🔺 Pathophysiology of HYPOthyroidism

 In the last few posts, we explored what happens when thyroid hormone levels are too high and how Graves’ disease, toxic nodules, and thyroiditis each disrupt the HPT axis in different ways. Now we turn to the opposite problem: hypothyroidism.

What happens when there’s not enough thyroid hormone in the body?

Unlike hyperthyroidism, where everything speeds up, hypothyroidism causes a gradual slowing of metabolic processes across multiple systems. Patients may feel tired, cold, constipated, and foggy - but these symptoms often creep in slowly, and are easy to miss unless you understand the underlying physiology.

Thyroid hormone (especially T3) acts as a metabolic accelerator. It increases mitochondrial activity, oxygen consumption, and protein turnover. It also sensitises tissues to catecholamines, regulates lipid and carbohydrate metabolism, and supports normal growth and development. So when levels fall, the whole system downshifts.

Here’s what that looks like:

🧠 Systemic Effects of Low T3 and T4

Thyroid hormones act on virtually every tissue in the body. T3, the active form, enters cells and binds nuclear receptors to regulate gene transcription, especially genes involved in metabolism, growth, and repair. When T3 and T4 levels fall, cellular activity slows down. These symptoms aren’t random, they reflect the loss of hormone action.

🧠 Neurological

• Symptoms: slowed cognition, depression, fatigue, myxoedema coma (in severe cases)

• Mechanism: T3 enhances synaptic transmission and neurotransmitter turnover. Without it, cerebral metabolism slows, leading to cognitive dulling and mood changes. In extreme cases, coma reflects global CNS depression.

❤️ Cardiovascular

• Symptoms: bradycardia, low cardiac output, pericardial effusion

• Mechanism: T3 increases heart rate, contractility, and stroke volume by upregulating β-adrenergic receptors and calcium cycling. Low T3 leads to reduced cardiac performance and fluid accumulation.

🍽️ Gastrointestinal

• Symptoms: constipation, bloating

• Mechanism: T3 stimulates smooth muscle contraction and gut motility. Without it, transit slows, leading to functional constipation and distension.

💪 Musculoskeletal

• Symptoms: weight gain, proximal myopathy, delayed reflexes

• Mechanism: T3 promotes mitochondrial activity and protein turnover. Low levels impair energy production and muscle repair, leading to weakness and slowed neuromuscular responses.

🧬 Reproductive

• Symptoms: menstrual irregularities, infertility, miscarriage risk

• Mechanism: Thyroid hormones modulate the hypothalamic-pituitary-gonadal (HPG) axis. Low T3 disrupts GnRH pulsatility and ovarian function, impairing fertility and increasing miscarriage risk.

🧖 Dermatological

• Symptoms: dry skin, hair thinning, cold intolerance

• Mechanism: T3 enhances blood flow and sweat gland activity. Low levels reduce perfusion and thermogenesis, leading to dry, brittle skin and intolerance to cold.

🩸 Haematological

• Symptoms: normocytic anaemia, hyperlipidaemia

• Mechanism: T3 stimulates erythropoiesis and hepatic LDL receptor expression. Low hormone levels impair red cell production and lipid clearance, raising cholesterol and triglycerides.

Clinical reasoning tip:

These symptoms reflect low hormone action, not just low hormone levels. That’s why some patients with borderline T4 — especially if T3 is low or conversion is impaired — still feel profoundly unwell. Always ask: Is the tissue getting enough active hormone? Not just Is the lab value in range?

🧠 What Causes Hypothyroidism?

To understand hypothyroidism, you need to understand the HPT axis, the hormonal feedback loop that regulates thyroid function. (go back and review the previous posts about this if you need a refresher).

•  The hypothalamus releases TRH (thyrotropin-releasing hormone)
• TRH stimulates the anterior pituitary to release TSH
• TSH stimulates the thyroid gland to produce T4 and T3
• Circulating T4 and T3 feed back to suppress TRH and TSH

If any part of this axis fails, or if the thyroid gland can’t respond, thyroid hormone levels fall. That’s hypothyroidism.

🔍 Classification: Primary, Secondary, and Tertiary

Understanding the level of dysfunction helps you interpret thyroid function tests and choose the right treatment.

1. Primary Hypothyroidism

This is the most common form. The thyroid gland itself is damaged or unable to produce hormone.

• TSH: high (the pituitary is trying to stimulate the gland)
• T4 and T3: low

Causes include:

• Hashimoto’s thyroiditis (autoimmune destruction)
• Iodine deficiency
• Post-thyroidectomy or radioactive iodine therapy
• Congenital absence or dysgenesis
• Drugs (e.g. lithium, amiodarone)

This is the classic pattern: high TSH, low T4. The gland isn’t responding, so the pituitary ramps up stimulation.

2. Secondary Hypothyroidism

Here, the pituitary gland fails to produce enough TSH.

• TSH: low or inappropriately normal
• T4 and T3: low

Causes include:

• Pituitary tumours
• Surgery or radiation to the pituitary
• Sheehan’s syndrome (postpartum pituitary infarction)

This pattern is trickier because TSH may look “normal,” but it’s not appropriate for the low T4. Always interpret TSH in context.

🧠 Sheehan’s Syndrome: Postpartum Pituitary Failure

Sheehan’s syndrome is a rare but important cause of secondary hypothyroidism — and a classic example of how pituitary damage can disrupt the entire endocrine axis.

What causes it?
During pregnancy, the pituitary gland enlarges to support increased hormonal demands. If a woman experiences severe postpartum haemorrhage, blood flow to the pituitary can drop suddenly, leading to ischaemic infarction — tissue death due to lack of oxygen.

Which hormones are affected?
The anterior pituitary controls multiple axes. Damage can lead to:

• ↓ TSH → secondary hypothyroidism
• ↓ ACTH → secondary adrenal insufficiency
• ↓ LH/FSH → amenorrhoea and infertility
• ↓ GH → fatigue and muscle weakness
• ↓ Prolactin → failure to lactate

What does this look like clinically?

• Fatigue, weight gain, cold intolerance
• Loss of menstrual periods
• Inability to breastfeed
• Low blood pressure and hyponatraemia (if cortisol is low)

How do you diagnose it?

• TFTs: low T4 and low or normal TSH
• Other pituitary hormones are also low
• MRI: may show an empty sella or pituitary atrophy
• History: severe postpartum bleeding is the key clue

Why does it matter?
Sheehan’s syndrome teaches you to think beyond the thyroid. If TSH isn’t elevated despite low T4, ask whether the pituitary is failing — and always consider the broader hormonal context.

3. Tertiary Hypothyroidism

This is rare. The hypothalamus fails to produce TRH, leading to low TSH and low T4.

• Causes include hypothalamic tumours, trauma, or infiltrative disease
• Often indistinguishable from secondary hypothyroidism on routine testing

🧪 Reasoning Tip: Always Ask “Where’s the Problem?”

When you see low T4, don’t just label it “hypothyroidism.” Ask:

• Is the thyroid gland failing? (primary)
• Is the pituitary failing to stimulate it? (secondary)
• Is the hypothalamus failing to drive the axis? (tertiary)

Why it matters:
This reasoning framework helps you interpret thyroid function tests (TFTs) correctly — and avoid missing central causes, which may be part of broader pituitary dysfunction.

🔬 Common Causes of Hypothyroidism: Different Mechanisms, Same Outcome

Hypothyroidism isn’t a single disease it’s a final common pathway. The body doesn’t have enough thyroid hormone to meet its metabolic needs, and that can happen for very different reasons. Some problems start in the thyroid gland itself. Others begin higher up, in the pituitary or hypothalamus. Some are due to immune attack, others to iodine deficiency, surgery, or drugs. But they all lead to the same outcome: low T4, low T3, and a system that slows down.

Here’s how to reason through the major causes:

🧬 Hashimoto’s Thyroiditis: Autoimmune Destruction

This is the most common cause of hypothyroidism in iodine-sufficient regions. It’s an autoimmune condition where the immune system gradually destroys thyroid tissue. The process is slow, often silent, and driven by autoreactive T cells and B cells that produce antibodies against thyroid peroxidase (TPO) and thyroglobulin.

Over time:

• Lymphocytes infiltrate the gland, forming germinal centres
• Follicular cells are damaged
• Hormone synthesis declines
• The pituitary compensates by increasing TSH
• Eventually, the gland can’t keep up — and hypothyroidism develops

The gland may be firm and enlarged (a goitre), but it’s not functioning properly. Hashimoto’s can begin silently, with normal TFTs, and progress slowly to overt hypothyroidism. Some patients fluctuate between normal and low levels before stabilising. You’ll explore this in detail in the  next blog post.

🧂 Iodine Deficiency: A Global Perspective

Thyroid hormone is made from iodine — specifically, iodide ions actively transported into follicular cells via the sodium-iodide symporter. Without iodine, the gland can’t synthesise T3 or T4, even if TSH is high.

In response:

• The pituitary increases TSH
• The thyroid enlarges, forming a goitre
• But hormone output remains low

This is a classic example of substrate deficiency, not gland failure. It’s rare in Australia due to iodised salt and supplementation, but still common in parts of the world with low dietary iodine.

🧪 Post-Treatment Hypothyroidism: When the Gland Is Gone

Sometimes hypothyroidism is expected because we’ve removed or destroyed the thyroid on purpose.

• After thyroidectomy, there’s no tissue left to produce hormone
• After radioactive iodine therapy, the gland is ablated
• After external beam radiation, the gland may be damaged

In these cases, patients require lifelong thyroxine replacement. The diagnosis is straightforward, but monitoring is essential, especially in patients who were previously hyperthyroid and may fluctuate before stabilising

🧠 Pituitary Failure: Central Hypothyroidism

In secondary hypothyroidism, the thyroid gland is intact — but it’s not being stimulated. The problem lies in the pituitary, which fails to produce adequate TSH.

This can occur due to:

• Non-functioning pituitary adenomas — which compress normal tissue
• Post-surgical or post-radiation damage
• Sheehan’s syndrome — infarction of the pituitary after postpartum haemorrhage
•  Infiltrative diseases — such as sarcoidosis, haemochromatosis, or Langerhans cell histiocytosis

In these cases:

• TSH is low or inappropriately normal
• T4 is low
• The thyroid scan may be normal — because the gland isn’t the problem

This pattern is easy to miss. Always interpret TSH in context. If T4 is low and TSH isn’t elevated, ask whether the pituitary is failing and check other axes (ACTH, LH/FSH, GH, prolactin) to assess broader hypopituitarism.

🧠 “Normal” TSH in Central Hypothyroidism

When T4 is low, you expect TSH to rise — that’s how the HPT axis maintains homeostasis. In central hypothyroidism (pituitary or hypothalamic disease), the drive is faulty, so TSH does not rise appropriately. A lab report may flag TSH as “normal,” but in this context “normal” is not normal.

Here’s how to reason through it:

• Low T4 + “normal” TSH = inappropriate TSH
  → The pituitary should increase TSH when T4 falls.
  → If it doesn’t, the axis is failing.
  → This is central hypothyroidism, even if TSH looks “fine.”
• TSH can be biologically weak
  → Pituitary TSH may have altered glycosylation: it’s measurable, but less active at the thyroid.
  → The thyroid doesn’t respond, so hormones stay low.
• Always interpret TSH in context
  → TSH is not a standalone test.
  → If T4 is low and the patient is symptomatic, ask: Is the pituitary failing to respond?
• Check other pituitary axes
  → ACTH/cortisol, LH/FSH ± sex steroids, GH/IGF-1, prolactin.
  → Central hypothyroidism is often part of broader hypopituitarism.

Key takeaway: A “normal” TSH is only normal if T4 is normal too. Low T4 with non-elevated TSH → think central hypothyroidism and investigate the pituitary.

🔍 Principles of Investigation: What to Order and Why

When you suspect hypothyroidism, the first step is to confirm it — and then figure out why it’s happening. That means interpreting thyroid function tests in the context of the HPT axis, and choosing investigations that help localise the problem.

🧪 Thyroid Function Tests (TFTs)

• TSH: This is the pituitary’s signal to the thyroid.

→ High TSH suggests primary gland failure

→ Low or “normal” TSH with low T4 suggests central failure

• Free T4: The most reliable measure of circulating thyroid hormone → Low in all forms of hypothyroidism
• Free T3: May be normal or low (less useful in early diagnosis) → T3 falls later, and conversion varies

Always interpret TSH and T4 together. A “normal” TSH doesn’t rule out hypothyroidism if T4 is low.

🧬 Autoantibodies

• TPOAb: Positive in Hashimoto’s thyroiditis
• TgAb: May also be present
• These confirm autoimmune thyroid disease, and help predict progression

🧠 Pituitary Workup (if central hypothyroidism suspected)

• Other pituitary hormones: ACTH, cortisol, LH/FSH, GH, prolactin
• MRI brain: To assess for pituitary adenoma, infarction, or infiltrative disease
• Visual fields: If a mass is present

Central hypothyroidism is often part of broader hypopituitarism — so always check the other axes.

🖥️ Imaging

• Thyroid ultrasound: Useful if goitre or nodules are present → May show hypoechoic areas in Hashimoto’s
• Radionuclide scan: Not routinely used in hypothyroidism → More useful in hyperthyroid states

🩺 Principles of Management: 

The goal of treatment is simple: restore normal thyroid hormone levels. But the approach depends on the cause, the severity, and the patient’s context.

💊 Thyroxine Replacement

• Levothyroxine (T4) is the standard treatment

→ Dose depends on age, weight, and cardiac status

→ Young healthy adults: ~1.6 mcg/kg/day

→ Start lower in elderly or cardiac patients

T4 is converted to T3 peripherally — so most patients don’t need T3 supplementation.

📈 Monitoring

• Check TFTs every 6–8 weeks after starting or changing dose

→ Aim for normal TSH in primary hypothyroidism

→ In central hypothyroidism, monitor free T4 directly

• Once stable, monitor every 6–12 months
• Adjust dose for pregnancy, weight changes, or drug interactions

🧠 Treat the Cause

•  If autoimmune: monitor for other autoimmune conditions
•  If central: manage pituitary disease and other hormone deficiencies
• If post-treatment: ensure lifelong replacement and patient education
• If iodine deficiency: correct dietary intake

🗣️ Patient Education

•  Explain that hypothyroidism is usually lifelong, but manageable
•  Emphasise the importance of medication adherence and regular monitoring
• Discuss symptoms of under- or over-replacement
• Reassure that most patients feel significantly better once stable

🤰 Hypothyroidism and Pregnancy — Two Critical Windows

1️⃣ Congenital Hypothyroidism: Missed Signals, Lifelong Impact

Congenital hypothyroidism occurs when a baby is born without adequate thyroid hormone. Common causes include:

• Thyroid dysgenesis (absent, ectopic, or hypoplastic gland)
• Dyshormonogenesis (enzyme defects in hormone synthesis)
• TSH-receptor or iodine-transport defects

Why it matters: Thyroid hormone is crucial for brain development in the first 2–3 years of life. Without it:

• Neuronal migration and myelination are impaired
• Intellectual disability and motor delay may occur
• Growth and skeletal maturation are delayed

How it’s detected:

• Newborn screening (heel-prick) measuring TSH and/or T4
• Early thyroxine replacement prevents irreversible damage

🧠 Reasoning tip: Even mild hypothyroidism in infancy can have major effects — the rapidly developing brain depends on T3 for structural and functional maturation.

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2️⃣ Maternal Hypothyroidism: A Hidden Risk in Pregnancy

During pregnancy, maternal thyroid hormone supports both mother and fetus — particularly before the fetal thyroid becomes functional (~12 weeks). Maternal hypothyroidism can lead to:

• Impaired fetal neurodevelopment
• Increased risk of miscarriage and preterm birth
• Placental dysfunction
• Maternal anaemia, hypertension, and poor lactation

What to monitor:

• Check TSH and free T4 early in pregnancy
• Ensure adequate iodine intake
• Increase thyroxine dose by 30–50% due to higher binding and clearance

🧩 Reasoning tip: Pregnancy increases demand for thyroid hormone — even well-controlled patients often need dose adjustments. Monitor closely and treat proactively to protect both maternal and fetal outcomes.

In summary

Although hypothyroidism always leads to low circulating thyroid hormone, the underlying mechanisms vary — and that’s what makes clinical reasoning essential. In primary hypothyroidism, the thyroid gland itself is failing, and the pituitary ramps up TSH in response. In central hypothyroidism, the signal is missing, and the gland sits idle despite low T4. In iodine deficiency, the gland is willing but unable. And in post-treatment cases, the gland is simply gone. Each cause leaves a distinct fingerprint on the HPT axis — and interpreting that pattern is the key to diagnosis. When you see low T4, don’t just name the condition. Ask why the system has slowed down, where the failure lies, and how the body is trying to compensate. That’s the heart of endocrine reasoning.

Next ... lets learn about the most common cause of hypothyroidism in Australia, Hashimotos thyroiditis. 

📚 Want to learn more?

• 🧠 All endocrine system posts →
• 🧬 The HPA axis →
• 🦋 The thyroid axis →
• 🔥 Pathophysiology of HYPERthyroidism →
• 🌡 Common Causes of Hyperthyroidism: Graves, TMNG and Thyroiditis →
• ❄️ Pathophysiology of HYPOthyroidism →
• 🩶 Common Causes of Hypothyroidism: Hashimoto’s Thyroiditis →
• 🧩 Clinical Cases in Endocrinology: The Thyroid Axis →