endocrinology 1

study of the endocrine system, its diseases, and the hormones it secretes We will focus on the following endocrine glands in this section: • Thyroid gland • Parathyroid gland • Adrenal gland • Pituitary gland

ductless glands that secrete their products directly into the blood.

Hormones are chemical messengers released from endocrine glands into the bloodstream to act on specific target cells. • There are three major classes of hormones: • Steroid • Protein • Amine ( amino acid derivatives)

• Synthesized from cholesterol by adrenal glands, gonads, andplacenta • Lipid soluble - Need a carrier protein to circulate in blood • Not stored (released immediately) Free hormone binds to intracellular receptors forming a complex Examples: • Aldosterone • Cortisol • Estrogen, Estradiol • Progesterone • Testosterone

Synthesized as prohormones by anterior pituitary, parathyroid glands, pancreas and placenta • Water soluble - Do not need a carrier protein to circulate in blood • Stored in secretory granules (vesicles) until needed • Hormones interact with receptors on cell membrane, which activates a secondmessenger system and initiates cellular activity Examples: • FSH, LH • TSH • PTH • hCG • Insulin • Growth Hormone • Prolactin

Synthesized from amino acids( particularly tyrosine) by thyroid and adrenal glands • Some are water soluble (epinephrine) - Others require a carrier protein • Stored until needed • Epinephrine and norepinephrine interact with receptor site on cell membrane. • Thyroid hormones: free hormone interacts with intracellular receptors Examples: • Epinephrine (Adrenaline) • Norepinephrine • Thyroxine (T4) • Triiodothyronine (T3)

• Methods to determine hormone concentrations must be sensitive. - Low levels of hormones in circulation Common methods used: • Enzyme-multiplied immunoassay technique (EMIT) • Fluorescent immunoassay (FIA) • Fluorescent polarization immunoassay (FPIA) • Chemiluminescent immunoassay (CLIA) • High-performance liquid chromatography (HPLC)

Diurnal or circadian rhythms • Cortisol concentrations can be 50% lower in the evening (8 pm) versus the morning (8 am) • Other hormones showing diurnal variations: growth hormone, ACTH, TSH, PTH, catecholamines Protein-binding • Only free or unbound hormone may be biologically active Assay Specificity • The antisera in some immunoassays may cross-react with other hormones in thespecimen and cause a falsely elevated result.

Positioned in lower anterior neck and shaped like a butterfly. • Made up of two lobes that rest on each side of the trachea. • A band of tissue (isthmus) runs anterior to the trachea and bridges the lobes. • Parathyroid glands are located posterior to the thyroid and regulate serum calcium levels.

• Two types of cells are responsible for synthesizing hormones: 1 • Follicular cells synthesize thyroid hormones ( T4 & T3) 2 • Parafollicular (C cells) synthesize calcitonin • The follicle is the basic unit of the thyroid gland. • In the center of the follicle is the lacuna containing colloid. • The colloid is predominately composed of thyroglobulin (Tg). • A basal lamina is located outside the follicularcells.

By 11 weeks gestation, the thyroid gland produces thyroid hormone Congenital hypothyroidism occurs in 1 in 4,000 live births. • Mother’s thyroid hormone crosses placenta during development. • Postpartum, infant needs to be given thyroid hormone

Iodine is an essential component of thyroid hormone. • Found in seafood, dairy products, breads, vitamins • Intake of < 50 μg/day leads to hypothyroidism. (RDI = 150 μg/day) - can lead to Mental retardation, stunted growth

Follicles* • Site of thyroid hormone synthesis • Spheres of thyroid cells surrounding a fluid core called colloid* Glycoprotein thyroglobulin* is a major component of colloid. • Produced by follicular cells • Rich in tyrosine • Inside the thyroid cells, iodide is oxidized and bound with tyrosine residues on thyroglobulin to form thyroid hormone.

thyroid gland secretes the following thyroid hormones: • Thyroxine T4 • Triiodothyronine T3 • Small amounts of: Reverse T3 ( rT3 ) • Minute quantities of precursors if T3 & T4: Monoiodotyrosine MIT Diiodotyrosine DIT

• Iodide is transported into the thyroid cell by the Na+/I- symporter. • Iodide diffuses to the apical side of the cell and is transported into the colloid. • Iodide is oxidized to iodine and incorporated into tyrosine residues (MIT & DIT) within thyroglobulin molecules. 4. The enzyme thyroid peroxidase (TPO) helps combine two diiodothyronine (DIT) molecules to form tetraiodothyronine (T4) OR monoiodothyronine (MIT) and diiodothyronine to form triiodothyronine (T3). • TSH signals the follicular cell to ingest a droplet of colloid (containing thyroglobulin) by endocytosis. Droplets are digested by intracellular lysosomes into T4, T3 • Tg is degraded in a secondary lysosome, releasing T4 and T3 into circulation

Synthesis is regulated by thyroid-stimulating hormone (TSH) from the pituitary. • TSH is also known as thyrotropin • TSH stimulates: • The iodine pump • Thyroglobulin (Tg) synthesis • Colloidal uptake by follicular cells

Goiter is caused by prolonged TSH stimulation which leads to increased vascularity and eventual hypertrophic enlargement of the thyroid gland

• Thyroid Hormone • Critical in regulating body metabolism, neurologic development, and other body functions • Calcitonin • Involved in calcium homeostasis Conditions affecting thyroid hormone levels are much more common than those affecting calcitonin.

Depends on the location and number of iodine atoms • Approx. 80% of T4 is metabolized into either T3 (35%) or rT3 (45%). • T3 is 3-8 times more metabolically active than T4. Forms of Thyroid Hormone: • Triiodothyronine (T3) - main active form • Tetraiodothyronine (T4) - main form secreted - also called thyroxine • Reverse T3 (rT3) - inactive form

In the liver, T4 undergoes peripheral deiodination of the outer ring to form T3 and rT3 • This deiodination is a rapid response control mechanism for thyroid hormone balance. • Formation of rT3 is favored in acute or chronic stress or illness. • Some medications can shift the deiodination towards rT3 as well.

Only 0.04% of T4 and 0.4% of T3 are free and available for hormonal activity. Three major binding proteins: • Thyroxine-binding globulin (TBG) ** MAIN ONE • Thyroxine-binding prealbumin or thransthyretin (TTR) • Albumin

Plasma Distribution: • 97% T4 • 2% T3 • <1% rT3 • Concentrations of free hormone in plasma are low • FT4:T4 = 1:3000 • FT3:T3 = 1:300 only free form are biologically active

hypothalamic-pituitary-thyroid axis regulates thyroid hormone production. Controlled by a negative feedback loop involving: • Thyrotropin-releasing hormone (TRH) from hypothalamus • TSH from pituitary • Thyroid hormones from the follicular cells of the thyroid gland Thyrotropin-releasing hormone (TRH) • Synthesized by neurons in the hypothalamus • When secreted, stimulates cells in the anterior pituitary gland to manufacture and release thyroid-stimulating hormone (TSH). Thyroid-stimulating hormone (TSH) • Circulates to the thyroid gland and increases production and release of thyroid hormone

• Thyrotropin-releasing hormone (TRH) stimulates the production and release of TSH. • TSH stimulates the thyroid gland to synthesize and secrete thyroid hormone. • T4 that is released by the thyroid gland is converted to T3 in the liver (and kidney). • T3 & T4 feedback inhibit TSH release through action at the pituitary and by ↓TRH release from hypothalamus.