Thyroid: II Thyroid Hormone Secretion And Action
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).