Thyroid: II Thyroid Hormone Secretion And
Action
Clinical scenario
A 56-year-old woman, Miss TM, presented to her GP complaining of gaining
weight, feeling cold and being tired all the time. Her hair and skin were very
dry. On questioning she had noticed feeling out of breath more frequently, she
was constipated and had generalized aches and pains with occasional tingling in
her hands and feet. The GP thought she might be hypothyroid and on examination
found her to have cool extremities with myxoedematous changes in the skin, her
face was pale with periorbital puffiness, she was bradycardic and her tendon
reflexes showed delayed relaxation. There was no goitre (Fig. 14a). The clinical
diagnosis was confirmed biochemically when her thyroid function tests showed fT4
of <2.0 pmol/L and TSH >75
mU/L. She had a high titre of thyroid peroxidase
antibodies. She was started on thyroxine replacement therapy and her symptoms
resolved over the next few weeks.
In the developed world, the vast majority of cases of primary
hypothyroidism are caused by autoimmune disease or following treatment of
thyrotoxicosis with radioactive iodine therapy or surgery. Autoimmune disease
is either associated with destructive thyroid antibodies (antithyroid
peroxidase antibodies) causing thyroid atrophy or, less commonly, with TSH-
receptor-blocking antibodies causing the goitre of Hashimoto’s disease.
Drug-induced hypothyroidism may be seen, particularly in people taking lithium
therapy and, rarely, congenital abnormalities of the thyroid or
dyshormonogenesis may be found. Secondary hypothyroidism, characterized by low
thyroxine and TSH concentrations and associated with disorders of the hypothalamo
pituitary axis, is rarely seen in general medical practice.
Control of thyroid hormone synthesis and secretion
Hypothalamic and pituitary control
Thyrotrophin-releasing hormone (TRH) is a tripeptide synthesized
in the paraventricular and supraoptic nuclei in the hypothalamus and stored in
the median eminence. The portal venous system transports TRH to the anterior
pituitary where it stimulates de novo TSH synthesis and also releases
TSH and prolactin. T3 directly inhibits the TRH and TSH genes, thus
regulating its own synthesis and release. TSH stimulates thyroid hormone
synthesis and release at several points. In addition, a hypothalamic pulse
regulator generates pulsatile release of TRH (Fig. 14b).
TSH belongs to a family of glycoproteins sharing common α and
specific β subunits. The α-subunit is identical for LH, FSH, TSH and placental
hCG. T3 and T4 inhibit synthesis and release of TSH.
Conversely, falling levels of T3 and T4 stimulate TSH
synthesis and release. TSH release is inhibited by other hormones and drugs,
for example dopamine, the dopamine agonist bromocriptine, glucocorticoids and
somatostatin. Hyperthyroidism will switch off TSH release altogether (Fig.
14c). Both TRH and TSH release may be impaired by hypothalamic or pituitary
lesions or tumours.
Four mechanisms affect growth and function of the thyroid:
1. Circulating
free thyroid hormones feed back at both hypothalamic and pituitary level to suppress
TRH and TSH synthesis and release respectively (Fig. 14b).
2. Deiodinase
enzymes in the pituitary modify the effects of T3 and T4.
The hypothalamic and pituitary deiodinases remove iodine from T4 to produce
the active metabolite T3. In hyperthyroidism, deiodinase activity is
down-regulated to lessen the feedback effects of circulating T4.
3. The
thyroid cell autoregulates iodination. In hypothyroidism, T3 is
preferentially synthesized. In hyperthyroidism thyroid hormone synthesis is down-regulated.
4. TSH
receptor antibodies may inhibit or stimulate thyroid function.
Actions of thyroid hormone (Fig. 14d) Calorigenesis. Homoeotherms
need to generate their own heat, and thyroid hormone does this by stimulating
mitochondrial oxygen consumption and production of ATP, which is required for
the sodium pump.
Carbohydrate and fat metabolism. Thyroid hormone has catabolic
actions. It:
1
stimulates intestinal absorption of glucose;
2
stimulates hepatic glycogenolysis;
3
stimulates insulin breakdown;
4
potentiates the glycogenolytic actions of epinephrine.
Thyroid hormone is strongly lipolytic, both through a direct action and
indirectly by potentiating the actions of other hormones, such as
glucocorticoids, glucagon, growth hormone and epinephine. Thyroid hormone also
increases oxidation of free fatty acids, which adds to the calorigenic effect.
Thyroid hormone decreases plasma cholesterol by stimulating bile acid formation
in the liver, which results in excretion in the faeces of cholesterol derivatives.
Growth and development. In humans, little T3 or T4
passes from the maternal to the fetal circulation. When the fetal thyroid is
differentiated and functional, at 10–11 weeks’ gestation, thyroid hormone
becomes essential for normal differentiation and maturation of fetal tissues,
although the hormone is not necessary for normal fetal growth. Therefore,
babies with congenital hypothyroidism have retarded brain and skeletal maturation,
but normal birth weight. In the brain, thyroid hormone causes myelinogenesis,
protein synthesis and axonal ramification. It may act, in part, by stimulating
production of nerve growth factor. Thyroid hormone is essential for normal
growth hormone (GH) production. In addition, GH is ineffective in the absence
of thyroid hormone.
Mechanism of action of thyroid hormone
At the cell membrane, T3 stimulates the Na+/K+–ATPase
pump, resulting in increased uptake of amino acids and glucose, which causes
calorigenesis. T3 combines with specific receptors on mitochondria
to generate energy and with intranuclear receptors which are transcription
modulators, resulting in altered protein synthesis. There is evidence for
different isoforms of the receptor, whose expression profiles vary with age and
tissue (Chapter 4).
