Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 20The Thyroid Gland 309

(RXR). The TR/RXR heterodimer does not bind 9-cis retinoic
acid, the usual ligand for RXR, but TR binding to DNA is
greatly enhanced in response to thyroid hormones when the
receptor is in the form of this heterodimer. There are also
coactivator and corepressor proteins that affect the actions of

TRs. Presumably, this complexity underlies the ability of thy-

roid hormones to produce many different effects in the body.

In most of its actions, T 3 acts more rapidly and is three to

five times more potent than T 4 (Figure 20–13). This is

because T 3 is less tightly bound to plasma proteins than is T 4 ,

but binds more avidly to thyroid hormone receptors. RT 3 is

inert (see Clinical Box 20–3).

CLINICAL BOX 20–1

Reduced Thyroid Function

The syndrome of adult hypothyroidism is generally called myx-

edema, although this term is also used to refer specifically to the

skin changes in the syndrome. Hypothyroidism may be the end

result of a number of diseases of the thyroid gland, or it may be

secondary to pituitary or hypothalamic failure. In the latter two

conditions, the thyroid remains able to respond to TSH. Thyroid

function may be reduced by a number of conditions (Table 20–

3). For example, when the dietary iodine intake falls below 50

μg/d, thyroid hormone synthesis is inadequate and secretion de-

clines. As a result of increased TSH secretion, the thyroid hyper-

trophies, producing an iodine deficiency goiter that may be-

come very large. Such “endemic goiters” have been substantially

reduced by the practice of adding iodide to table salt. Drugs may

also inhibit thyroid function. Most do so either by interfering

with the iodide-trapping mechanism or by blocking the organic

binding of iodine. In either case, TSH secretion is stimulated by

the decline in circulating thyroid hormones, and a goiter is pro-

duced. The thioureylenes, a group of compounds related to

thiourea, inhibit the iodination of monoiodotyrosine and block

the coupling reaction. The two used clinically are propylthioura-

cil and methimazole (Figure 20–11). Iodination of tyrosine is in-

hibited because propylthiouracil and methimazole compete

with tyrosine residues for iodine and become iodinated. In addi-

tion, propylthiouracil but not methimazole inhibits D 2 deiodi-

nase, reducing the conversion of T 4 to T 3 in many extrathyroidal

tissues. Paradoxically, another substance that inhibits thyroid

function under certain conditions is iodide itself. In normal indi-

viduals, large doses of iodide act directly on the thyroid to pro-

duce a mild and transient inhibition of organic binding of iodide

and hence of hormone synthesis. This inhibition is known as the

Wolff–Chaikoff effect.

In completely athyreotic adults, the BMR falls to about 40%.

The hair is coarse and sparse, the skin is dry and yellowish

(carotenemia), and cold is poorly tolerated. Mentation is slow,

memory is poor, and in some patients there are severe mental

symptoms (“myxedema madness”). Plasma cholesterol is ele-

vated. Children who are hypothyroid from birth or before are

called cretins. They are dwarfed and mentally retarded.

Worldwide, congenital hypothyroidism is one of the most

common causes of preventable mental retardation. The main

causes are included in Table 20–3. They include not only ma-

ternal iodine deficiency and various congenital abnormalities

of the fetal hypothalamo–pituitary–thyroid axis, but also ma-

ternal antithyroid antibodies that cross the placenta and

damage the fetal thyroid. T 4 crosses the placenta, and unless

the mother is hypothyroid, growth and development are nor-

mal until birth. If treatment is started at birth, the prognosis for

normal growth and development is good, and mental retarda-

tion can generally be avoided; for this reason, screening tests

for congenital hypothyroidism are becoming routine. When

the mother is hypothyroid as well, as in the case of iodine defi-

ciency, the mental deficiency is more severe and less respon-

sive to treatment after birth. It has been estimated that 20 mil-

lion people in the world now have various degrees of brain

damage caused by iodine deficiency in utero.

Uptake of tracer doses of radioactive iodine can be used to

assess thyroid function (contrast this with the use of large

doses to ablate thyroid tissue in cases of hyperthyroidism

(Clinical Box 20–2). An analysis of the kinetics of iodine han-

dling also provides insights into the basic physiology of the

gland (Figure 20–12).

TABLE 20–3 Causes of congenital hypothyroidism.

Maternal iodine deficiency

Fetal thyroid dysgenesis

Inborn errors of thyroid hormone synthesis

Maternal antithyroid antibodies that cross the placenta

Fetal hypopituitary hypothyroidism

FIGURE 20–11 Structure of commonly used thioureylenes.

C

CC 3 H 7

NH O

C CH

NH

S

Propylthiouracil

C

CH

3 NCH H

C

N

HS

Methimazole