Thyroid Physiology PDF 2025

Thyroid Gland Physiology Todd Leff, PhD Department of Pathology 2025 Learning Objectives After listening to the lecture and reading the notes, you should know/understand: 1. Anatomy/...

Thyroid Gland Physiology Todd Leff, PhD Department of Pathology 2025 Learning Objectives After listening to the lecture and reading the notes, you should know/understand: 1. Anatomy/morphology of the thyroid gland 2. Thyroid hormone biosynthetic pathway 3. Hypothalamic-pituitary-thyroid axis and the regulation of thyroid hormone release 4. Molecular and cellular action of thyroid hormone 5. Physiological effects of thyroid hormone 6. Pathologies associated with thyroid dysfunction Page 1 of 13 Thyroid - LEFF Overview of the Thyroid Hormone System The thyroid hormone production is regulated by the anterior pituitary hormone TSH, which itself is regulated by the hypothalamic hormone TRH. The three components for a hypothalamic-pituitary- thyroid or HPT axis. Page 2 of 13 Thyroid - LEFF Anatomy and Histology of the Thyroid Gland Unique characteristics of the thyroid gland: palpable thyroid hormone is the only hormone that needs an essential element hormone is stored in proteinaceous substance called colloid Endocrine cells of the thyroid gland: follicular cells synthesize thyroid calcitonin synthesized by Parafollicular cells Page 3 of 13 Thyroid - LEFF Histological changes in response to stimulation by TRH Follicular cells normally have a cuboidal morphology Stimulation with TSH causes follicular cells to elongate Larger cells produce greater amounts of thyroid hormone Page 4 of 13 Thyroid - LEFF The structure of thyroid hormones The active form of the hormone is T3, which is essentially two aromatic rings (derived from tyrosine), decorated with three Iodine residues. Much of the secreted T4 is ultimately converted to T3 in circulation and in target cells The hormone is is highly hydrophobic, a property which effects multiple aspects of thyroid hormone physiology. 1. Hormone secretion: unlike most hydrophobic hormones (e.g. steroid hormones), T3 does not immediately diffuse out of the cell after synthesis. It is stored as a protein conjugate in colloidal form until needed. 2. Since the hormone is not soluble in aqueous solutions (e.g. blood) it circulated in complexes with carrier proteins. 3. Since it can pass through cellular membranes its receptor is a nuclear receptor (same family of receptors as the steroid hormone receptors) which located in the cell (as opposed to the cell surface. Page 5 of 13 Thyroid - LEFF Initial steps in thyroid hormone production Ty: tyrosine residues of thyroglobulin Iodine (Iº) formed from iodide (I-) Iodide is taken up actively into follicular cells by a sodium-iodide symporter (NIS) Iodide uptake is fueled by the energy of the Na+ electrochemical gradient and can function against a gradient of up to 250:1 The pendrin transporter, transports iodide into the lumen where thyroid peroxidase converts it to iodine and bonds it to tyrosine residues of thyroglobulin. Page 6 of 13 Thyroid - LEFF Initial steps in thyroid hormone synthesis in the lumen. 1. Iodination by thyroid peroxidase 2. Conjugation of iodinated tyrosines by thyroid peroxidase Page 7 of 13 Thyroid - LEFF Overview of thyroid hormone production and release DIT: di-iodothryonine, MIT: mono-iodothryonine The synthesis and release of T4 and T3 occurs in seven steps. Inside the follicular cell, a deiodinase converts some of the T4 to T3. TSH stimulates each of these steps except step 2. In addition, TSH exerts a growth or hyperplastic effect on the follicular cells. Secretion of hormone Colloid containing iodinated thyroglobulin is transported into follicular cells by endocytosis, where endocytic vesicles condense with lysosomes. In lysosomes, thyroglobulin is proteolytically cleaved into AAs, MIT, DIT, T3 and T4. MIT and DIT are deiodinated, and te resulting iodide and the AAs released by proteolysis of TGB are recycled into new TGB. T3 and T4 are released into circulation from vesicles near the basolateral membrane Page 8 of 13 Thyroid - LEFF Fate of secreted T4 90 µg T4 secreted per day, compared to 1-2 µg of T3 T4 circulates at 50-fold higher levels than T3 35% of secreted T4 is converted to T3, 45% is converted to reverse T3, 10% is destroyed Sources of circulating T3 80% comes from T4 conversion (T4 serves as a major circulating reserve for T3) 20% comes directly from thyroid Most thyroid hormone in circulation is bound to carrier proteins >99% of T3 and T4 are bound to plasma proteins Thyroxine binding globulin (TBG) carries 45-60% of plasma T3 and 75% of plasma T4 Thyroxine binding prealbumin (or Transthyretin) binds 15-35% plasma T4, but does not bind T3 Albumin Binds 15% of T4 and 25% of T3 0.1% of plasma T4 is free (3 ng/100 ml) 0.5% of plasma T3 is free (1.5 ng/100 ml) Protein-bound T3/T4 serves as a pool of circulating thyroid hormone Protein-bound T3/T4 has a much longer half-life than free hormone Overall half lives in plasma are 8 days for T4 and 1-2 days for T3 Page 9 of 13 Thyroid - LEFF Hypothalamic-Pituitary-Thyroid-Axis Neurons in ARN and ME secrete TRH (thyrotropin releasing hormone) TRH is released via portal veins and binds a GPCR on thyrotrophs in the anterior lobe of the pituitary. This binding activates DAG-PKC and PLC/ IP3 pathway, leading to increased protein phosphorylation and release of calcium stores. Calcium/phosphorylation triggers synthesis and release of TSH (thyrotropin). TSH stimulates follicular cells on the thyroid gland to promote synthesis and release of T3 and T4. T3 and T4 negatively feedback on thyrotrophs and TRH secreting neurons in ARN and ME. Somatostatin (released by PVN) and dopamine can create a new set-point for thyroid hormone release by inhibiting thyrotrophs. Neurons in ARN and ME secrete TRH (thyrotropin releasing hormone) TRH is released via portal veins and binds a GPCR on thyrotrophs in the anterior pituitary. This binding activates DAG-PKC and PLC/IP3 pathway, leading to increased protein phosphorylation and release of calcium stores. Calcium release and phosphorylation cascades trigger synthesis and release of TSH. TSH stimulates follicular cells on the thyroid gland to synthesize and release T3 and T4. T3 and T4 negatively feedback on thyrotrophs and TRH secreting neurons in ARN and ME. Somatostatin (released by PVN) and dopamine can create a new setpoint for thyroid hormone release by inhibiting thyrotrophs. Page 10 of 13 Thyroid - LEFF Cellular Action of Thyroid Hormone Action of thyroid hormones on target cells. Free extracellular T4 and T3 enter the target cell. Once T4 is inside the cell, a cytoplasmic 5′/3′-monodeiodinase converts much of the T4 to T3, so cytoplasmic levels of T4 and T3 are about equal. The thyroid hormone receptor (TR) is a nuclear receptor; the same superfamily of receptors as the steroid hormone receptors. TR binds to DNA at thyroid response elements in the promoter region of genes regulated by thyroid hormones. The binding of T3 or T4 to the receptor regulates the transcription of these genes. Of the total thyroid hormone bound to receptor, ~90% is T3. T3 is more biological active than T4 because more T3 is free (not protein bound), and T3 has a higher affinity for the receptor than T4. The receptor that binds to the DNA is is a heterodimer of the TR and RXR. Page 11 of 13 Thyroid - LEFF Physiological effects of Thyroid Hormone The Overall effect of T3: Increased metabolic activity Increased rate of glycogenesis and glycogenolysis, with no net change in glycogen stores (a kind of futile cycling) Increased rate of gluconeogenesis Reduced protein production Increased rates of lipogenesis and lipolysis. The balance is slightly in favor of lipolysis leading to an overall reduction in fat stores Increased rate of cholesterol synthesis and degradation, with the balance slightly in favor of degradation, leading to decreased plasma cholesterol (used to assess thyroid status) T3 is required for normal growth and development Congenital hypothyroidism causes intellectual disability T3 must be present in first 3 months of life or intellectual disability can be permanent T3 Excess during development can lead to stunted growth, premature closure of epiphyseal plates Page 12 of 13 Thyroid - LEFF Effects of T3 on the nervous system T3 deficiency in adults: listless, sleepy, weak, general decreased nervous system function T3 excess: hyper-excitable nervous system (T3 increases β-adrenergic receptors on cells Pathologies associated with the thyroid gland Simple goiter ‣ Enlarged gland, normal hormone secretion. ‣ Can be caused by iodine deficiency Hyperthyroidism ‣ Symptoms: irritability, elevated BMR, fatigue, weight loss, increased body temperature, exophthalmos, elevated activity and heart rate ‣ Causes: Graves disease (autoimmune stimulation of the TSH receptor), thyroid tumor, pituitary adenoma (elevated TSH production) Hypothyroidism ‣ Symptoms: ‣ Neonates & children: intellectual disability, reduced growth rate, ‣ Adults: sluggishness, thick and dry skin, cold sensitivity, increased sleep ‣ Causes: ‣ Developmental abnormalities of the thyroid gland ‣ Impaired sensitivity to thyroid hormone (ISTH) caused by a rare genetic mutation (usually no goiter) ‣ Reduced production of thyroid hormones caused by a defect in one of the components of the hormone production system ‣ Hashimoto's disease - autoimmune destruction of the thyroid gland Page 13 of 13 Thyroid - LEFF