Physiology - An Illustrated Review

25. Thyroid Hormones

25.1 Triiodothyronine and Thyroxine

The primary function of the thyroid gland is to synthesize and secrete two hormones into the circulation: triiodothyronine (T3) and thyroxine (T4). T3 and T4 control essential functions, such as the regulation of energy metabolism and basal metabolic rate (BMR) and the promotion of protein synthesis and growth (Fig. 25.1).

Fig. 25.1 image Thyroid hormones (overview).

Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). TSH is involved in regulating each step in thyroid hormone synthesis. Thyroid follicular cells preferentially synthesize T4, which is then converted to T3 (a more physiologically active form) in the periphery. T3 causes feedback inhibition of TSH to maintain optimal thyroid hormone levels. (SIH, somatostatin)



T3 and T4 are iodine-containing derivatives of tyrosine that are synthesized in thyroid follicular cells (Figs. 25.2 and 25.3). The steps involved in thyroid hormone synthesis are as follows:

– Thyroid follicular cells synthesize and store thyroglobulin (TG), a glycoprotein with tyrosine residues.

– The Na+−I pump on the follicular cell membrane actively transports iodide (I) into the colloid.

– Iodide is oxidized to iodine (I2) by thyroid peroxidase as it moves through the membrane into the colloid.

– Thyroid peroxidase also conjugates the iodine onto the tyrosine residues of TG, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). Thus, iodine found in the follicular colloid is bound to TG and is not free.

– MIT and DIT undergo coupling reactions while bound to TG. T4 is produced when two molecules of DIT combine, and T3 is formed when one molecule of MIT and one molecule of DIT combine.

– Iodinated TG in colloid is endocytosed into follicular cells under stimulation of thyroid-stimulating hormone (TSH).

– Endocytotic vesicles fuse with lysosomes, and proteolysis of TG occurs. This releases T4, T3, MIT, and DIT.

– T4 and T3 are released into the circulation. MIT and DIT are deiodinated by iodotyrosine dehalogenase, and the iodine is recycled.

The synthesis of T4 is generally favored over that of T3 (10–20:1).

Na+−I pump

Iodine (from ingested food) is necessary for thyroid hormone synthesis. Because dietary intake inevitably varies, the thyroid gland must sequester iodine so that adequate amounts are always available for thyroid hormone synthesis. It does this via the Na+−I pump on the cell membrane. This pump binds iodide with high affinity and specificity. The transport of iodide into the cytoplasm requires oxidative phosphorylation and a membrane Na+−K+ ATPase. TSH is the major physiological regulator of the iodide pump, but high intracellular levels of iodide inhibit the activity of the pump.


Fig. 25.2 image Thyroid hormone synthesis and secretion.

Thyroglobulin (TG) is synthesized from tyrosine residues and carbohydrates in thyroid follicular cells. TG is packaged in vesicles that are exocytosed in colloid. Iodide is actively transported into the follicular cells by the Na+−I symporter. Iodide is oxidized to iodine as it moves through the follicular membrane into colloid. Thyroid peroxidase also causes iodine to attach to TG, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT combine to form T3 and T4 in the colloid. T3 and T4 are then endocytosed into the follicular cell, where they fuse with lysozymes, whose proteolytic enzymes cleave off TG. T3 and T4 are released into the circulation. The iodine is removed from MIT and DIT, and it pools in the follicular cell for reuse. Each of these steps is regulated by TSH.


Regulation of Secretion

Hypothalamic–anterior pituitary control. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to release TSH. TSH then acts on the thyroid gland to increase the synthesis and release of T3 and T4 (Table 25.1).


Fig. 25.3 image Synthesis, storage, and mobilization of the thyroid hormones.

TG is exocytosed from the follicular cell into colloid. Iodide also moves into colloid in exchange for Cl, and as it does so, it is oxidized to iodine. TG and iodine combine to form MIT or DIT. One molecule of MIT and one of DIT form T3, and two molecules of DIT combine to form T4. TG is then endocytosed back into the follicular cell where it is cleaved to release T3 and T4 into the circulation. (TPO, thyroid peroxidase)


Negative feedback control. Both TRH and TSH are controlled by the level of circulating thyroid hormone (T4, which is converted to T3 in pituitary cells) in a classic negative feedback loop, but TRH release also increases in response to increased metabolic demand.

Iodine regulation of T3 and T4. Increased levels of iodine prevent thyroid hormone production in the following ways:

– Acute increases in circulating iodine inhibit iodine incorporation into TG.

– Chronic increases in iodine reduce the number of iodide pump molecules.

– High intracellular levels of iodine decrease iodide pump activity. The iodine molecules also compete with thyroid peroxidase conjugation of TG and iodine.

Wolff–Chaikoff effect

The Wolff–Chaikoff effect is a reduction in the synthesis and release of thyroid hormones caused by a large amount of iodine. This effect lasts ~10 days, after which iodine incorporation into TG and thyroid peroxidase function returns to normal. It is widely believed that the resumption of normal functioning is due to downregulation of the iodide pump on the follicular cell membrane. The Wolff-Chaikoff effect is the principle behind the use of iodine for the treatment of hyperthyroidism.



Plasma-binding proteins. T3 and T4 mainly circulate bound to thyroid-binding globulin (TBG). Thyroid hormones that are bound to plasma proteins are biologically inactive but provide a reservoir to buffer against changes in thyroid gland function or metabolic demand, which increases their half-life (decreased renal clearance).

T4 conversion to T3. T4 is converted to T3 in peripheral tissues by 5’– monodeiodination. This accounts for 80% of T3.

Reverse T3 (rT3) is an inactive metabolite of T4 that is formed during this deiodination.


Development. T3 is essential for the development of the central nervous system (CNS). Fetal deficiencies in thyroid function lead to a slowing of all intellectual functions due to irreversible CNS lesions (cretinism). If hypothyroidism develops from ~2 years of age onward, the effects on mental development are minor and reversible.

Growth. Growth depends on the normal function of the thyroid in postnatal life. Thyroid hormones promote growth by

– ↑protein synthesis

– ↑bone formation with growth hormone (GH) and insulinlike growth factor (IGF)

– ↑ossification and fusion of growth plates

Basal metabolic rate. T3 and T4 increase BMR to provide an increased amount of substrate for adenosine triphosphate (ATP) production in the face of higher oxygen consumption throughout the body.

T3 stimulates Na+−K+ ATPase activity, thus increasing the use of ATP by the Na+−K+ pump. This requires higher oxygen consumption.

The increase in BMR and ATP hydrolysis combines to cause an increase in heat production.

Metabolic. Thyroid hormones are catabolic and stimulate the following:

– ↑intestinal absorption of glucose

– ↑ gluconeogenesis, glycogenolysis, and glucose oxidation

– ↑lipolysis

– ↑cholesterol turnover and plasma clearance of cholesterol

– T3 potentiates the “hypoglycemic” actions of insulin by increasing glucose uptake into muscle and adipose tissue.

Systemic. T3 upregulates adrenergic β-receptors, leading to increased heart rate, cardiac output, and ventilation and decreased peripheral vascular resistance. These actions support increased oxygen demand in tissues.

T3 also potentiates epinephrine, enhancing adrenergic-mediated glycogenolysis.

T3 facilitates the actions of cortisol, glucagon, and GH.


The causes of thyroid hormone derangement are illustrated in Fig. 25.4.

Fig. 25.4 image Causes of hypothyroidism, hyperthyroidism, and goiter.

Hypothyroidism is usually caused by dysfunction of the thyroid gland itself. Defects may occur at any step of thyroid hormone synthesis or at the target organ receptors. It is very commonly caused by inflammatory damage to the gland or due to thyroidectomy (for cancer). It is rarely due to defects of the hypothalamus or anterior pituitary. Hyperthyroidism is commonly due to autoimmune disease where thyroid-stimulating immunoglobulin (TSI) mimics TSH at its receptors (Graves disease). Other causes are tumors, thyroiditis, excess TSH, and excessive supply of thyroid hormones. Goiter is caused by uncontrolled thyroid cell proliferation due to a tumor or overstimulation by TSH or TSI. (DIT, diiodotyrosine, MIT, monoiodotyrosine)


Hypothyroidism. Table 25.2 summarizes the causes, effects, symptoms, and treatment of hypothyroidism. The pathophysiological mechanism of hypothyroidism is illustrated in Fig. 25.5.


Hyperthyroidism. Table 25.3 summarizes hyperthyroidism. The pathophysiological mechanism of hyperthyroidism is illustrated in Fig. 25.6.


Thyrotoxic storm

Thyrotoxic storm is a life-threatening condition in which there is severe hyperthyroidism, fever, sweating, restlessness, shaking, tachycardia, diarrhea, and vomiting. It may precipitate heart failure, pulmonary edema, and coma and may be fatal. It usually occurs in people with untreated hyper-thyroidism who encounter a stressor, such as infection or trauma. Treatment involves reducing thyroid hormone synthesis and secretion with propylthiouracil and Lugol solution (iodine solution), systemic steroids (dexamethasone) for insufficiency and to stabilize the integrity of blood vessels, β-blockers to control the β-mediated effects, antibiotics (if infection is causative), and fluid replacement.


Drugs for hyperthyroidism

Propylthiouracil and methimazole act by inhibiting the iodination of tyrosyl residues in TG, and the coupling of iodotyrosines, by inhibiting the peroxidase enzyme. Effects are not apparent until the thyroid reserve is depleted. It is common for patients taking these drugs to develop a rash.


Thyroid opthalmopathy

Thyroid opthalmopathy occurs in Graves disease, in which autoantibodies cause inflammation and lymphocytic infiltration around the orbit. This condition tends to affect men more than women and may occur before other signs of hyperthyroidism are evident. Upper lid retraction is the most common sign, but others include decreased visual acuity, proptosis, lid lag, diplopia (double vision), edema, erythema, conjunctivitis, incapacity to fully close the eyelids (lagophthalmos), dysfunction of the lacrimal gland, and limitation of eye movement (especially upward gaze, due to tethering and fibrosis of the inferior rectus muscle). The patient may complain of eyes feeling dry and gritty. In severe cases, the optic nerve may be compressed, which, if untreated, could lead to blindness. Treatment involves normalizing thyroid hormone levels (opthalmopathy may not respond to this), smoking cessation, artificial tears, tarsorrhaphy (eyelids are partially sutured together), systemic steroids to reduce inflammation, surgical decompression of the optic nerve, and other surgeries to improve the patient’s comfort level (e.g., lid lengthening).


Recurrent laryngeal nerve paralysis with thyroidectomy

The recurrent laryngeal nerve (RLN) is a branch of the vagus nerve (cranial nerve X). It supplies visceromotor innervation to the posterior cricothyroid, the muscle that abducts the vocal cords. It also supplies sensation to the laryngeal mucosa. The recurrent laryngeal nerves, especially the right RLN, is vulnerable to damage during thyroidectomy, as they run immediately posterior to the thyroid gland. Unilateral RLN damage results in hoarseness; bilateral damage causes respiratory distress (dyspnea) and aphonia. Aspiration pneumonia may occur as a complication. The presence of damage may be confirmed by laryngoscopy showing the absence of movement of the vocal cord on the affected side. There is no cure for this condition, but there are surgical options that may help prevent aspiration.


Thyroid function tests

There are several tests for measuring the function of the thyroid gland. The most common is a simple blood test for TSH, free T4 (FT4), and T3 levels. Usually TSH and FT4 are combined to identify thyroid dysfunction. A high TSH level combined with a low FT4 is indicative of primary hypothyroidism (the thyroid gland itself is failing). A low TSH combined with a low FT4 is indicative of secondary hypothyroidism (pituitary gland dysfunction), and low TSH/high FT4 is indicative of hyperthyroidism. T3 will also be high in hyperthyroidism, but it is not useful for the diagnosis of hypothyroidism, as T3 is the last to become abnormal. Thyroid antibody titers for autoimmune thyroid disorders (Hashimoto thyroiditis and Graves disease) can also be measured in a blood test. Additional tests include radioactive iodine uptake (RAIU) and thyroid scans. These tests can determine whether the thyroid is overactive or underactive.


Fig. 25.5 image Pathophysiology of hypothyroidism.

Each of the signs and symptoms of hypothyroidism can be related to hyposecretion of thyroid hormones and the effect this has on development, growth, and metabolism. (CO, cardiac output; VLDL, very-low-density lipoprotein)


Fig. 25.6 image Pathophysiology of hyperthyroidism.

Each of the symptoms of hyperthyroidism can be related to hypersecretion of thyroid hormones and the effect this has on development, growth, and metabolism. (GFR, glomerular filtration rate; LDL, low-density lipoprotein; RPF, renal plasma flow; VLDL, very-low-density lipoprotein)