• Thyroid hormones generally increase nuclear transcription of many genes (Fig. 77.5).
• Therefore, in almost all body cells, they increase production of protein enzymes, structural proteins, transport proteins, and other substances.
• The overall result is a general increase in functional activity throughout the body.
• Before thyroid hormone acts on genes, most T₄ loses one iodide and becomes T₃.
• T₃ binds much more strongly to intracellular thyroid hormone receptors.
• Therefore, more than 90% of thyroid hormone bound to receptors is T₃.
• Thyroid hormone receptors are attached to or located near DNA.
• The receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone response elements on DNA.
• When thyroid hormone binds, the receptors become activated and start transcription.
• Many different types of messenger RNA (mRNA) are produced.
• The mRNA is then translated by cytoplasmic ribosomes, producing hundreds of new intracellular proteins.
• Different proteins increase by different amounts, from slight increases to about 6-fold.
• Most thyroid hormone effects result from the enzymatic and other functions of these newly formed proteins.
• Thyroid hormones also produce nongenomic effects, which do not depend on gene transcription.
• Some of these effects occur within minutes, too quickly to result from new protein synthesis.
• These effects are also not prevented by inhibitors of gene transcription or translation.
• Nongenomic actions occur in tissues such as the heart, pituitary, and adipose tissue.
• Their sites of action appear to include the plasma membrane, cytoplasm, and possibly mitochondria.
• These actions include regulation of ion channels and oxidative phosphorylation.
• They can also activate intracellular signaling systems such as cAMP and protein kinase cascades.

KEY CONCEPT

• T₄ → loses iodine → T₃ → nuclear receptor → DNA transcription → mRNA → new proteins → increased cellular activity.
• T₃ is the main receptor-bound thyroid hormone (>90%).
• Thyroid hormones act by:
  • Genomic pathway: slower, through gene transcription and new proteins.
  • Nongenomic pathway: faster, through membrane/cytoplasmic signaling.

CONCEPTUAL EXAMPLES

• Gene effect: T₃ binds receptor → DNA transcription increases → new proteins form → cell activity increases.
• Protein effect: New enzymes and transport proteins → increased cellular functions.
• Rapid effect: Thyroid hormone → membrane/cytoplasmic signaling → effect within minutes.
• Nongenomic effect: Thyroid hormone → cAMP/protein kinase signaling → rapid cellular response.

This figure is the “WHAT THYROID HORMONES DO INSIDE THE TARGET CELL” figure.

The previous figure explained how T₃/T₄ are made.
This one explains how T₃/T₄ produce their effects.

🧠 BIG IDEA — 10 SECONDS

T₄/T₃ → enter cell → T₄ becomes T₃ → T₃ enters nucleus → binds thyroid receptor → DNA → mRNA → new proteins → body effects

Think:

T₃ is the main “ON switch” for thyroid-hormone gene activity.

🚪 1. T₄ AND T₃ ENTER THE CELL

At the top:

T₄ + T₃

⬇️
cross the cell membrane

The figure says this occurs through a:

carrier-mediated transport system

So don’t imagine them simply floating through the membrane randomly.

🔄 2. T₄ → T₃

This is VERY important.

Inside many cells:

T₄

⬇️ deiodinase

T₃

Think:

T₄ = mostly the circulating/storage form

T₃ = more active form

So:

Deiodinase = converts T₄ → T₃

Some T₄ can also remain T₄.

⭐ HIGH-YIELD

T₄ enters → gets converted to T₃ → T₃ does most of the receptor activation

This is one of the key concepts in the whole figure.

🧠 3. T₃ GOES TO THE NUCLEUS

T₃ travels into the:

Nucleus

Why?

Because the thyroid hormone receptor is associated with DNA inside the nucleus.

🧲 4. T₃ BINDS THYROID HORMONE RECEPTOR

Inside the nucleus:

T₃ + thyroid hormone receptor

The receptor is already associated with DNA through a:

Thyroid hormone response element

Think:

DNA has a special “thyroid hormone switch.”

T₃ activates that switch.🤝 5. THYROID RECEPTOR + RETINOID X RECEPTOR

Look at the two receptors:

Thyroid hormone receptor

and

Retinoid X receptor (RXR)

They form a pair (heterodimer) that binds the DNA response element.

For exam purposes:

TR + RXR → binds thyroid hormone response element

Then T₃ binding changes the receptor complex so that gene transcription is regulated.

🧬 6. GENE TRANSCRIPTION

Once the receptor is activated:

Target gene

⬇️

Gene transcription

⬇️

mRNA

Meaning:

The DNA instruction is copied into an mRNA message.

🏭 7. mRNA → NEW PROTEINS

mRNA leaves the nucleus.

⬇️

Protein synthesis

⬇️

New proteins

And these proteins actually create the cell’s physiological effects.

This is why thyroid hormone effects are generally slower to develop but longer-lasting than many membrane-receptor hormone effects.

🎯 8. WHAT DO THESE NEW PROTEINS DO?

The bottom of the figure gives the major effects.

🫀 CARDIOVASCULAR SYSTEM

Thyroid hormone causes:

⬆️ Cardiac output

⬆️ Tissue blood flow

⬆️ Heart rate

⬆️ Heart strength

⬆️ Respiration

Easy idea:

Thyroid hormone makes the cardiovascular system more active.

🔥 9. METABOLISM

This is one of the most important sections.

Thyroid hormone increases:

⬆️ Mitochondria

More cellular energy machinery.

⬆️ Na⁺-K⁺ ATPase

More ion pumping.

⬆️ O₂ consumption

Cells use more oxygen.

⬆️ Glucose absorption

More glucose handling.

⬆️ Gluconeogenesis

Make new glucose.

⬆️ Glycogenolysis

Break glycogen into glucose.

⬆️ Lipolysis

Break down fat.

⬆️ Protein synthesis

Build proteins.

⬆️ BMR

Basal metabolic rate.

🔥 THE BIG METABOLIC IDEA

Don’t memorize the list as 10 unrelated things.

Think:

Thyroid hormone turns up the cell’s metabolic machinery.

Therefore:

↑ Energy production/use

↑ Oxygen consumption

↑ Heat production

↑ BMR

🧠 10. CNS DEVELOPMENT

Thyroid hormones are important for:

Central nervous system development

Especially during development.

So:

Thyroid hormone → normal brain/CNS development

🦴 11. GROWTH

Thyroid hormone supports:

Normal growth

It works together with other growth-related hormones.

So remember:

GH/IGF-1 provide major growth stimulation, but thyroid hormone is essential for normal growth and development.

🧩 “MANY OTHER SYSTEMS”

The figure also shows:

Many other systems

Why?

Because thyroid hormone receptors are present in many tissues.

Therefore thyroid hormones have widespread effects throughout the body.

🔗 NOW CONNECT THE WHOLE FIGURE

Step 1

T₄/T₃ enter cell

⬇️

Step 2

T₄ → T₃ by deiodinase

⬇️

Step 3

T₃ enters nucleus

⬇️

Step 4

T₃ binds thyroid hormone receptor

⬇️

Step 5

TR/RXR interacts with DNA response element

⬇️

Step 6

Gene transcription

⬇️

Step 7

mRNA

⬇️

Step 8

New protein synthesis

⬇️

Physiological effects

🧠 STORY

Imagine the cell is a factory.

T₄ = inactive-ish delivery package 📦

Deiodinase = activation machine 🔧

T₃ = active instruction 🟢

Nuclear receptor = switch 🎛️

DNA = factory instruction manual 📖

mRNA = copied instruction 📄

Protein = newly built machine ⚙️

Physiological effect = factory works faster 🚀

🚨 EXAM TRAPS

❌ T₄ is the main active intracellular hormone

✅ T₃ is generally more active.

❌ T₄ cannot become T₃

✅ Deiodinase converts T₄ → T₃.

❌ Thyroid hormone acts mainly through a membrane receptor

✅ Its major effects are through nuclear receptors regulating gene transcription.

❌ T₃ directly makes protein

✅ T₃ → gene transcription → mRNA → protein synthesis.

❌ Thyroid hormone immediately changes cell function

✅ Many major effects require new protein synthesis, so they develop relatively slowly.

🏆 THE 5 THINGS TO MEMORIZE

1. T₄ → T₃

Deiodinase

2. T₃ → nuclear receptor

3. Receptor → DNA response element

4. DNA → mRNA → protein

5. Proteins → growth + CNS development + cardiovascular + metabolism

🔥 ONE-LINE MASTER MEMORY

T₄ enters → T₃ activates → nuclear receptor → DNA → mRNA → protein → metabolism & growth

And the ultimate concept:

Thyroid hormone doesn’t simply “push” the cell directly—it changes which genes are expressed, causing the cell to manufacture new proteins that produce the long-term physiological effects.

THYROID HORMONES INCREASE CELLULAR METABOLIC ACTIVITY

• Thyroid hormones increase metabolic activity in almost all body tissues.
• Large amounts can increase the basal metabolic rate (BMR) by 60–100%.
• They greatly accelerate the use of food for energy.
• They increase both protein synthesis and protein breakdown.
• They greatly accelerate growth in young people, stimulate mental activity, and increase activity of many other endocrine glands.
• Thyroxine and triiodothyronine increase the size and number of mitochondria in many cells.
• Mitochondrial membrane area also increases roughly with the increase in whole-body metabolic rate.
• More active mitochondria increase ATP formation, providing energy for cellular functions.
• Thyroid hormone may therefore increase mitochondrial activity, although increased cell activity may also contribute to these mitochondrial changes.
• Thyroid hormone receptors are also found in mitochondria of the heart, skeletal muscle, liver, kidney, and brain.
• Thyroid hormones may also increase transcription of mitochondrial oxidative-phosphorylation genes.
• Thyroid hormones increase Na⁺-K⁺ ATPase activity, increasing Na⁺ and K⁺ transport across cell membranes.
• This uses energy and increases heat production.
• Thyroid hormones also make most cell membranes more leaky to Na⁺, further stimulating the sodium pump and heat production.

EFFECT OF THYROID HORMONES ON GROWTH

• Thyroid hormones have both general and specific effects on growth.
• They are essential for normal growth in children.
• In hypothyroidism, growth is greatly slowed.
• In hyperthyroidism, skeletal growth may occur too rapidly, but bones also mature and epiphyses close early, so final adult height may actually be shortened.
• Thyroid hormones are essential for brain growth and development during fetal life and the first few years after birth.
• Insufficient thyroid hormone during this period greatly retards brain growth and maturation.
• Without thyroid therapy soon after birth, a child without a thyroid gland may remain mentally deficient throughout life.

EFFECTS OF THYROID HORMONES ON SPECIFIC BODY FUNCTIONS

• Thyroid hormones stimulate almost every major aspect of carbohydrate metabolism.
• They increase glucose uptake, glycolysis, gluconeogenesis, gastrointestinal glucose absorption, and insulin secretion.
• These effects largely result from increased production of cellular metabolic enzymes.
• Thyroid hormones also increase almost every aspect of fat metabolism.
• They rapidly mobilize fat from adipose tissue, reducing body fat stores.
• They increase plasma free fatty acids and their oxidation by cells.
• Increased thyroid hormone decreases plasma cholesterol, phospholipids, and triglycerides, even though free fatty acids increase.
• Reduced thyroid secretion does the opposite and can cause excessive fat deposition in the liver.
• Prolonged hypothyroidism can cause marked hypercholesterolemia associated with severe atherosclerosis.
• Thyroid hormone increases cholesterol removal through bile and feces.
• It may do this partly by increasing LDL receptors in liver cells, causing faster removal of LDL from plasma.
• Because thyroid hormones increase many enzymes, they also increase the body’s need for vitamins.
• Excess thyroid hormone can therefore produce a relative vitamin deficiency if vitamin supply does not increase.
• Excess thyroid hormone can increase BMR by 60–100%.
• With no thyroid hormone production, BMR can fall to about 50% of normal (Fig. 77.6).
• Very high thyroid hormone levels are required to produce very high BMR.
• Large increases in thyroid hormone usually decrease body weight, while large decreases usually increase body weight.
• This effect can be partly opposed because thyroid hormone also increases appetite.
• Increased metabolism increases oxygen use and metabolic waste production, causing vasodilation and increased blood flow.
• Skin blood flow especially increases to help remove heat.
• Cardiac output can rise to 60% or more above normal with excess thyroid hormone and fall to about 50% of normal in severe hypothyroidism.
• Thyroid hormone markedly increases heart rate, partly through a direct effect on cardiac excitability.
• A slight excess of thyroid hormone increases heart strength.
• Marked excess can weaken the heart because of prolonged protein catabolism and increased cardiac workload.
• Mean arterial pressure usually remains approximately normal.
• Pulse pressure increases because systolic pressure rises and diastolic pressure falls.
• In hyperthyroidism, systolic pressure may rise 10–15 mm Hg, with a corresponding fall in diastolic pressure.
• Increased metabolism raises oxygen consumption and carbon dioxide production.
• These changes increase the rate and depth of respiration.
• Thyroid hormone increases digestive secretion and gastrointestinal motility.
• Hyperthyroidism may therefore cause diarrhea, whereas thyroid hormone deficiency may cause constipation.
• Thyroid hormone generally increases the rapidity of cerebral activity.
• Hyperthyroidism may cause nervousness, anxiety, extreme worry, and paranoia.
• Lack of thyroid hormone decreases the rapidity of mental processes.
• A slight increase in thyroid hormone makes muscles react more vigorously.
• Excess thyroid hormone weakens muscles because of increased protein breakdown.
• Lack of thyroid hormone makes muscles sluggish, with slow relaxation after contraction.
• A characteristic sign of hyperthyroidism is a fine muscle tremor.
• It occurs at about 10–15 times per second and differs from the coarse tremor of Parkinson disease or shivering.
• It is thought to result from increased reactivity of neuronal synapses controlling muscle tone.
• The tremor helps assess the degree of thyroid hormone effect on the central nervous system.
• Hyperthyroidism often causes tiredness but difficulty sleeping because thyroid hormone both exhausts the body and excites the nervous system.
• Hypothyroidism can cause extreme sleepiness, sometimes 12–14 hours of sleep per day.
• Increased thyroid hormone increases secretion of several other endocrine hormones while also increasing the tissues’ need for those hormones.
• Increased glucose metabolism increases the need for insulin.
• Increased bone-forming activity increases the need for parathyroid hormone.
• Thyroid hormone also increases liver inactivation of adrenal glucocorticoids, which increases ACTH and consequently glucocorticoid secretion.
• Normal thyroid hormone levels are important for normal sexual function.
• In men, deficiency may reduce libido, while marked excess may sometimes cause impotence.
• In women, deficiency may cause menorrhagia, polymenorrhea, irregular periods, or amenorrhea.
• Hyperthyroidism commonly causes oligomenorrhea and occasionally amenorrhea.
• Thyroid hormone effects on the gonads probably result from both direct metabolic effects and feedback effects through anterior pituitary hormones.

KEY CONCEPT

• Thyroid hormone ↑ cellular metabolism → ↑ energy use → ↑ ATP demand → ↑ heat production.
• Mitochondria ↑ activity → ATP ↑.
• Na⁺-K⁺ ATPase ↑ → ion transport ↑ → energy use and heat ↑.
• Growth: essential for normal skeletal and brain development.
• Carbohydrates: ↑ glucose use.
• Fats: ↑ fat mobilization and oxidation.
• Heart: ↑ heart rate and usually ↑ cardiac output.
• GI tract: ↑ motility.
• CNS: ↑ activity.
• Excess: high metabolism, weight loss, tremor, nervousness, diarrhea, and difficulty sleeping.
• Deficiency: low metabolism, slowed growth, sluggish muscles, constipation, and excessive sleepiness.

CONCEPTUAL EXAMPLES

• Thyroid hormone ↑ → mitochondria ↑ → ATP production ↑ → cellular activity ↑.
• Thyroid hormone ↑ → Na⁺-K⁺ ATPase ↑ → energy use ↑ → heat production ↑.
• Hyperthyroidism → metabolism ↑ → blood flow ↑ → cardiac output ↑.
• Hyperthyroidism → GI motility ↑ → diarrhea.
• Hypothyroidism → metabolism ↓ → constipation and sluggishness.
• Childhood thyroid deficiency → impaired growth and brain development.
• Excess thyroid hormone → fat mobilization ↑ → body weight usually ↓.

THYROID HORMONE vs BASAL METABOLIC RATE

🎯 BIG IDEA

More thyroid hormone → faster metabolism 🔥
Less thyroid hormone → slower metabolism 🐢

📊 Axes

➡️ X-axis = Thyroid hormone secretion (mg/day)
How much T₃ + T₄ the thyroid releases.

⬆️ Y-axis = Change in basal metabolic rate (%)
How much the body’s basic energy use changes compared with normal.

⚫ NORMAL = the middle point

At about 100 mg/day:

Thyroid hormone = normal
↓
BMR = 0% change

So 0% = normal baseline.

🔵 LEFT SIDE = HYPOTHYROID

Thyroid hormone ↓↓↓
↓
BMR ↓↓↓

Example:

Hormone very low → BMR can fall to about −45%.

🧠 Think:

Not enough thyroid hormone = body slows down 🐢

🔴 RIGHT SIDE = HYPERTHYROID

Thyroid hormone ↑↑↑
↓
BMR ↑↑↑

At very high hormone secretion, BMR can rise to around +25–30%.

🧠 Think:

Too much thyroid hormone = body speeds up 🔥

📈 Why does the curve rise?

The red curve shows a positive relationship:

Hormone ↑ → BMR ↑

But notice the relationship isn’t perfectly straight at very low hormone levels—the response becomes progressively larger as thyroid hormone increases.

⭐ 10-SECOND MEMORY

LOW T3/T4 → LOW BMR → HYPOthyroid 🐢

NORMAL T3/T4 → NORMAL BMR ⚖️

HIGH T3/T4 → HIGH BMR → HYPERthyroid 🔥

🔥 Ultimate concept:

Thyroid hormone is the body’s metabolic “accelerator”: decrease it → metabolism slows; increase it → metabolism speeds up.