The Thyroid Axis

 The thyroid axis is one of the most common clinically encountered endocrine systems. It regulates metabolism, temperature, energy, and mood. Understanding how it works helps you reason through symptoms like fatigue, weight change, palpitations, constipation, and menstrual irregularities.

🧠 What Is the Thyroid?

The thyroid gland is located in the anterior neck, just below the larynx. Its job is to produce thyroid hormones - thyroxine (T4) and triiodothyronine (T3) - which regulate the body’s metabolic rate. These hormones affect nearly every cell in the body, influencing how fast cells use energy, how warm you feel, how your heart beats, and how your brain functions.

Thyroid anatomy

The thyroid gland is a soft, reddish-brown organ shaped like a butterfly, sitting low in the anterior neck. It wraps around the trachea just below the cricoid cartilage, with two lateral lobes connected by a thin central isthmus. In some people, there’s a small upward extension called the pyramidal lobe — a remnant of embryological development.

📍 Location and Relations

•             Anteriorly: Covered by skin, fascia, and the infrahyoid (strap) muscles.

•             Posteriorly: Lies against the trachea and oesophagus.

•             Laterally: Adjacent to the carotid sheath (containing the carotid artery, internal jugular vein, and vagus nerve).

•             Superiorly: Near the thyroid cartilage of the larynx.

•             Inferiorly: Extends toward the suprasternal notch.

💡 Clinical Relevance

This close relationship with the airway and major vessels explains why thyroid enlargement (goitre) can cause dysphagia, dyspnoea, or hoarseness — especially if the recurrent laryngeal nerve is compressed.

🩸 Blood Supply

The thyroid is highly vascular — appropriate for a hormone-producing gland.

Arterial supply:

•             Superior thyroid artery (from external carotid)

•             Inferior thyroid artery (from thyrocervical trunk)

•             Occasionally a thyroid ima artery (from brachiocephalic trunk)

Venous drainage:

•             Superior, middle, and inferior thyroid veins drain into the internal jugular and brachiocephalic veins.

💡 Clinical Relevance

This rich blood supply is why thyroid surgery carries bleeding risks — and why radioactive iodine therapy is effective. The thyroid rapidly takes up iodine, allowing targeted treatment of hyperfunctioning tissue or residual thyroid cancer.

🧫 Histology

The thyroid is made up of follicles — spherical structures lined by follicular cells and filled with colloid, a protein-rich substance containing thyroglobulin.

•             Follicular cells: Make and secrete T3 and T4.

•             Colloid: Stores iodinated thyroglobulin until needed.

•             Parafollicular cells (C cells): Located between follicles; secrete calcitonin, a hormone involved in calcium regulation (though less clinically relevant than parathyroid hormone).

🧬 Embryology and Development

•             The thyroid originates from the floor of the primitive pharynx and descends to its final position via the thyroglossal duct.

•             Remnants of this duct can form thyroglossal cysts, often presenting as midline neck lumps that move with swallowing or tongue protrusion.

•             The pyramidal lobe is a vestige of this descent.

Understanding this descent helps explain congenital anomalies and why thyroid tissue can sometimes be found in unusual locations (e.g. lingual thyroid).

🔬 How Is Thyroid Hormone Made?

Thyroid hormone synthesis is a multi-step biochemical process that takes place within the thyroid follicles — spherical structures lined by follicular cells and filled with colloid. 

Here’s how it works:

1.           Iodine uptake:

The thyroid gland actively concentrates iodine from the bloodstream using a sodium-iodide symporter on the basolateral membrane of follicular cells. This is energy-dependent and highly efficient — the thyroid can concentrate iodine up to 30–50 times the plasma level.

💡 Clinical Relevance

Iodine deficiency remains a public health issue in Australia due to low soil iodine. This is why iodised salt and fortified bread are recommended as part of population-wide preventive measures.

2.           Thyroglobulin production:

Follicular cells synthesise thyroglobulin — a large glycoprotein rich in tyrosine residues — and secrete it into the follicle lumen (colloid). This acts as the scaffold for hormone synthesis.

3.           Iodination and coupling:

Inside the colloid, iodine is oxidised by thyroid peroxidase (TPO) and attached to tyrosine residues on thyroglobulin, forming:

• Monoiodotyrosine (MIT) — one iodine
• Diiodotyrosine (DIT) — two iodines

These iodinated tyrosines are then coupled:

• MIT + DIT → T3
• DIT + DIT → T4

💡 Clinical Relevance

Thyroid peroxidase (TPO) is a key autoantigen in Hashimoto’s thyroiditis. TPO antibodies are often elevated in autoimmune thyroid disease and can help confirm the diagnosis.

4.           Storage and release:

The iodinated thyroglobulin remains stored in the colloid until needed. When stimulated by TSH, follicular cells endocytose the colloid, digest thyroglobulin, and release free T3 and T4 into the bloodstream.

🧠 Note: This storage mechanism allows the thyroid to maintain hormone production for weeks even if iodine intake suddenly drops.

5.           Peripheral conversion:

Most circulating T4 is converted to T3 in peripheral tissues — especially the liver, kidney, and skeletal muscle — by deiodinase enzymes. T3 is 3–5 times more potent than T4 and binds more strongly to nuclear receptors.

💡 Clinical Relevance

In illness or starvation, conversion of T4 to T3 may be impaired, leading to euthyroid sick syndrome — characterised by low T3 with normal TSH and T4 levels.

🧠 The Axis in Action

The thyroid axis follows the same three-step cascade as other hypothalamic–pituitary axes:

1.           The hypothalamus releases thyrotropin-releasing hormone (TRH).

2.           TRH stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).

3.           TSH acts on the thyroid gland, prompting it to produce thyroxine (T4) and triiodothyronine (T3).

T4 is the main hormone released, but T3 is the more active form. Most T3 is produced by peripheral conversion of T4 in tissues like the liver and kidney.

As T4 and T3 levels rise, they feed back to suppress both TRH and TSH — maintaining balance.

🧪 What Do Thyroid Hormones Do?

Thyroid hormones (primarily T3 and T4) exert widespread effects by binding to nuclear receptors in nearly every tissue. Their actions are essential for normal development, metabolic regulation, and physiological homeostasis. Key domains include:

🧠 Neurological

• Developmental role: In utero and early infancy, thyroid hormone is critical for neuronal migration, myelination, and synaptogenesis. Deficiency during this window leads to irreversible intellectual disability — hence the importance of newborn screening for congenital hypothyroidism.

• Adult function: Modulates mood, cognition, and reflexes. Hypothyroidism may present with depression, slowed thought processes, and fatigue; hyperthyroidism with anxiety, restlessness, and insomnia.

🔥 Metabolism

• Basal metabolic rate (BMR): Increases mitochondrial activity and uncoupling protein expression, raising oxygen consumption and heat production.

• Macronutrient metabolism: Enhances lipolysis, gluconeogenesis, and carbohydrate absorption. Clinically, hyperthyroidism may cause weight loss despite increased appetite; hypothyroidism often leads to weight gain and cold intolerance.

❤️ Cardiovascular

• Chronotropic and inotropic effects: Upregulates β-adrenergic receptors in the heart, increasing heart rate and contractility.

• Peripheral vasodilation: Reduces systemic vascular resistance, which may lead to widened pulse pressure in hyperthyroidism.

• Clinical relevance: Atrial fibrillation and high-output heart failure are risks in thyrotoxicosis; bradycardia and pericardial effusion may occur in severe hypothyroidism.

🦴 Musculoskeletal

• Growth and bone turnover: Stimulates growth hormone secretion and bone remodelling. In children, deficiency causes growth retardation; in adults, excess may accelerate osteoporosis.

• Muscle tone: Hypothyroidism can cause proximal muscle weakness and myopathy; hyperthyroidism may lead to tremors and muscle wasting.

🧬 Reproductive

• Menstrual cycles: Hypothyroidism often leads to menorrhagia and anovulation; hyperthyroidism may cause oligomenorrhea.

• Fertility and pregnancy: Adequate thyroid hormone is essential for ovulation, implantation, and foetal neurodevelopment. Subclinical hypothyroidism can impair fertility and increase miscarriage risk.

🍽️ Gastrointestinal

• Motility: Stimulates peristalsis. Hypothyroidism may cause constipation and ileus; hyperthyroidism can lead to diarrhoea and malabsorption.

🔍 Reasoning Through Thyroid Dysfunction

Let’s apply the logic of feedback loops to clinical reasoning.

Case 1: Primary Hypothyroidism

A 38-year-old woman presents with fatigue, weight gain, dry skin, and constipation. Her blood tests show low T4 and high TSH.

🧠 Reasoning: The thyroid gland isn’t producing enough hormone. The pituitary is trying to compensate by increasing TSH. This is a primary gland failure — most commonly autoimmune (Hashimoto’s thyroiditis).

Case 2: Central Hypothyroidism

A 45-year-old man with a history of head trauma presents with fatigue and cold intolerance. His T4 and TSH are both low.

🧠 Reasoning: The pituitary isn’t producing enough TSH, so the thyroid isn’t being stimulated. This is a secondary failure — central in origin.

Case 3: Hyperthyroidism

A 25-year-old woman reports weight loss, anxiety, palpitations, and heat intolerance. Her T4 is high and TSH is suppressed.
🧠 Reasoning: The thyroid is overproducing hormone, and the pituitary is responding appropriately by reducing TSH. This is primary hyperthyroidism — often due to Graves’ disease or a toxic nodule.

🩺 Why This Axis Matters

Thyroid dysfunction is common, and symptoms often mimic other conditions. Reasoning through the axis helps you:

• Distinguish between primary and central causes.
• Interpret lab results in context.
• Understand why thyroid disease affects mood, energy, and menstrual cycles.
• Recognise when symptoms might be endocrine — even if they seem vague.

🧡 Closing Thoughts

The thyroid axis is your first real test of endocrine reasoning. It’s simple in structure, but rich in clinical relevance. Learn the logic now, and you’ll carry it with you throughout your career.

Next - we will look at some common causes of thyroid dysfunction before moving on to the next axis! 

📚 Want to learn more?

• 🧠 All endocrine system posts →
• 🧬 The HPA axis →
• 🦋 The thyroid axis →
• 🔥 Pathophysiology of Hyperthyroidism →