Thyroid Hormones And Metabolic Rate
The
thyroid gland is attached to the anterior surface of the trachea just below the larynx. It releases two
iodine-containing hormones, thyroxine (also known as T4) and tri-iodothyronine
(T3; Fig. 45a), the main effect of which is to increase heat
production (thermogenesis) throughout the body and thereby induce an
increase in metabolic rate. The hormones also have a crucial role in growth and
development.
Synthesis and release
The thyroid gland is formed from
clusters of cells (follicles) that surround a gel-like matrix or
colloid, the primary constituent of which is the glycoprotein thyroglobulin.
The follicle cells actively accumulate iodide (I−) ions by means of an Na+–I−
symporter (Chapter 4) driven by the inward sodium gradient (Fig. 45b). The
formation of T3 and T4 occurs in two steps: (i) the amino acid tyrosine is
iodinated to form mono- (T1) or di-iodotyrosine (T2) (Fig. 45a); (ii) T2 is then
coupled to T1 or T2 by thyroperoxidase to form the thyroid hormones. This
process occurs with the tyrosine residues attached to thyroglobulin, so that,
at any one time, this protein is festooned with molecules of T1, T2, T3 and T4
(Fig. 45b). The thyroid hormones and their intermediates are highly lipophilic
and would escape from the gland were they not incorporated into thyroglobulin,
which thus acts as a nucleus for the manufacture of the hormones and as a
storage site. The hormones are released under the control of thyroid-stimulating
hormone (TSH) from the anterior pituitary, which is obligatory for
normal thyroid function (Chapter 44; Fig. 45c). Under the action of TSH,
thyroid follicle cells pinch off small quantities of colloid by pinocytosis.
Lysozymal protease enzymes then act on the thyroglobulin to liberate the
iodinated compounds into the cell and thence into the bloodstream (Fig. 45b).
Free T1 and T2 are deiodinated by
enzymatic action before they can leave the cell. The average plasma concentration
of T3 is roughly one-sixth of that of T4, and much of that derives from deiodinated
T4. Most of the thyroid hormones in the blood are bound to thyroxine-binding
protein and are thus unavailable to their receptors, which are located inside
target cells, attached directly to deoxyribonucleic acid (DNA). The small
amounts of free T3 and T4 in plasma readily cross the cell membranes to bind to
thyroid hormone receptors (the most important of which is TRa1). Thyroid
receptors are linked to a DNA sequence known as the thyroid-response element
(TRE) which initiates the transcription of thyroid-responsive genes.
T3 is some 10 times more potent than T4 in activating TRα1 and consequently
mediates most thyroid hormone actions, notwithstanding its lower levels in
plasma. Thyroid receptors are present in almost all tissues, with particularly
high levels in the liver and low levels in the spleen and testes.
Physiological roles of thyroid
hormones Basal levels of thyroid hormone release are
essential to maintain a normal metabolic rate. Situations requiring increased
heat production, for instance when
the core temperature falls, lead to enhanced activation of the thyroid axis.
The effects take up to 4 days to reach a maximum, a slow time course that is
characteristic of hormones acting through nuclear receptors. The primary action
of thyroid hormones is an increase in the synthesis of Na+–K+
ATPase (Chapter 4), an enzyme that consumes large amounts of metabolic energy,
to increase heat production. The hormones may also enhance the production of uncoupling
proteins (UCPs). These molecules act in mitochondria to divert the H+
ion gradient generated by the electron transport chain (Chapter 4), so that it
produces heat rather than driving adenosine triphosphate (ATP) synthase.
Although UCP-1 is found only in brown fat, a tissue that is uncommon in adult
humans, two other members of the family (UCP-2 and UCP-3) are present in muscle
and other tissues, and may thus contribute to thyroid-stimulated thermogenesis.
Other important actions of thyroid hormones include a generalized increase in
protein turnover (i.e. breakdown and synthesis), an increase in cardiac
output caused by the enhancement of the effects of adrenaline (epinephrine) at β-adrenoceptors
(Chapters 7 and 49), and a strong lipolytic effect that arises from the
potentiation of responses to cortisol, glucagon, growth hormone and adrenaline.
These actions can be described as generally catabolic (Chapter 43), but it
should be noted that low doses of thyroid hormones have an overall anabolic
action and that the hormones are essential to normal postnatal growth.
Disorders of the thyroid gland
Lack of dietary iodide or a failure
of iodide uptake mechanisms in the thyroid gland produces the conditions of hypothyroidism.
In fetal and neonatal life, underproduction of thyroid hormones causes
inadequate somatic and neural development and gives rise to cretinism, a
condition characterized by subnormal stature and mental ability. In adults, the
main symptoms of thyroid insufficiency are lethargy, sluggishness and an
intolerance to cold. In severe cases, there is excess production of
water-retaining mucoproteins in subcutaneous tissues, giving rise to tissue
bloating, known as myxoedema. Such conditions are treated with
injections of T4. When the cause of hypothyroidism is an insufficiency of
iodide intake, cells of the thyroid gland undergo hypertrophy and the gland
becomes enlarged to form a goitre. This (now very uncommon) condition is
treated by ensuring an adequate supply of dietary iodide. The overproduction of
T3 and T4 leads to hyperthyroidism (Graves’ disease), characterized by exophthalmia
(bulging eyes), increased behavioural excitability, tremor, weight loss and
chronic tachycardia (high heart rate). The last of these symptoms can
eventually lead to ventricular arrhythmias and/or heart failure, and so
treatment, usually surgical removal of part of the gland or antithyroid drugs, is highly recommended.
