1. Two Main Functions (Must-know)

a. Thyroid Hormones (T3, T4)

• Maintain metabolic rate.
• ↑ O₂ consumption in most cells.
• Regulate lipid + carbohydrate metabolism.
• Affect body weight, heat production, and mentation.

b. Calcitonin

• Secreted by C-cells.
• Role: ↓ serum calcium (minor compared to PTH/Vit D).

2. Regulation (Core MCQ Area)

TSH from anterior pituitary

• Main controller of thyroid hormone secretion.

TRH from hypothalamus

• ↑ TSH secretion.

Negative Feedback

• High free T3/T4 suppress:
• TRH (hypothalamus)
• TSH (anterior pituitary)
• This is the central exam point in endocrine regulation.

3. Clinical Importance of Thyroid Dysfunction

Hypothyroidism

• Mental + physical slowing
• Cold intolerance
• Weight gain
• In fetus/neonate → cretinism (mental retardation + dwarfism)

Hyperthyroidism

• Weight loss
• Heat intolerance
• Nervousness, tremor
• Tachycardia

(These features appear in every exam.)

4. Key Anatomy (Only the core tested points)

Location

• Butterfly-shaped gland in front of trachea.

Development

• From pharyngeal floor → migrates down as thyroglossal duct (may persist).

Structure

• Two lobes + isthmus
• Sometimes pyramidal lobe (high-yield anatomy spotter)

Blood Supply

• Very high blood flow per gram → explains:
• Bruising risk during surgery
• Rapid delivery of iodide

5. Follicle Structure (Super high yield)

• Functional unit: Thyroid follicle = spherical acinus.
• Lined by single layer of epithelial (follicular) cells.
• Filled with colloid (thyroglobulin) — storage form of thyroid hormone.
• Inactive gland:
• Large follicles, flat epithelial cells
• Lots of colloid
• Active gland:
• Small follicles, cuboidal/columnar cells
• Reabsorption lacunae (very common MCQ image)

6. Cellular Features (Only the key 3 you need)

• Microvilli extend into colloid
• Well-developed ER (for protein synthesis)
• Fenestrated capillaries around follicles — typical endocrine feature

THYROID HORMONE FORMATION

1. The 4 Big Concepts (Everything in this chapter revolves around these)

(1) What hormones are made?

• Main secretion = T4
• Smaller amount = T3
• T3 is the active hormone (T4 is a pro-hormone)
• T3 is mostly made in peripheral tissues by deiodination of T4
• Reverse T3 (rT3) = inactive

👉 If you know this: you answer 80% of MCQs on “thyroid hormone types.”

(2) Iodine is essential — and handled in a predictable pathway

Need ~150 µg/day

Most people eat 500 µg/day (salt fortified)

Where iodine goes:

• 20% → thyroid
• 80% → urine

Thyroid uses iodine like this:

• 120 µg/day enters the gland
• Secretes 80 µg/day as T3+T4
• 40 µg/day leaks back to ECF
• Another 60 µg/day comes from metabolism of old thyroid hormones
• Some iodine reabsorbed from bile

👉 Exams LOVE the “20% goes to thyroid / 80% urine” ratio.

(3) How iodide enters and leaves the thyrocyte

Entry into cell (basolateral membrane)

NIS (Na⁺/I⁻ symporter)

• Brings 2 Na⁺ + 1 I⁻ into cell
• Creates intracellular iodide 20–40× plasma levels
• Stimulated by TSH

👉 This is why radioiodine therapy works.

Exit into colloid (apical membrane)

Pendrin (Cl⁻/I⁻ exchanger)

• Moves iodide into colloid
• Mutated in Pendred syndrome (thyroid dysfunction + deafness)

(4) How thyroid hormone is MADE (4 steps only!)

This is where 80% of questions come from.

Step 1 — Thyroglobulin (Tg) synthesis

• Thyroglobulin = huge 660 kDa glycoprotein
• Made in thyrocytes
• Exocytosed into colloid
• Contains ~123 tyrosines but only 4–8 become hormones

Step 2 — Iodide → iodine (oxidation)

• Occurs at apical membrane
• Catalyzed by thyroid peroxidase (TPO)

— target for thioureylenes (carbimazole, PTU)

Step 3 — Organification (iodination of tyrosine)

• Tyrosine + 1 iodine → MIT
• MIT + 1 iodine → DIT

MIT = mono

DIT = di

👉 High-yield fact: MIT and DIT are NOT secreted.

Step 4 — Coupling (forming T3 and T4)

• DIT + DIT → T4
• MIT + DIT → T3
• Both reactions catalyzed by TPO

After this, hormones remain stored inside thyroglobulin in colloid

— humans can survive 2 months with no dietary iodine

5. Secretion — FINAL STEP

When the body needs hormone:

1. Thyrocyte endocytoses colloid
2. Lysosomes digest thyroglobulin
3. Free T3 and T4 released into blood
4. MIT and DIT are deiodinated inside the gland → iodine is recycled

👉 Up to 2/3 of iodine is recycled from MIT/DIT.

If the enzyme iodotyrosine deiodinase is absent:

• MIT & DIT appear in urine
• Patient develops iodine deficiency symptoms even with normal intake

6. Daily secretion numbers (VERY high yield)

• T4: 80 µg/day
• T3: 4 µg/day
• rT3: 2 µg/day

Ratio T4:T3 secretion = 20:1

But in plasma, ratio is much closer because T3 is formed peripherally.

7. Killer exam sentence

“Iodine is essential for thyroid hormone synthesis, but both deficiency AND excess inhibit thyroid function.”

This appears in:

• goiter
• Wolff–Chaikoff effect
• thyrotoxicosis treatment

✅ THYROID HORMONE TRANSPORT & METABOLISM

1. Only FREE T3/T4 matter (core fact for exams)

• Total T4 ≈ 8 µg/dL
• Total T3 ≈ 0.15 µg/dL
• But free levels are tiny:
• Free T4 = 2 ng/dL
• Free T3 = 0.3 ng/dL
• Free hormones = active hormones
• Only free T3/T4 regulate feedback on TSH

👉 Total T3/T4 can be misleading if binding proteins change.

👉 Free T3/T4 are clinically reliable.

2. Three binding proteins — and one main boss

Thyroid hormones bind to:

1. TBG (thyroxine-binding globulin) — highest affinity → carries most hormone
2. Transthyretin (prealbumin) — less
3. Albumin — biggest capacity, lowest affinity

Binding %

• T4: 99.98% bound
• T3: 99.8% bound

Consequences:

• T4 half-life = 6–7 days (long)
• T3 half-life = 1 day (short, rapid action)

👉 More tightly bound = longer half-life. Less tightly bound = faster action.

3. Changes in binding proteins DO NOT cause hyper/hypothyroidism

If TBG ↑:

• Free T4 falls temporarily
• TSH rises
• Thyroid makes more T4
• New steady state: Total T4 ↑ but free T4 normal
• Patient = euthyroid

If TBG ↓:

• Opposite sequence → still euthyroid

👉 TBG changes alter total T4/T3, NOT free T4/T3.

👉 Patients remain euthyroid.

4. What increases or decreases TBG? (VERY high yield)

↑ TBG (total T4 rises, free T4 normal)

• Pregnancy
• Estrogens (COCP, HRT)
• Drugs: tamoxifen, methadone
• Hepatitis

↓ TBG (total T4 falls, free T4 normal)

• Androgens
• Glucocorticoids
• Danazol
• L-asparaginase

Drugs that displace T4/T3 from TBG

(→ same effect as ↓TBG)

• Salicylates
• Phenytoin
• Mitotane
• 5-FU

👉 These are exam favorites.

5. Deiodination — THE most tested part of metabolism

3 types of deiodinases

All contain selenocysteine, need selenium.

D1

• Liver, kidney, thyroid
• Makes plasma T3

D2

• Brain, pituitary, brown fat
• Generates local T3 for tissues (especially neurons)

D3

• Brain + reproductive tissues
• Makes reverse T3 (inactive)
• Inactivates T3

👉 D1 + D2 activate

👉 D3 inactivates

6. Where plasma T3 and rT3 REALLY come from

T3 in blood

• 13% directly from thyroid
• 87% from T4 → T3 conversion

rT3 in blood

• 5% from thyroid
• 95% from T4 → rT3 conversion via D3

👉 This is why:

• T4 is the main secretion
• But T3 is the main active hormone

7. Non-thyroidal illness (“low T3 syndrome”)

In serious illness:

• ↓ D1 and D2 activity
• ↑ D3 activity
• T3 ↓, rT3 ↑
• TSH normal or mildly low
• Patient is NOT hypothyroid — they recover spontaneously

Seen in:

• Burns
• Trauma
• Sepsis
• Chronic kidney disease
• Liver failure
• Cancer
• MI

👉 Exam key: Sick euthyroid syndrome ≠ hypothyroidism.

8. Fasting/starvation effect — VERY HIGH YIELD

During fasting:

• T3 falls (10–50%)
• rT3 rises
• T4 normal
• BMR decreases
• Nitrogen losses fall → protein conservation

During overfeeding:

• T3 ↑
• rT3 ↓

👉 Key metabolic principle: Low T3 saves energy.

✅ REGULATION OF THYROID SECRETION

1. The Central Control Axis (TSH–TRH–T3/T4 negative feedback)

This is THE most important concept.

TSH (pituitary)

• Main controller of thyroid hormone synthesis.
• ↑ TSH → ↑ T3/T4 → thyroid growth.
• ↓ TSH → ↓ thyroid function → atrophy.

TRH (hypothalamus)

• Stimulates TSH.
• Stress ↓ TRH.
• Cold ↑ TRH in babies/animals (NOT adults).

Negative Feedback

• Free T3/T4 suppress TRH & TSH.
• T4 converted to T3 inside pituitary by D2, which makes feedback stronger.

👉 KEY EXAM SENTENCE:

“T3 is the main feedback regulator of TSH.”

2. TSH Structure & Metabolism (super high yield)

TSH is a glycoprotein with α + β subunits

• α-subunit = same as LH, FSH, hCG
• β-subunit = gives its specificity

👉 High hCG can stimulate TSH receptors → mild hyperthyroidism in pregnancy/tumors.

TSH facts

• Half-life ≈ 60 minutes
• Pulsatile secretion
• Peaks around midnight
• Mostly metabolized in kidneys

3. Effects of TSH on the Thyroid (very high yield)

TSH stimulates EVERY step of thyroid hormone production:

1. ↑ Iodide trapping
2. ↑ Thyroglobulin synthesis
3. ↑ MIT/DIT, T3/T4 formation
4. ↑ Colloid endocytosis
5. ↑ T3/T4 release
6. ↑ Blood flow
7. Long-term: hypertrophy → goiter

👉 If TSH is high for a long time → goiter

👉 If TSH is absent → thyroid atrophy

4. TSH Receptor (classic MCQ)

• GPCR (Gs → ↑ cAMP)
• Also activates PLC pathway
• Target for TSH, thyroid-stimulating antibodies (Graves)

5. Other Growth Factors

(One-liners only; that’s all exams need.)

• IGF-1 & EGF → stimulate growth
• TNF-α & interferon-γ → inhibit growth (inflammation → ↓ thyroid function)

6. Low T3/T4 → High TSH → Goiter (except in secondary/tertiary hypothyroidism)

Primary hypothyroidism:

• Thyroid failure
• ↓ T3/T4
• ↑ TSH
• Goiter

Secondary/Tertiary hypothyroidism:

• Pituitary or hypothalamic failure
• ↓ T3/T4
• ↓ TSH
• No goiter

👉 EXAM CLASSIC!

7. Iodine-Related Regulation (VERY HIGH YIELD)

Iodine deficiency

• ↓ T4 → ↑ TSH → goiter
• Endemic goiter

Excess iodine → Wolff–Chaikoff effect

• High iodine acutely blocks TPO
• ↓ T3/T4 synthesis
• Temporary hypothyroidism
• Used therapeutically in thyroid storm

👉 Key pairing: Iodine excess → Wolff–Chaikoff

8. Best Test of Thyroid Function = TSH

• Because of sensitive negative feedback
• T4 dose titration in hypothyroidism is based on TSH normalization

👉 Exam sentence:

“Normalizing TSH—not BMR—is the target in treating hypothyroidism.”

9. High-Yield Clinical Scenarios

❗ Myxedema (adult hypothyroidism)

• Slow mentation
• Cold intolerance
• Dry skin
• High cholesterol

❗ Cretinism (congenital hypothyroidism)

• Mental retardation
• Dwarfism
• Preventable if T4 given early
• Causes: iodine deficiency, dysgenesis, maternal antibodies

❗ Graves Disease (MOST COMMON hyperthyroidism)

• Anti-TSH receptor antibodies stimulate TSH receptor
• ↓ TSH
• ↑ T3/T4
• Goiter
• Exophthalmos

❗ Hashimoto thyroiditis

• Early phase → transient hyperthyroidism
• Late phase → hypothyroidism
• Anti-TPO + anti-thyroglobulin antibodies

10. Drugs that affect regulation (super high yield)

Hyperthyroidism treatment

• Thioureylenes (PTU, methimazole)
• Block iodination and coupling
• PTU also blocks D2 → ↓ T3
• Radioiodine
• Surgery (large goiters)

Hypothyroidism treatment

• Levothyroxine (T4)
• Monitor using TSH, not symptoms

EFFECTS OF THYROID HORMONES

1️⃣ Mechanism of Action – HOW T3/T4 Work (Core Concept)

• T3 and T4 enter cells (lipophilic).
• Inside the cell:
• T3 binds strongly to thyroid hormone receptors (TRs) in the nucleus.
• T4 can bind, but less strongly → many of its actions are via conversion to T3.
• TRs = nuclear transcription factors:
• TRs bind DNA (via zinc fingers).
• Change transcription of many genes: some upregulated, some downregulated.
• TR forms heterodimers with RXR → this enhances DNA binding and transcriptional effects.

Key exam points:

• T3 is 3–5× more potent than T4.
• T3 is less protein-bound but binds TR more avidly.
• TRα & TRβ = receptor isoforms; widespread distribution explains wide effects.

👉 Take-home: Thyroid hormones act like “master gene regulators” for metabolism, growth, heart, brain, etc.

2️⃣ Calorigenic Effect – The Classic Thyroid Signature

• T3/T4 ↑ O₂ consumption and ↑ metabolic rate in almost all metabolically active tissues.
• Exceptions (no ↑ O₂ consumption):

Adult brain, testes, uterus, lymph nodes, spleen, anterior pituitary.

• Mechanisms:
• ↑ Na⁺/K⁺ ATPase activity in many tissues → more ATP usage → more O₂ demand.
• Mobilization and oxidation of fatty acids.

Clinical logic:

• Hyperthyroid → ↑ BMR, weight loss (if intake not increased), heat intolerance.
• Hypothyroid → ↓ BMR, weight gain, cold intolerance.

3️⃣ Protein, Fat, Vitamins & Skin – Secondary Effects of Calorigenesis

Protein & Nitrogen

• Hyperthyroid adult:
• ↑ protein catabolism → muscle wasting
• ↑ urinary N, K⁺, uric acid, hexosamine → negative nitrogen balance.
• Hypothyroid child (small doses):
• Low dose thyroid hormone → positive nitrogen balance & growth.
• Excess dose → catabolism just like adult.

Vitamins

• ↑ metabolism → ↑ requirement for all vitamins → deficiency can unmask.
• Thyroid hormones needed for hepatic conversion of carotene → vitamin A:
• Hypothyroidism → carotene accumulates → yellowish skin (carotenemia).
• Carotenemia: yellow skin but sclera are normal (unlike jaundice).

Myxedema (skin)

• In hypothyroidism:
• Mucopolysaccharide–protein complexes build up in skin → bind water → non-pitting puffiness (myxedema).
• Giving T4/T3 → ↑ breakdown of these proteins → diuresis until swelling clears.

4️⃣ Cardiovascular Effects – VERY High Yield

Overall pattern in hyperthyroidism:

• ↑ heart rate, ↑ contractility, ↑ cardiac output.
• ↓ peripheral resistance (cutaneous vasodilation for heat loss).
• ↑ blood volume, ↑ pulse pressure, shorter circulation time.

At molecular level in the heart:

• T3 ↑ expression of:
• α-myosin heavy chain (α-MHC) (high ATPase → faster contraction)
• SR Ca²⁺ ATPase
• β-adrenergic receptors
• G proteins, Na⁺/K⁺ ATPase, some K⁺ channels
• T3 ↓ expression of:
• β-MHC (slower myosin)
• Phospholamban
• Some adenylyl cyclase isoforms
• Na⁺–Ca²⁺ exchanger (NCX)
• Its own receptor (T3 receptor) – negative feedback

👉 Net effect: faster and stronger heart, more responsive to catecholamines.

Hypothyroidism → opposite shift: more β-MHC → slower contraction, less powerful heart.

5️⃣ Nervous System Effects – Adult vs Development

In Adults

• Hypothyroid:
• Slow mentation, poor concentration, dullness.
• CSF protein ↑.
• Hyperthyroid:
• Rapid thinking, irritability, restlessness, anxiety.
• Stretch reflexes:
• Hyperthyroid → short relaxation time (quick ankle jerk).
• Hypothyroid → prolonged relaxation (slow ankle jerk).

(Not specific, but classic exam association.)

In Development (HUGE high-yield takeaway)

• Thyroid hormones are crucial for:
• Cerebral cortex
• Basal ganglia
• Cochlea
• Deficiency in fetal/neonatal period →

mental retardation, motor rigidity, deaf-mutism (cretinism picture).

• Pendred syndrome: defective iodide transport in thyrocytes → thyroid dysfunction + deafness.

👉 Moral: Normal T3/T4 in pregnancy and early life = critical for brain & hearing.

6️⃣ Relationship with Catecholamines – Why β-blockers Help

• Catecholamines (adrenaline, noradrenaline) and thyroid hormones share:
• ↑ metabolic rate
• ↑ heart rate
• ↑ nervous system excitability
• Thyroid hormones:
• ↑ β-adrenergic receptor expression.
• ↑ post-receptor signalling proteins.

So in hyperthyroidism:

• Catecholamine levels = often normal

but tissues are hypersensitive to them.

Therapeutic implications:

• β-blockers (e.g. propranolol):
• ↓ palpitations, tremor, anxiety, sweating.
• Slightly ↓ T4→T3 conversion.
• Do not correct underlying thyroid hormone excess, but blunt symptoms.

👉 Classic exam point: “Many symptoms of thyrotoxicosis are mediated by increased β-adrenergic sensitivity.”

7️⃣ Skeletal Muscle

• Hyperthyroid:
• Muscle weakness → thyrotoxic myopathy (proximal weakness, wasting).
• Mechanism: ↑ protein catabolism + altered MHC expression.
• Hypothyroid:
• Weakness, cramps, stiffness.

👉 Both extremes cause muscle problems, but mechanism differs.

8️⃣ Carbohydrate & Lipid Metabolism – Very Examinable

Carbohydrate

• ↑ intestinal absorption of glucose.
• After a carb meal in hyperthyroid:
• Plasma glucose rises faster and higher.
• Falls fast again (↑ utilization).

Cholesterol

• Thyroid hormones ↓ plasma cholesterol by:
• ↑ hepatic LDL receptor expression → ↑ LDL removal.
• Hypothyroid → high cholesterol.
• Hyperthyroid → low cholesterol.

👉 Treating hypothyroidism often normalizes high cholesterol.

9️⃣ Growth & Bone

• Thyroid hormones are essential for normal growth and skeletal maturation.
• Hypothyroid child:
• Slowed bone growth.
• Delayed epiphyseal closure.
• T3/T4 potentiate GH:
• Without thyroid hormone, GH secretion and GH effect are reduced → growth failure.

👉 High-yield sentence:

“Thyroid hormones are permissive for growth hormone.”

🔟 Thyroid Hormone Resistance – Key Clinical Logic

• Usually due to TRβ mutations.
• Typical pattern:
• T3/T4 high
• TSH not suppressed appropriately (normal or mildly high)
• Patient often clinically euthyroid due to compensation.

Clinical importance:

• Must distinguish from Graves disease:
• Graves: high T3/T4, TSH low.
• Resistance: high T3/T4, TSH not low, often goiter, usually no classic thyrotoxic state.
• Sometimes peripheral resistance only → hypometabolism despite normal labs.