation.
2. Phospholipase C - IP3/DAG/Ca2+ (via Gq protein): Activates protein kinase C and Ca2+-calmodulin pathways.
3. Calcium-Calmodulin: Ca2+ acts as second messenger, activating CaM kinases.
4. Tyrosine Kinase / JAK-STAT (Insulin, GH, Prolactin): Phosphorylation cascades or direct gene transcription via STAT proteins.
5. Nuclear receptor / Steroid mechanism (Steroid and thyroid hormones): Directly regulates gene transcription; slow onset but prolonged duration of action.
6. Guanylate cyclase - cGMP (ANP, NO): Causes vasodilation and natriuresis via PKG.

• Guyton AC, Hall JE. Textbook of Medical Physiology, 14th Ed. Elsevier. (Chapter 75)
• Costanzo LS. Physiology, 7th Ed. Elsevier. (Chapter 9, pp. 405-410)
• Goldman L, Schafer AI. Goldman-Cecil Medicine, 27th Ed. Elsevier. (Chapter 203)

Mechanism of Hormone Action

1. Introduction

"Hormone does not act on the target cell directly. It combines with receptor to form hormone-receptor complex, which in turn produces the hormonal actions."

• Sembulingam K, Essentials of Medical Physiology, Chapter on Endocrine System

2. Hormone Receptors

Properties of Receptors:

• They are highly specific - each receptor binds only one type of hormone
• They have high affinity - they bind even trace amounts of hormone
• They have limited binding capacity - finite number of binding sites
• Binding is reversible

Location of Receptors:

3. Classification of Mechanisms of Hormone Action

1. Membrane Receptor Mechanism (for water-soluble hormones)
   • a. Cyclic AMP (cAMP) mechanism
   • b. Phosphatidylinositol mechanism (IP3/DAG)
   • c. Tyrosine kinase mechanism
2. Intracellular Receptor Mechanism (for lipid-soluble hormones)
   • Steroid hormone mechanism
   • Thyroid hormone mechanism

4. Membrane Receptor Mechanism

4A. Cyclic AMP (cAMP) Mechanism

• ACTH, TSH, FSH, LH, ADH (V2 receptor), PTH
• Glucagon, Calcitonin, MSH, HCG, CRH

Steps:

• In the resting state, GDP is bound to the α subunit → G protein is inactive
• On receptor activation, GDP is replaced by GTP → G protein becomes active
• The α subunit (αs) dissociates from βγ and moves along the inner surface of the membrane

ATP  →(Adenylyl cyclase)→  cAMP + PPi

• In its inactive form, PKA consists of two catalytic (C) subunits bound to two regulatory (R) subunits: R2C2 complex (inactive)
• cAMP binds to the R subunits → R and C subunits separate
• Free C subunits (catalytic) = active PKA

Protein + ATP  →(PKA)→  Phosphoprotein + ADP

• Phosphodiesterase breaks down cAMP → 5'-AMP (inactive) → signal is switched off
• Phosphoprotein phosphatase removes the phosphate from phosphoproteins, returning them to baseline

Signal Amplification: One hormone molecule activates one receptor → activates many G proteins → activates many adenylyl cyclase molecules → forms thousands of cAMP molecules → activates many PKA molecules → phosphorylates thousands of proteins. This cascade amplification explains why hormones are effective at extremely low concentrations (nanomolar range).

4B. Phosphatidylinositol Mechanism (IP3/DAG Mechanism)

Steps:

• IP3 (inositol 1,4,5-triphosphate) - water-soluble, diffuses into cytoplasm
• DAG (diacylglycerol) - lipid-soluble, remains in the membrane

• IP3 binds to IP3-gated Ca2+ channels on the endoplasmic reticulum (ER)
• Ca2+ is released from ER into the cytoplasm → raises intracellular [Ca2+]
• Ca2+ acts as a third messenger, binding to calmodulin (Ca2+-binding protein)
• Ca2+-calmodulin complex activates calmodulin-dependent protein kinases (CaM kinases)
• CaM kinases phosphorylate proteins → cellular response

• DAG, along with Ca2+, activates protein kinase C (PKC)
• PKC phosphorylates specific cellular proteins → cellular response
• DAG is also cleaved to release arachidonic acid, which forms prostaglandins (local hormones)

• IP3 is dephosphorylated → inactive
• DAG is phosphorylated → returns to membrane phospholipid pool

4C. Tyrosine Kinase Mechanism

Type 1 - Receptor Tyrosine Kinase (e.g., Insulin receptor):

• Increased glucose uptake (GLUT-4 translocation to membrane)
• Protein synthesis
• Glycogen synthesis
• Cell growth and proliferation

Type 2 - JAK-STAT Mechanism (e.g., Growth Hormone, Prolactin):

5. Intracellular Receptor Mechanism

5A. Steroid Hormone Mechanism

Steps (as described by Sembulingam):

• In the unbound state, the receptor is associated with heat shock proteins (HSP 90, HSP 70) that keep it inactive
• Hormone binding causes dissociation of HSPs → receptor undergoes conformational change and is activated

Example: Aldosterone enters renal tubular cells → binds to mineralocorticoid receptor → new proteins formed (aldosterone-induced proteins) → increased activity of Na+/K+ ATPase → Na+ reabsorption and K+ secretion in collecting duct.

Onset of action is delayed: Because gene transcription and protein synthesis take time, the effect of steroid hormones begins 45 minutes to several hours after hormone secretion. Effects may last hours to days.

5B. Thyroid Hormone Mechanism

Steps:

Thyroid hormones also have non-genomic effects (rapid actions) not involving transcription - e.g., direct effects on mitochondria and membrane ion channels.

6. Cyclic GMP (cGMP) Mechanism

Steps:

1. Hormone (e.g., ANP) binds to a receptor that has guanylyl cyclase activity on its intracellular domain.
2. Guanylyl cyclase converts GTP → cGMP.
3. cGMP activates cGMP-dependent protein kinase (PKG).
4. PKG phosphorylates proteins → causes vasodilation and natriuresis (increased Na+ excretion in urine).

• NO is formed in vascular endothelial cells and diffuses into smooth muscle cells
• NO activates soluble guanylyl cyclase → cGMP → PKG → vascular smooth muscle relaxation

7. Calcium-Calmodulin Mechanism

Mechanism:

1. Intracellular Ca2+ rises (from ER via IP3, or via membrane Ca2+ channels)
2. Ca2+ binds to calmodulin (a 16.7 kDa intracellular protein with 4 Ca2+ binding sites)
3. Ca2+-calmodulin complex activates calmodulin kinase (CaM kinase)
4. CaM kinase phosphorylates target proteins

Examples:

• Activates myosin light chain kinase (MLCK) → smooth muscle contraction
• Activates phosphorylase kinase → glycogen breakdown

Normal intracellular Ca2+ = 10-7 mol/L (resting). Calmodulin is activated when Ca2+ rises to 10-6 mol/L.

8. Comparison of Mechanisms of Hormone Action

9. Permissive Action of Hormones

• Up-regulates adrenergic receptors on blood vessel walls
• Maintains the responsiveness of receptor systems to catecholamines

10. Regulation of Hormone Receptors

a. Down-Regulation (Desensitization):

• When hormone levels are high for prolonged periods, the target cell decreases the number of receptors
• Prevents overstimulation of the cell
• Example: In Type 2 Diabetes Mellitus, chronically high insulin levels → down-regulation of insulin receptors → insulin resistance

b. Up-Regulation:

• When hormone levels are low or when another hormone stimulates it, the target cell increases the number of receptors
• Increases cell sensitivity
• Example: Estrogen up-regulates progesterone receptors in the uterus

11. Summary

• Water-soluble hormones (peptides, proteins, catecholamines) cannot enter the cell. They act through membrane receptors and use second messengers (cAMP, IP3/DAG/Ca2+, cGMP) to relay the signal inside the cell, ultimately leading to protein phosphorylation by protein kinases.
• Lipid-soluble hormones (steroids, thyroid hormones) cross the cell membrane freely and act on intracellular receptors. The hormone-receptor complex acts directly on DNA to regulate gene transcription and new protein synthesis. Their effects are slow in onset but long in duration.
• Insulin and growth factors use the tyrosine kinase mechanism, in which receptor activation leads to autophosphorylation and downstream signaling cascades.

• Some hormones act in seconds (adrenaline) while others take hours (cortisol)
• The same second messenger (cAMP) produces different effects in different tissues
• Receptor up/down regulation controls hormonal sensitivity
• Many drugs act by mimicking or blocking hormone receptors

References

1. Sembulingam K, Sembulingam P. Essentials of Medical Physiology, 8th Edition. Jaypee Brothers Medical Publishers, New Delhi. Chapter 58 - General Physiology of Endocrine Glands (Section on Mechanism of Hormonal Action), pp. 347-355.
2. Guyton AC, Hall JE. Textbook of Medical Physiology, 14th Ed. Elsevier. Chapter 75.
3. Costanzo LS. Physiology, 7th Ed. Elsevier. Chapter 9, pp. 405-410.

THYROID GLAND AND THYROID HORMONES

1. Introduction

2. Structure of the Thyroid Gland

• Weight: 25-30 grams in adults
• Shape: Butterfly-shaped; consists of two lobes (right and left) connected by an isthmus
• Location: Anterior to the 2nd, 3rd, and 4th tracheal rings

Histological Structure:

• The gland is made up of numerous follicles (functional units)
• Each follicle is lined by a single layer of follicular cells (thyrocytes)
• The center of the follicle contains a gelatinous material called colloid, which is mainly composed of thyroglobulin (a glycoprotein - the storage form of thyroid hormones)
• Parafollicular cells (C cells) are found between follicles and secrete calcitonin

3. Thyroid Hormones - Chemistry

• Daily secretion: T4 = ~80 µg/day; T3 = ~4 µg/day
• In the tissues, T4 is converted to T3 by the enzyme deiodinase (5'-deiodinase)
• T3 is the biologically active form that acts on the nucleus
• Reverse T3 (rT3) is an inactive isomer formed from T4

4. Synthesis of Thyroid Hormones

Step 1: Trapping of Iodide (Iodide Pump / Iodide Trapping)

• Iodine is consumed through diet (recommended daily intake = 150 µg/day)
• In the GI tract, iodine is reduced to iodide (I-) and absorbed into the bloodstream
• Iodide from blood is actively transported into the thyroid follicular cells by Sodium-Iodide Symporter (NIS) - an active transport mechanism
• The thyroid concentrates iodide 25-50 times more than in plasma (can go up to 250 times when stimulated by TSH)
• This active transport mechanism is called the iodide pump or iodide trapping
• The iodide is then transported to the colloid via pendrin (a chloride-iodide transporter on the apical membrane)

Step 2: Synthesis and Secretion of Thyroglobulin

• Thyroglobulin (Tg) is a large glycoprotein (molecular weight = 660,000 daltons) made up of two subunits
• It contains 123 tyrosine residues, of which only 4-8 participate in hormone synthesis
• Thyroglobulin is synthesized in the follicular cells and secreted into the colloid by exocytosis

Step 3: Oxidation of Iodide (Organification)

• Iodide (I-) is oxidized to active iodine (I0 or I+) by the enzyme thyroid peroxidase (TPO) in the presence of hydrogen peroxide (H2O2)
• This active iodine then reacts with tyrosine residues on thyroglobulin
• This process is called organification (organic binding of iodine to thyroglobulin)

Step 4: Iodination of Tyrosine

• Tyrosine + 1 iodine → Monoiodotyrosine (MIT)
• Tyrosine + 2 iodine → Diiodotyrosine (DIT)

Step 5: Coupling Reaction (Formation of T3 and T4)

DIT + DIT  →  Thyroxine (T4) + Alanine
MIT + DIT  →  Triiodothyronine (T3) + Alanine
DIT + MIT  →  Reverse T3 (rT3) + Alanine

Note: MIT and DIT themselves are not secreted into the blood. They are deiodinated by iodotyrosine deiodinase, and the recovered iodide is recycled within the gland.

5. Secretion of Thyroid Hormones

1. TSH stimulus activates follicular cells
2. Follicular cells extend pseudopodia into the colloid and engulf thyroglobulin by endocytosis (pinocytosis)
3. The engulfed thyroglobulin-containing vesicles fuse with lysosomes
4. Lysosomal proteases hydrolyze (digest) thyroglobulin → releasing free T3 and T4
5. Free T3 and T4 diffuse across the basal membrane into the blood capillaries

More T4 is secreted than T3 (ratio approximately 20:1), but T4 is converted to T3 in peripheral tissues. T3 is the active hormone at the cellular level.

6. Transport of Thyroid Hormones in Blood

• Only the free (unbound) fraction is biologically active:
  • Free T4 = ~0.03% of total T4
  • Free T3 = ~0.3% of total T3
• T3 is less protein-bound than T4, so more T3 is available in free (active) form
• Normal plasma levels: Total T4 = 5-12 µg/dL; Total T3 = 80-200 ng/dL

7. Peripheral Metabolism of Thyroid Hormones

• In peripheral tissues (liver, kidney, muscles), T4 undergoes deiodination by the enzyme 5'-deiodinase:
  • T4 → T3 (active, 5'-deiodination) - provides 80% of circulating T3
  • T4 → Reverse T3 (rT3) (inactive, 5-deiodination)
• T3 is 3-5 times more potent than T4 and has a shorter half-life (T3 half-life = 1 day; T4 half-life = 7 days)
• Thyroid hormones are finally conjugated in the liver (glucuronide/sulfate conjugates) and excreted in bile

8. Regulation of Secretion of Thyroid Hormones

A. Role of Hypothalamus - TRH

• Hypothalamus secretes Thyrotropin-Releasing Hormone (TRH)
• TRH is released into the hypothalamo-hypophyseal portal vessels and reaches the anterior pituitary
• TRH stimulates anterior pituitary to secrete TSH

B. Role of Anterior Pituitary - TSH

• Thyroid-Stimulating Hormone (TSH) (also called thyrotropin) is secreted by thyrotroph cells of the anterior pituitary
• TSH is the major regulator of thyroid hormone synthesis and secretion
• TSH acts through the cAMP second messenger mechanism (binds to TSH receptor on follicular cell membrane → activates Gs protein → adenylyl cyclase → cAMP → PKA)
• Actions of TSH on the thyroid gland:
  1. Increases iodide trapping (activates NIS)
  2. Increases thyroglobulin synthesis
  3. Increases organification of iodine
  4. Increases iodination of tyrosine
  5. Increases coupling reaction
  6. Increases endocytosis and proteolysis of thyroglobulin
  7. Causes hypertrophy and hyperplasia of thyroid follicular cells (increases gland size)

C. Negative Feedback Control

• Rising levels of T3 and T4 in the blood inhibit both TRH (from hypothalamus) and TSH (from anterior pituitary) - this is negative feedback
• T3 is the main hormone acting in feedback inhibition (T4 is converted to T3 in pituitary)
• This maintains thyroid hormone levels within a narrow normal range

Hypothalamus → TRH → Anterior Pituitary → TSH → Thyroid Gland
                                                      ↓
                                              T3 and T4 secreted
                                                      ↓
                          Negative feedback ←─────────┘
                    (inhibits TRH and TSH)

D. Role of Iodide - Wolff-Chaikoff Effect

• Moderate iodide intake: Normal T3 and T4 synthesis
• High iodide intake: Excess iodide inhibits thyroid peroxidase → suppresses thyroid hormone synthesis → this is the Wolff-Chaikoff effect
• This protective effect is transient (gland "escapes" after a few weeks)
• Used clinically: Large doses of iodide are given before thyroid surgery (Lugol's iodine) to reduce vascularity of the gland

E. Other Factors

1. Low basal metabolic rate
2. Cold temperature (especially in infants)
3. Leptin (from adipose tissue) - increases TRH release
4. α-Melanocyte-stimulating hormone (α-MSH) - increases TRH release
5. Stress, pregnancy

1. Excess thyroid hormones (feedback)
2. High iodide (Wolff-Chaikoff effect)
3. Antithyroid drugs (propylthiouracil, methimazole - inhibit TPO)
4. Glucocorticoids (suppress TSH)

9. Functions of Thyroid Hormones

A. Effect on Metabolic Rate (Calorigenic Effect)

• Thyroid hormones increase the Basal Metabolic Rate (BMR) of almost all body cells (exceptions: brain, retina, spleen, testes, uterus)
• They increase oxygen consumption and heat production in cells
• A 100% increase in thyroid hormone secretion can double the BMR
• Mechanism: T3 increases the number and activity of mitochondria, uncouples oxidative phosphorylation, increases Na+/K+ ATPase activity

B. Effect on Carbohydrate Metabolism

• Increase intestinal absorption of glucose
• Promote glycogenolysis (breakdown of glycogen) and gluconeogenesis
• Increase cellular uptake and utilization of glucose
• Excess thyroid hormones → hyperglycemia

C. Effect on Protein Metabolism

• Physiological levels: Promote protein synthesis (anabolic effect) → necessary for growth
• Excess levels (hyperthyroidism): Cause protein breakdown → negative nitrogen balance → muscle wasting and weakness

D. Effect on Fat Metabolism

• Promote lipolysis (fat breakdown) and mobilization of fatty acids from adipose tissue
• Increase oxidation of fatty acids
• Decrease serum cholesterol and triglycerides (by increasing LDL receptor formation)
• Hypothyroidism → hypercholesterolemia

E. Effect on Growth and Development

• Essential for normal growth - work synergistically with Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1)
• Required for normal ossification and bone development
• Required for normal brain development - especially in fetal life and early infancy
• Absence in neonatal period → cretinism (mental retardation + dwarfism)

F. Effect on the Nervous System

• Required for normal development of the nervous system (myelination of nerves)
• Hyperthyroidism → hyperreflexia, nervousness, tremors, anxiety, irritability
• Hypothyroidism → slow reflexes, lethargy, mental slowness, depression

G. Effect on the Cardiovascular System

• Increase heart rate (chronotropic) and force of contraction (inotropic)
• Increase cardiac output
• Mechanism: Up-regulate β1-adrenergic receptors in the heart → sensitize the heart to catecholamines
• Hyperthyroidism → palpitations, tachycardia, atrial fibrillation
• Hypothyroidism → bradycardia, low cardiac output

H. Effect on the Respiratory System

• Increase the rate and depth of respiration to meet increased O2 demand
• Stimulate erythropoietin production → increase red cell production

I. Effect on the Gastrointestinal System

• Increase GI motility (intestinal peristalsis)
• Hyperthyroidism → diarrhea, increased appetite
• Hypothyroidism → constipation

J. Effect on Reproductive System

• Required for normal gonadal function and fertility
• Hypothyroidism → menstrual irregularities, anovulation, infertility
• Required for normal lactation

K. Effect on the Musculoskeletal System

• Normal levels: Promote muscle function
• Excess: Muscle wasting and weakness (thyrotoxic myopathy)
• Deficiency in children: Retarded skeletal growth and delayed bone maturation

10. Mode of Action of Thyroid Hormones

Steps:

1. T3 and T4 diffuse freely across the cell membrane (lipid bilayer)
2. Inside the cell, T4 is converted to T3 by deiodinase
3. T3 enters the nucleus and binds to specific Thyroid Hormone Receptors (TR-α and TR-β) - members of the nuclear receptor superfamily
4. The T3-receptor complex binds to Thyroid Hormone Response Elements (TREs) on the promoter region of target genes
5. This activates RNA polymerase → gene transcription → synthesis of mRNA
6. mRNA moves to ribosomes → translation → synthesis of new nuclear proteins and enzymes
7. These new proteins bring about the specific physiological effects of thyroid hormones

T3 is 3-5 times more potent than T4 because T3 has a higher affinity for thyroid hormone receptors.

Non-genomic effects also exist - T3 has rapid effects on mitochondria and membrane ion channels, independent of gene transcription.

11. Thyroid Function Tests

Serum TSH is the most sensitive and specific test for detecting thyroid dysfunction.

12. Applied Physiology - Disorders of Thyroid Gland

A. Hypothyroidism

Types:

• Occurs due to thyroid hormone deficiency during fetal and early neonatal period
• Causes: Agenesis of thyroid gland, iodine deficiency during pregnancy, inborn errors of thyroid hormone synthesis
• Features:
  • Mental retardation (most important feature - irreversible)
  • Dwarfism (short stature due to impaired bone growth)
  • Pot belly, protruding tongue (macroglossia)
  • Flat nose, puffy face
  • Delayed dentition
  • Umbilical hernia
  • Delayed puberty
  • Low BMR, bradycardia, constipation

Early neonatal screening for TSH (heel-prick test) and prompt treatment with thyroid hormone replacement can prevent mental retardation if started within 2 weeks of birth.

• Occurs due to thyroid hormone deficiency in adults
• Causes: Hashimoto's thyroiditis (most common - autoimmune), iodine deficiency, thyroidectomy, radioiodine therapy
• Features:
  • Decreased BMR, weight gain despite poor appetite
  • Cold intolerance, dry skin, coarse hair
  • Bradycardia, low cardiac output
  • Lethargy, mental slowness, depression
  • Myxedema - non-pitting edema due to accumulation of hyaluronic acid and glycosaminoglycans in subcutaneous tissues
  • Constipation, menorrhagia
  • Hoarseness of voice (due to mucin deposition in vocal cords)
  • Hypercholesterolemia
  • Periorbital puffiness, drooping eyelids

• Enlargement of thyroid gland due to iodine deficiency
• Common in mountainous regions (far from sea) → "endemic goiter"
• Low iodine → low T3/T4 → high TSH (feedback) → hypertrophy of gland → goiter
• Treated by iodized salt supplementation

B. Hyperthyroidism (Thyrotoxicosis)

1. Graves' disease (most common) - autoimmune; B-lymphocytes produce Thyroid-Stimulating Antibodies (TSAb/LATS) that mimic TSH → continuous stimulation of thyroid → excess T3/T4
2. Toxic multinodular goiter
3. Thyroid adenoma
4. Excess TSH secretion (rare)

• Increased BMR (up to 60-100% above normal)
• Weight loss despite increased appetite
• Excessive heat production and sweating
• Negative nitrogen balance

• Tachycardia (rapid heart rate), palpitations
• Increased cardiac output
• Atrial fibrillation in severe cases

• Nervousness, anxiety, irritability
• Tremors of hands and fingers
• Hyperreflexia

• Exophthalmos (proptosis) - protrusion of eyeballs
  • Due to inflammatory edema and fibrosis of retro-orbital fat and extraocular muscles
  • Specific to Graves' disease (caused by TSH receptor antibodies on retro-orbital tissues)
• Lid retraction, lid lag

• Muscle weakness (thyrotoxic myopathy)
• Fine tremor

• Increased appetite (polyphagia), diarrhea, malabsorption

• Oligomenorrhea (scanty periods) or amenorrhea
• Infertility

Comparison Table - Hypo vs Hyperthyroidism

C. Treatment of Thyroid Disorders

• Oral levothyroxine (L-T4) replacement therapy - treatment of choice
• Dose adjusted to normalize TSH

1. Antithyroid drugs:
   • Propylthiouracil (PTU) - inhibits TPO (blocks organification and coupling); also inhibits peripheral T4→T3 conversion
   • Methimazole (Carbimazole) - inhibits TPO
2. Radioactive Iodine (131I): Destroys thyroid tissue (used in Graves' disease and toxic nodular goiter)
3. Surgery (Thyroidectomy): Surgical removal of most of the thyroid gland
4. β-blockers (Propranolol): Adjunct therapy - controls sympathetic symptoms (tachycardia, tremors) by blocking β-adrenergic receptors; also inhibits T4→T3 conversion

13. Summary

References

1. Sembulingam K, Sembulingam P. Essentials of Medical Physiology, 10th Edition. Jaypee Brothers Medical Publishers, New Delhi, 2022. Chapter 67 - Thyroid Gland, pp. 388-398.
2. Ganong WF. Review of Medical Physiology (Ganong's), 26th Ed. McGraw-Hill. Chapter 20.
3. Costanzo LS. Physiology, 7th Ed. Elsevier. Chapter 9, pp. 420-432.
4. Guyton AC, Hall JE. Textbook of Medical Physiology, 14th Ed. Elsevier. Chapter 76.