Ch3 Thyroid

• The pineal gland is located in the epithalamus (dorsal diencephalon) in humans.
• The pineal gland is derived from serotonin (5-HT) and its main function is the regulation of endogenous rhythms, such as sleep and wake.
• The thyroid axis in mammals involves the synthesis of MIT, DIT, T 4 , and conversion of T 4 to T 3 and rT 3 by thyroid deiodinase enzymes, as shown in Figure 3 - 32.
• Thyroxine, precursors, and some deiodinated metabolites are shown in Figure 3 - 31.
• The pineal gland has influence on reproduction in animals through seasonal changes indicated by day length.
• The pineal gland has "anti-aging" potency, as evidenced by its effect on free radicals and immune function.
• Melatonin secretion from the pineal gland oscillates on a 24h cycle, with secretion increased during the dark phase of the diurnal cycle.
• The cycle of melatonin secretion is regulated via the rate-limiting enzyme N-acetyltransferase.
• Melatonin release is periodic.
• All cells in the body have a transcriptional clock: a 24 hour cycle.
• Neuronal MCT8 allows import of T3.
• MCT8 is one of several transporters that allow T4 to cross blood-brain barrier.
• Allan-Herndon-Dudley syndrome affects 1 in 10,000 people.
• Mutations in MCT8 cause Allan-Herndon-Dudley syndrome, a condition that causes abnormal brain development.
• MCT8 transporter is important for TH actions in the brain.
• Graves disease causes symptoms such as protruding eyes, weight loss, restlessness, heat intolerance, diarrhea, heart palpitations, and fatigue.
• Graves disease affects 3% of women and 0.5% of men.
• T4 is converted to T3 by astrocytes.
• Graves disease, also known as 2º hyperthyroidism, is an autoimmune condition where LATS immunoglobulin binds to the TSH receptor.
• The suprachiasmatic nucleus (SCN), a region of the hypothalamus, is the body’s master clock, active during the day, less active during the night, and it synchronizes clocks in other parts of the body, including the pineal gland.
• The SCN controls the pineal gland through an indirect pathway, making inhibitory connections with the PVN (also in the hypothalamus), and the PVN excites intermedial (IML) cells: preganglionic sympathetic neurons of the lateral horn of the spinal cord.
• IML neurons excite superior cervical ganglia (SCG), which are noradrenergic.
• Thyroid peroxidase (TPO) plus another enzyme called DUOX catalyzes the addition of I to the benzene ring of tyrosine, oxidizes I- to I2, and then H2O2 further oxidizes to I+, leading to the addition to the ring.
• Peripheral metabolism of THs involves deiodination, glucuronide conjugation, sulfate conjugation, ether-link cleavage, deamination, decarboxylation, and more.
• The synthesis of thyroid hormones involves the accumulation of iodide (I-) by follicular cells, the synthesis of thyroglobulin, a 660 kD dimeric protein (each subunit is 2768 aa), the oxidation of iodide to iodine radicals, the binding of iodine radicals to tyrosine residues in thyroglobulin, the coupling of iodinated tyrosines to form thyroxine, and the storage of thyroglobulin containing thyroxine in the lumen of the follicle.
• Thyroid peroxidase reaction involves the engulfing of colloid by follicular cells (endocytosis), the hydrolysis of thyroglobulin to release T4, the conversion of some T4 to T3, and the entry of T4 and T3 into the general circulation.
• Thyroglobulin is a secreted protein that is exocytosed into the follicular lumen.
• Each TG monomer has 66 tyrosine residues; around 30 of these can be iodinated.
• Only a small subset of these tyrosine residues are hormonogenic (contribute to T4 or T3).
• The metabolic actions of THs include the stimulation of development and maturation of many organs, including brain, heart, lung, and skeletal bones.
• Severe maternal hypothyroidism during pregnancy results in cretinism of the newborn.
• Organic anion transport proteins that transport thyroid hormones across the blood-brain barrier (BBB) and into neurons include Monocarboxylic acid transporter 8 (MCT8), organic anion transporting polypeptide 1C1 (OATP1C1), and large neutral amino acid transporters 1 and 2 (LAT 1 and 2).
• The thyroid axis in mammals has a biphasic effect on carbohydrate, lipid, and protein metabolism, with low levels being anabolic and high levels being catabolic.
• “Untreated congenital hypothyroidism, with or without a goiter, can cause mild to severe impairment of both physical and mental growth and development.
• Once transported across the blood-brain barrier, T 4 is deiodinated to T 3 by neighboring astrocytes and then transported into neurons by MCT8.
• Some endocrine disruptors affect the HPT axis.
• Nervous tissue development is highly sensitive to abnormal TH levels.
• Thermogenic action, or cold adaptation, involves the upregulation of basal metabolic rate (BMR) with increased oxygen consumption and glucose oxidation, and the uncoupling of oxidative phosphorylation via an increase in uncoupling protein 1 (UCP-1).
• The effects of HPT axis disorders on development can be severe, causing cretinism, mental retardation, and impaired physical and mental growth and development.
• Eye, brain, and thyroid glands are controlled by the HPT axis.