17.

4 The Thyroid Gland

Learning Objectives

By the end of this section, you will be able to:

 Describe the location and anatomy of the thyroid gland

 Discuss the synthesis of triiodothyronine and thyroxine
 Explain the role of thyroid hormones in the regulation of basal
metabolism
 Identify the hormone produced by the parafollicular cells of the thyroid
 ANATOMY AND PHYSIOLOGY

A butterfly-shaped organ, the thyroid gland is located anterior to the trachea, just
inferior to the larynx (Figure 1). The medial region, called the isthmus, is flanked by
wing-shaped left and right lobes. Each of the thyroid lobes are embedded with
parathyroid glands, primarily on their posterior surfaces. The tissue of the thyroid gland
is composed mostly of thyroid follicles. The follicles are made up of a central cavity filled
with a sticky fluid called colloid. Surrounded by a wall of epithelial follicle cells, the
colloid is the center of thyroid hormone production, and that production is dependent
on the hormones’ essential and unique component: iodine.
 Figure 1. Thyroid Gland. The thyroid gland is located in the neck where it wraps around the trachea. (a)
Anterior view of the thyroid gland. (b) Posterior view of the thyroid gland. (c) The glandular tissue is composed
primarily of thyroid follicles. The larger parafollicular cells often appear within the matrix of follicle cells. LM ×
1332. (Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Synthesis and Release of Thyroid Hormones

Hormones are produced in the colloid when atoms of the mineral iodine attach to a glycoprotein,
called thyroglobulin, that is secreted into the colloid by the follicle cells. The following steps
outline the hormones’ assembly:

1. Binding of TSH to its receptors in the follicle cells of the thyroid gland causes the cells to actively
transport iodide ions (I–) across their cell membrane, from the bloodstream into the cytosol. As a result,
the concentration of iodide ions “trapped” in the follicular cells is many times higher than the
concentration in the bloodstream.
2. Iodide ions then move to the lumen of the follicle cells that border the colloid. There, the ions undergo
oxidation (their negatively charged electrons are removed). The oxidation of two iodide ions (2 I–) results
in iodine (I2), which passes through the follicle cell membrane into the colloid.
3. In the colloid, peroxidase enzymes link the iodine to the tyrosine amino acids in thyroglobulin to
produce two intermediaries: a tyrosine attached to one iodine and a tyrosine attached to two iodines.
When one of each of these intermediaries is linked by covalent bonds, the resulting compound
is triiodothyronine (T3), a thyroid hormone with three iodines. Much more commonly, two copies of the
second intermediary bond, forming tetraiodothyronine, also known as thyroxine (T4), a thyroid hormone
with four iodines.

These hormones remain in the colloid center of the thyroid follicles until TSH stimulates
endocytosis of colloid back into the follicle cells. There, lysosomal enzymes break apart the
thyroglobulin colloid, releasing free T3and T4, which diffuse across the follicle cell membrane
and enter the bloodstream.

In the bloodstream, less than one percent of the circulating T3 and T4 remains unbound. This free
T3 and T4 can cross the lipid bilayer of cell membranes and be taken up by cells. The remaining
99 percent of circulating T3 and T4 is bound to specialized transport proteins called thyroxine-
binding globulins (TBGs), to albumin, or to other plasma proteins. This “packaging” prevents
their free diffusion into body cells. When blood levels of T3 and T4 begin to decline, bound T3 and
T4 are released from these plasma proteins and readily cross the membrane of target cells. T3 is
more potent than T4, and many cells convert T4 to T3through the removal of an iodine atom.

Regulation of TH Synthesis
The release of T3 and T4 from the thyroid gland is regulated by thyroid-stimulating hormone
(TSH). As shown in Figure 2, low blood levels of T3 and T4 stimulate the release of thyrotropin-
releasing hormone (TRH) from the hypothalamus, which triggers secretion of TSH from the
anterior pituitary. In turn, TSH stimulates the thyroid gland to secrete T3 and T4. The levels of
TRH, TSH, T3, and T4 are regulated by a negative feedback system in which increasing levels of
T3 and T4 decrease the production and secretion of TSH.
Figure 2. Classic Negative Feedback Loop. A classic negative feedback loop controls the regulation of thyroid
hormone levels.

Functions of Thyroid Hormones

The thyroid hormones, T3 and T4, are often referred to as metabolic hormones because their
levels influence the body’s basal metabolic rate, the amount of energy used by the body at rest.
When T3 and T4 bind to intracellular receptors located on the mitochondria, they cause an
increase in nutrient breakdown and the use of oxygen to produce ATP. In addition, T3 and
T4 initiate the transcription of genes involved in glucose oxidation. Although these mechanisms
prompt cells to produce more ATP, the process is inefficient, and an abnormally increased level
of heat is released as a byproduct of these reactions. This so-called calorigenic effect (calor- =
“heat”) raises body temperature.

Adequate levels of thyroid hormones are also required for protein synthesis and for fetal and
childhood tissue development and growth. They are especially critical for normal development
of the nervous system both in utero and in early childhood, and they continue to support
neurological function in adults. As noted earlier, these thyroid hormones have a complex
interrelationship with reproductive hormones, and deficiencies can influence libido, fertility, and
other aspects of reproductive function. Finally, thyroid hormones increase the body’s sensitivity
to catecholamines (epinephrine and norepinephrine) from the adrenal medulla by upregulation of
receptors in the blood vessels. When levels of T3 and T4 hormones are excessive, this effect
accelerates the heart rate, strengthens the heartbeat, and increases blood pressure. Because
thyroid hormones regulate metabolism, heat production, protein synthesis, and many other body
functions, thyroid disorders can have severe and widespread consequences.

Disorders of the…

Endocrine System: Iodine Deficiency, Hypothyroidism, and Hyperthyroidism

As discussed above, dietary iodine is required for the synthesis of T3 and T4. But for much of the
world’s population, foods do not provide adequate levels of this mineral, because the amount
varies according to the level in the soil in which the food was grown, as well as the irrigation and
fertilizers used. Marine fish and shrimp tend to have high levels because they concentrate iodine
from seawater, but many people in landlocked regions lack access to seafood. Thus, the primary
source of dietary iodine in many countries is iodized salt. Fortification of salt with iodine began
in the United States in 1924, and international efforts to iodize salt in the world’s poorest nations
continue today.

Dietary iodine deficiency can result in the impaired ability to synthesize T3 and T4, leading to a
variety of severe disorders. When T3 and T4 cannot be produced, TSH is secreted in increasing
amounts. As a result of this hyperstimulation, thyroglobulin accumulates in the thyroid gland
follicles, increasing their deposits of colloid. The accumulation of colloid increases the overall
size of the thyroid gland, a condition called a goiter (Figure 3). A goiter is only a visible
indication of the deficiency. Other iodine deficiency disorders include impaired growth and
development, decreased fertility, and prenatal and infant death. Moreover, iodine deficiency is
the primary cause of preventable mental retardation worldwide. Neonatal
 hypothyroidism (cretinism) is characterized by cognitive deficits, short stature, and sometimes
deafness and muteness in children and adults born to mothers who were iodine-deficient during
pregnancy.

Figure 3. Goiter. (credit: “Almazi”/Wikimedia Commons)

In areas of the world with access to iodized salt, dietary deficiency is rare. Instead, inflammation
of the thyroid gland is the more common cause of low blood levels of thyroid hormones.
Called hypothyroidism, the condition is characterized by a low metabolic rate, weight gain, cold
extremities, constipation, reduced libido, menstrual irregularities, and reduced mental activity. In
contrast, hyperthyroidism—an abnormally elevated blood level of thyroid hormones—is often
caused by a pituitary or thyroid tumor. In Graves’ disease, the hyperthyroid state results from an
autoimmune reaction in which antibodies overstimulate the follicle cells of the thyroid gland.
Hyperthyroidism can lead to an increased metabolic rate, excessive body heat and sweating,
diarrhea, weight loss, tremors, and increased heart rate. The person’s eyes may bulge (called
exophthalmos) as antibodies produce inflammation in the soft tissues of the orbits. The person
may also develop a goiter.

Calcitonin
The thyroid gland also secretes a hormone called calcitonin that is produced by the parafollicular
cells (also called C cells) that stud the tissue between distinct follicles. Calcitonin is released in
response to a rise in blood calcium levels. It appears to have a function in decreasing blood
calcium concentrations by:

 Inhibiting the activity of osteoclasts, bone cells that release calcium into the circulation by degrading
bone matrix
 Increasing osteoblastic activity
 Decreasing calcium absorption in the intestines
 Increasing calcium loss in the urine

However, these functions are usually not significant in maintaining calcium homeostasis, so the
importance of calcitonin is not entirely understood. Pharmaceutical preparations of calcitonin are
sometimes prescribed to reduce osteoclast activity in people with osteoporosis and to reduce the
degradation of cartilage in people with osteoarthritis. The hormones secreted by thyroid are
summarized in Table 4.
 Thyroid Hormones (Table 4)

Associated hormones Chemical class Effect

Thyroxine (T4), triiodothyronine (T3) Amine Stimulate basal metabolic rate

Calcitonin Peptide Reduces blood Ca2+levels

Of course, calcium is critical for many other biological processes. It is a second messenger in
many signaling pathways, and is essential for muscle contraction, nerve impulse transmission,
and blood clotting. Given these roles, it is not surprising that blood calcium levels are tightly
regulated by the endocrine system. The organs involved in the regulation are the parathyroid
glands.

Chapter Review
The thyroid gland is a butterfly-shaped organ located in the neck anterior to the trachea. Its
hormones regulate basal metabolism, oxygen use, nutrient metabolism, the production of ATP,
and calcium homeostasis. They also contribute to protein synthesis and the normal growth and
development of body tissues, including maturation of the nervous system, and they increase the
body’s sensitivity to catecholamines. The thyroid hormones triiodothyronine (T3) and thyroxine
(T4) are produced and secreted by the thyroid gland in response to thyroid-stimulating hormone
(TSH) from the anterior pituitary. Synthesis of the amino acid–derived T3 and T4 hormones
requires iodine. Insufficient amounts of iodine in the diet can lead to goiter, cretinism, and many
other disorders.

Review Questions