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240 Hormones

Thyroid Hormone Therapy

Thyroid hormones accelerate metabolism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of thyroid hormones rises; by means of this negative feedback mechanism, hormone production is “automatically” adjusted to demand.

The thyroid releases predominantly thyroxine (T4). However, the active form appears to be triiodothyronine (T3); T4 is converted in part toT3, receptor af nity in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly and has a shorter duration than does that of T4. Plasma elimination t½ for T4 is about 7 days; that for T3, however, is only 1.5 days. Conversion of T4 toT3 releases iodide; 150 µg T4 contains 100 µg of iodine.

For therapeutic purposes, T4 is chosen, although T3 is the active form and better absorbed from the gut. With T4 administration, more constant blood levels can be achieved because T4 degradation is so slow. Since T4 absorption is maximal from an empty stomach, T4 is taken about half an hour before breakfast.

Replacement therapy of hypothyroidism.

Whether primary, i.e., caused by thyroid disease, or secondary, i.e., resulting from TSH deficiency, hypothyroidism is treated by oral administration of T4. Since too rapid activation of metabolism entails the hazard of cardiac overload (angina pectoris, myocardial infarction), therapy is usually started with low doses and gradually increased. The final maintenance dose required to restore a euthyroid state depends on individual needs (~ 150 µg/day).

Thyroid suppression therapy of euthyroid goiter (B). The cause of goiter (struma) is usually a dietary deficiency of iodine. Owing to increased TSH action, the thyroid is acti-

vated to raise utilization of the little iodine available to a level at which hypothyroidism is averted. Accordingly, the thyroid increases in size. In addition, intrathyroid depletion of iodine stimulates growth.

Because of the negative feedback regulation of thyroid function, thyroid activation can be inhibited by administration of T4 doses equivalent to the endogenous daily output (~ 150 µg/day). Deprived of stimulation, the inactive thyroid regresses in size.

If a euthyroid goiter has not persisted for too long, increasing iodine supply (with potassium iodide tablets) can also be effective in reversing overgrowth of the gland.

In older patients with goiter due to iodine deficiency, there is arisk of provoking hyperthyroidism by increasing iodine intake (p.243B). During chronic maximal stimulation, thyroid follicles can become independent of TSH stimulation (“autonomic tissue” containing TSH receptor mutants with spontaneous “constitutive activity”). If the iodine supply is increased, thyroid hormone production increases while TSH secretion decreases owing to feedback inhibition. The activity of autonomic tissue, however, persists at a high level; thyroxine is released in excess, resulting in iodine-induced hyperthyroidism.

Iodized salt prophylaxis. Goiter is endemic in regions where soils are deficient in iodine. Use of iodized table salt allows iodine requirements (150–300 µg/day) to be met and effectively prevents goiter.

Thyroid Hormone Therapy

241

A. Thyroid hormones – release, effects, degradation

 

 

 

 

 

 

 

Hypothalamus

 

 

I

6'

I

 

6

 

 

 

 

 

 

 

 

5'

 

5

 

 

 

 

TRH

 

 

HO 4'

1'

O 4

 

1

CH2

CH

COOH

 

 

 

 

 

3'

2'

 

3

2

 

NH2

 

 

 

 

 

 

I

 

I

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Decrease in

L-Thyroxine, Levothyroxine,

 

 

 

 

3,5,3´,5´-Tetraiodothyronine, T4

 

 

 

sensitivity

 

 

Hypophysis

to TRH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

I

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

TSH

 

 

HO

 

 

O

 

 

CH2

CH

COOH

 

 

 

 

 

I

 

I

 

 

 

NH2

 

 

 

 

 

 

 

 

 

 

 

 

Thyroid

 

 

 

Liothyronine

 

 

 

 

 

 

 

 

 

3,5,3´-Triiodothyronine, T3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Effector cell:

 

 

 

~ 9

g/day

 

 

 

 

 

receptor affinity

 

~ 90 g/day

 

 

 

 

 

T3

10

 

 

 

 

 

 

 

 

 

 

T4

= 1

 

 

Thyroxine

Triiodothyronine

 

 

 

 

 

 

 

 

 

 

~ 25 g/day

 

Duration

 

 

 

 

 

 

 

Deiodinase

 

2.

9.

Day

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

I-

I-

Deiodination

 

 

 

 

 

 

 

 

 

 

coupling

 

 

 

 

 

 

 

 

 

 

“reverse T3

 

 

 

T3

 

 

 

T4

 

 

 

 

 

Urine

Feces

 

10

 

20

 

30

 

40 Days

3,3´,5´-Triiodothyronine

 

 

 

 

B. Endemic goiter and its treatment with thyroxine

 

 

Hypophysis

 

 

 

 

 

TSH

 

TSH

Inhibition

 

 

 

 

 

I

-

Normal

 

 

Therap.

state

I-

I-

admini-

 

stration

 

 

T4, T3

 

T4, T3

T4

242 Hormones

 

Hyperthyroidism and Antithyroid

Antithyroid drugs for long-term therapy

 

(C). Thiourea-derivatives (thioamides) in-

 

Drugs

 

hibit peroxidase and, hence, hormone syn-

 

 

 

Thyroid overactivity in Graves disease (A)

thesis. To restore a euthyroid state, two ther-

 

results from formation of IgG antibodies that

apeutic principles can be applied in Graves

 

bind to and activate TSH receptors. Conse-

disease: (a) monotherapy with a thioamide,

 

quently, there is overproduction of hormone

with gradual dose reduction as the disease

 

with cessation of TSH secretion. Graves dis-

abates; (b) administration of high doses of a

 

ease can abate spontaneously after 1–2

thioamide, with concurrent administration

 

years; therefore, initial therapy consists in

of thyroxine to offset diminished hormone

 

reversible suppression of thyroid activity by

synthesis. Adverse effects of thioamides are

 

means of antithyroid drugs. In other forms of

rare, but the possibility of agranulocytosis

 

 

hyperthyroidism, such as hormone-produc-

has to be kept in mind.

 

ing (morphologically benign) thyroid adeno-

Perchlorate, given orally as the sodium

 

ma, the preferred therapeutic method is re-

salt, inhibits the iodide pump. Adverse reac-

 

moval of tissue, either by surgery or by ad-

tions include aplastic anemia. Compared

 

ministration of iodine-131 (131I) in suf cient

with thioamides, its therapeutic importance

 

dosage. Radioiodine is enriched in thyroid

is low.

 

cells and destroys tissue within a sphere of

 

 

a few millimeters by emitting β-particles

Short-term thyroid suppression (C). Iodine

 

(electrons) during its radioactive decay.

in high dosage(> 6000 µg/day) exertsatran-

 

Antithyroid drugs inhibit thyroid func-

sient “thyrostatic” effect in hyperthyroid, but

 

tion. Release of thyroid hormone (C) is pre-

usually not in euthyroid, individuals. Since

 

ceded bya chain of events. A membrane Na+/

release is also blocked, the effect develops

 

Isymporter actively accumulates iodide in

more rapidly than does that of thioamides.

 

thyroid cells (the required energy comes

Clinical applications include preoperative

 

from a Na+/K+-ATPase located in the baso-

suppression of thyroid secretion according

 

lateral membrane region); this is followed

to Plummer with Lugol’s solution (5% iodine

 

by oxidation to iodine, iodination of tyrosine

+ 10% potassium iodide, 50–100 mg iodine/

 

residues in thyroglobulin, conjugationof two

day for a maximum of 10 days). In thyrotoxic

 

diiodotyrosine groups, and formation of T4

crisis, Lugol’s solution is given together with

 

moieties. These reactions are catalyzed by

thioamides and β-blockers. Adverse effects:

 

thyroid peroxidase, which is localized in

allergies. Contraindications: iodine-induced

 

the apical border of the follicular cell mem-

thyrotoxicosis.

 

brane. T4-containing thyroglobulin is stored

Lithium ions inhibit thyroxine release.

 

inside the thyroid follicles in the form of

Lithium salts can be used instead of iodine

 

thyrocolloid. Upon endocytotic uptake, col-

for rapid thyroid suppression in iodine-in-

 

loid undergoes lysosomal enzymatic hydro-

duced thyrotoxicosis. Regarding administra-

 

lysis, enabling thyroid hormone to be re-

tion of lithium in manic-depressive illness,

 

leased as required. A “thyrostatic” effect

see p.230.

 

can result from inhibition of synthesis or

 

 

release. When synthesis is arrested, the an-

 

 

tithyroid effect develops after a delay, as

 

 

stored colloid continues to be utilized.

 

 

 

 

 

Hyperthyroidism and Antithyroid Drugs

243

A. Graves' disease

 

 

 

B. Iodine hyperthyroidosis in endemic goiter

 

 

 

 

 

Hypophysis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

TSH

Autonomous

 

 

 

 

 

 

 

 

 

tissue

 

 

 

TSH-

 

 

 

 

I-

 

 

I-

 

 

 

like

 

 

 

 

 

 

 

 

 

 

 

anti-

T4, T3

 

 

 

 

T4, T3

 

T4, T3

 

bodies

 

 

 

 

 

 

C. Antithyroid drugs and their modes of action

 

 

 

 

Thioamides

 

 

 

 

Conversion

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

H3C

CH2

CH2

N

S

CH3

 

during

N

S

 

 

 

 

 

 

 

N

 

absorption

 

 

 

 

 

 

 

NH

S

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

NH

 

 

C

O

CH2

CH3

 

 

 

 

 

 

 

 

 

 

 

Thiamazole

 

O

 

 

 

Propylthiouracil

 

 

 

 

Carbimazole

 

 

Methimazole

 

 

 

I-

 

 

 

 

 

 

e

 

 

 

 

 

 

 

 

 

Peroxidase

 

 

 

ClO -

 

 

 

 

 

 

I-

Tyrosine

 

 

 

 

 

 

 

 

I

TG

 

 

4

 

 

 

 

 

Synthesis

 

 

 

 

 

 

 

 

 

 

I

 

 

Iodine in

 

 

 

 

 

 

 

 

Tyrosine

 

 

 

 

 

 

 

 

I

 

 

high dose

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T4-

 

 

 

 

 

 

 

 

Release

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

T4

 

T4-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Storage

 

 

 

 

 

 

 

 

 

 

in colloid

 

 

 

 

Lysosome

 

Lithium

 

 

 

 

 

 

 

 

 

ions