Normal body metabolism requires precisely controlled thyroid hormone secretion.
The hypothalamus and anterior pituitary gland use feedback mechanisms to control the rate of thyroid hormone secretion.
TSH (thyrotropin) is an anterior pituitary glycoprotein hormone with a molecular weight of about 28,000.
TSH increases thyroid secretion of thyroxine (T₄) and triiodothyronine (T₃).
TSH increases thyroid activity in several ways:
- ↑ Proteolysis of stored thyroglobulin → ↑ T₄ and T₃ release into blood.
- ↑ Iodide pump activity → ↑ iodide trapping by thyroid cells.
- ↑ Iodination of tyrosine → ↑ thyroid hormone formation.
- ↑ Size and secretory activity of thyroid cells.
- ↑ Number of thyroid cells, with cells changing from cuboidal to columnar and the follicular epithelium becoming more folded.
Therefore, TSH increases essentially all secretory activities of thyroid cells.
The earliest major effect of TSH is proteolysis of thyroglobulin.
This releases T₄ and T₃ into the blood within about 30 minutes.
The other effects develop more slowly, over hours, days, or weeks.
Most TSH effects occur through the cAMP second-messenger system.
TSH first binds to G protein-coupled TSH receptors on the basal membrane of thyroid cells.
The receptor activates adenylyl cyclase.
Adenylyl cyclase increases cAMP inside the cell.
cAMP acts as a second messenger and activates protein kinase.
Protein kinase causes multiple protein phosphorylations inside the cell.
These changes produce both an immediate increase in thyroid hormone secretion and prolonged growth of thyroid tissue.

KEY CONCEPT

TSH → TSH receptor → G protein → adenylyl cyclase → ↑ cAMP → protein kinase → phosphorylation → ↑ thyroid hormone secretion + thyroid growth

Fast effect: Proteolysis of thyroglobulin → T₄/T₃ release within ~30 min.
Slow effects: ↑ iodide trapping, ↑ iodination, ↑ cell size/activity, ↑ cell number.

CONCEPTUAL EXAMPLES

TSH ↑ → proteolysis ↑ → stored T₄/T₃ released → blood.
TSH ↑ → iodide pump ↑ → iodide trapping ↑.
TSH → cAMP ↑ → protein kinase ↑ → thyroid secretion ↑.
TSH → cAMP → prolonged stimulation → thyroid tissue growth.

ANTERIOR PITUITARY SECRETION OF TSH IS REGULATED BY THYROTROPIN-RELEASING HORMONE FROM THE HYPOTHALAMUS

TRH (thyrotropin-releasing hormone) from the hypothalamus controls TSH secretion from the anterior pituitary.
TRH is made by neurons in the paraventricular nucleus (PVN) of the hypothalamus.
These neurons release TRH into the median eminence.
TRH then travels through the hypothalamic-hypophysial portal blood to the anterior pituitary.
TRH is a tripeptide amide: pyroglutamyl-histidyl-proline-amide.
TRH stimulates anterior pituitary cells to increase TSH secretion.
If the hypothalamic–pituitary portal blood supply is blocked, TSH secretion falls greatly but does not reach zero.
TRH first binds to TRH receptors on pituitary cell membranes.
This activates the phospholipase C second-messenger system.
Phospholipase C produces a cascade involving Ca²⁺ and diacylglycerol (DAG).
These second messengers ultimately cause TSH release.
Cold exposure is an important stimulus for increasing TRH and therefore TSH secretion.
Cold likely stimulates hypothalamic centers responsible for body-temperature control.
Severe cold exposure in rats can increase thyroid hormone output to more than 100% of normal and increase BMR by up to 50%.
People moving to Arctic regions may develop BMRs about 15–20% above normal.
TRH neurons in the PVN also receive signals from leptin-responsive neurons in the arcuate nucleus that regulate energy balance.
During prolonged fasting, leptin levels fall.
Low leptin decreases POMC activity, increases NPY/AGRP activity, and may directly inhibit TRH neurons.
These effects reduce TRH → TSH → thyroid hormone secretion.
The resulting lower metabolic rate helps conserve energy when food is scarce.
Emotional states can also affect TRH and TSH secretion.
Excitement and anxiety can cause an acute decrease in TSH secretion, possibly because increased metabolic activity and body heat affect the hypothalamic heat-control center.

KEY CONCEPT

Hypothalamus (TRH) → anterior pituitary → TSH → thyroid → T₄/T₃

TRH → phospholipase C → Ca²⁺ + DAG → TSH release.
Cold → TRH ↑ → TSH ↑ → thyroid hormones ↑.
Prolonged fasting → leptin ↓ → TRH ↓ → TSH ↓ → thyroid hormones ↓ → energy conservation.

CONCEPTUAL EXAMPLES

TRH reaches pituitary → PLC activated → Ca²⁺/DAG → TSH released.
Cold exposure → TRH ↑ → TSH ↑ → thyroid hormones ↑ → metabolic activity ↑.
Fasting → leptin ↓ → TRH ↓ → TSH ↓ → thyroid hormones ↓.
Anxiety/excitement → acute TSH ↓.

FEEDBACK EFFECT OF THYROID HORMONE TO DECREASE ANTERIOR PITUITARY SECRETION OF TSH

When thyroid hormone levels increase, TSH secretion from the anterior pituitary decreases.
When thyroid hormone secretion reaches about 1.75 × normal, TSH secretion falls to almost zero.
Most of this negative feedback occurs even when the anterior pituitary is separated from the hypothalamus.
Therefore, increased thyroid hormone mainly inhibits TSH secretion through a direct effect on the anterior pituitary (Fig. 77.7).
Thyroid hormone also provides negative feedback to the hypothalamus, reducing TRH secretion.
These feedback mechanisms help maintain an almost constant level of free thyroid hormones in the blood.

KEY CONCEPT

Thyroid hormone ↑ → pituitary TSH ↓ + hypothalamic TRH ↓ → thyroid hormone returns toward normal.

~1.75 × normal thyroid hormone → TSH ≈ zero.
Main feedback site: anterior pituitary.
Additional feedback site: hypothalamus.

CONCEPTUAL EXAMPLES

T₃/T₄ ↑ → TSH ↓ → thyroid stimulation ↓.
T₃/T₄ ↑ → TRH ↓ → TSH ↓.
Purpose: Keep free thyroid hormone levels nearly constant.

🧠 BIG IDEA — Thyroid Regulation

This figure is simply showing the thermostat system of thyroid hormone:

Cold → Hypothalamus → TRH → Pituitary → TSH → Thyroid → T₃/T₄ → ↑ Metabolism

And when T₃/T₄ become high:

T₃/T₄ → STOP hypothalamus + pituitary ⛔

This is negative feedback.

🔥 FOLLOW THE ARROWS

1️⃣ Temperature falls ❄️

At the top:

Hypothalamus detects decreased temperature

⬇️

It becomes more active.

Think:

Cold = “We need more heat!”

2️⃣ HYPOTHALAMUS RELEASES TRH

Hypothalamus releases:

TRH

= Thyrotropin-Releasing Hormone

⬇️

TRH travels to the:

Anterior pituitary3️⃣ ANTERIOR PITUITARY RELEASES TSH

TRH stimulates the anterior pituitary.

The pituitary releases:

TSH

= Thyroid-Stimulating Hormone

⬇️

TSH travels through blood to the:

Thyroid glandTIMULATES THYROID

TSH tells the thyroid:

“Work harder!”

Therefore thyroid:

↑ Thyroid hormone secretion

Mainly:

T₄ + T₃

And TSH also causes:

Thyroid hypertrophy

Meaning:

Thyroid cells grow/enlarge when stimulation is prolonged.

5️⃣ T₃ + T₄ INCREASE METABOLISM 🔥

T₃/T₄ travel through blood to body cells.

They increase:

Cellular metabolism

⬆️ metabolism

⬇️

⬆️ energy use

⬇️

⬆️ heat production

So in cold conditions:

❄️ Cold → thyroid hormone ↑ → metabolism ↑ → heat ↑ 🔥 6️⃣ NOW THE MOST IMPORTANT PART: NEGATIVE FEEDBACK

Look at the red dashed lines with − signs.

They represent:

Negative feedback

When T₃ and T₄ increase sufficiently:

T₃/T₄ ⛔ Hypothalamus

and

T₃/T₄ ⛔ Anterior pituitary

Therefore:

↓ TRH

↓ TSH

↓ thyroid stimulation

↓ T₃/T₄ production

🔄 WHY IS THIS CALLED NEGATIVE FEEDBACK?

Because the final product:

T₃/T₄

goes back and reduces the signals that produced it.

Think of a thermostat:

Room cold ❄️

→ heater ON 🔥

Room warm enough 🌡️

→ heater OFF ⛔

Exactly the same basic principle.

🧠 WHAT DOES IODINE DO HERE?

The green arrow says:

Iodine → thyroid

Iodine is the raw material needed to make T₃ and T₄.

So:

TSH = tells thyroid “make more”

Iodine = provides the material to make it

Don’t confuse them.

🎯 EVERY PART OF THE IMAGE

❄️ Decreased temperature

Stimulates hypothalamus.

↓

🧠 Hypothalamus

Releases TRH

↓