Download Endocrine System

Endocrine System
by Dr. Pi-Hsueh Li
May 1, 2013
Thyroid and Parathyroid Hormones
Introduction to thyroid gland (甲狀腺)
- The thyroid gland was the first endocrine gland to be recognized as such by those
symptoms associated with excess or deficient function.
- This recognition occurred in the mid-nineteenth century.
- The early speculation that the deficiency of an internal secretion caused the clinical state
associated with atrophy of the gland was borne out when replacement with crude
thyroid extracts became the first example of successful hormonal therapy in 1891.
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The thyroid gland is the only tissue of the body capable of accumulating iodine(碘) in great
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quantities and combine it into thyroxine(四碘甲狀腺素).
The basic unit of the thyroid gland is the thyroid follicle which consists of a hollow sphere
made up of a single layer of epithelial cells which enclose a colloid-filled space.
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Function of thyroid cells: 1) collect and transport iodine, 2) synthesize thyroglobulin(甲狀
腺球蛋白) and secrete it into the colloid(膠質), and 3) remove the thyroid hormones from
thyroglobulin and secrete them into the circulation.
Iodide trapping(誘捕)
- Iodine is a raw material essential for thyroid hormone synthesis.
- Ingested iodine is converted to iodide and absorbed.
- The thyroid concentrates iodide by actively transporting it from the circulation to the
colloid. The transport mechanism is frequently called the "iodide trapping mechanism" or
"iodide pump".
Thyroid hormone biosynthesis
- The principal hormones secreted by the thyroid are thyroxine (T4) and triiodothyronine (T3;
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三碘甲狀腺素).
T4 and T3 are synthesized in the colloid by iodination of tyrosine and condensation of
tyrosine molecules bound in peptide linkage in thyroglobulin.
- The steps in thyroid hormone biosynthesis are as follows:
- Iodide (I-) is actively taken into the cells and converted to iodine (I2) by a
peroxidase reaction at the inner surface of the cells.
- Release of free iodine causes iodination of the tyrosine molecules on the surface of
the thyroglobulin molecule, forming monoiodotyrosine (MIT) or diiodotyrosine
(DIT). These then couple spontaneously to form T4 or a small amount of T3.
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When required colloid is taken back into the cells by pinocytosis(胞飲作用), the
thyroglobulin is degraded and the thyroid hormone is released into the blood. This
degradation occurs by means of the enzymes in lysosomes(溶酶體). MIT and DIT
are also liberated by this means and are further split into iodide and tyrosine, giving
an iodine cycle.
Control of synthesis and secretion of thyroid hormones
- The primary control of thyroxine secretion is influenced by changes in the circulating level
of thyroid-stimulating hormone (TSH; 甲促素).
- TSH secretion is increased by thyrotropin-releasing hormone (TRH; 甲釋素), which is
produced in hypothalamus and released into median eminence (中隆組織) to
hypophysioportal system.
- TSH secretion is inhibited in a negative feedback fashion by free serum fraction of T4 and
T3.
- TSH secretion is also inhibited by stress, e.g. increased by cold and decreased by warmth.
Transport of thyroid hormones in blood
- Most T4 and T3 are bound in the circulation to plasma proteins which are as follows:
- thyroxine-binding globulin (TBG)
- thyroxine-binding prealbumin (TBPA)
- albumin.
- Albumin has the largest capacity to bind T4 .
- Globulin has the highest affinity for T4 .
- Most of the circulating T4 is bound to TBG.
- Bound T4 and T3 are physiologically inactive, whereas free T4 and T3 are active and able
to inhibit TSH secretion.
- Estrogen administration and pregnancy: increase TBG, decrease free T4 and T3, increase
TSH
- Overall results: total plasma thyroxine is high; free T4 and T3 are normal.
Physiological effects of thyroid hormones
- The thyroid hormones regulate the metabolism of most of the tissues, skeletal muscle, heart,
liver, kidney, but do not normally affect the lungs, gonads and accessory organs.
1. In the growing mammal
- T4 and T3 are required for brain development, normal nerve growth and bone
maturation.
- Thyroid hormone deficiency during infancy resulting from iodine shortage or
congenital thyroid insufficiency causes mental retardation in cretinism.
2. Interaction with growth hormone
- Thyroid hormones and growth hormone are synergistic (greater in total effect than
the sum of their effects).
- The hormone permits normal growth and maturation of certain tissues (particularly
brain and bone). When absent, inadequate development occurs.
3. Effect of the thyroid hormone on calorigenesis
- Enhance O2 utilization and stimulate calorigenesis in many key tissues and organs.
- Is a major contributor to the maintenance of the body temperature of homeotherms.
- In human myxedema (thyroid deficiency in the adult), this heat-regulating
mechanism is impaired.
Characteristics of thyroid malfunctions
- Effects of overproduction – hyperthyroidism(甲狀腺機能亢進)
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Graves' disease(格雷夫司氏病; 凸眼甲狀腺腫) - hyperthyroidism
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A thyroid disease originating from autoimmune(自體免疫的) disorder.
Thyroid is enlarged and hyperplastic.
Protrusion of the eyeballs.
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Patients have circulating antibodies, TSI (thyroid-stimulating immunoglobulin 甲狀腺
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刺激免疫球蛋白).
- Some TSI - against TSH receptors, inhibit thyroid function.
- Some TSI - mimic TSH action, stimulating thyroid hormone secretion.
Anti-thyroid compounds (goitrogens; 致甲狀腺腫物)
- An anti-thyroid drug may be defined as a drug which interferes with basal metabolism rate
by altering the synthesis, release, or peripheral action of the thyroid hormone.
- A classification of anti-thyroid drugs and substances can be made according to mode of
action:
- Inhibition of iodide trapping: thiocyanates (raw soybeans, cabbage), perchlorates
- Inhibition of thyroxine synthesis (iodination & coupling): thiouracil, propylthiouracil,
methylthiouracil, thiourea, methimazole
- Destruction of thyroid tissue: 131I in large dosage
- Mode of action unknown - iodide in much higher dosage than dietary requirements.
- In either case, TSH secretion is stimulated by the decline in circulating thyroid
hormones, and goiter(甲狀腺腫大) is produced.
Calcitonin(降鈣素)
- Calcitonin is a small (32 amino acid) peptide hormone produced by thyroid
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parafollicular(旁濾泡) C cells.
Calcitonin is released in response to calcium levels above normal (9.5 mg/100 ml).
Its primary effect is to block osteoclast(蝕骨細胞) mediated bone resorption(吸收)
and calcium mobilization. Calcitonin lowers the circulating calcium levels by
inhibiting bone resorption.
Parathyroid hormone (副甲狀腺素) and vitamin D (維生素 D)
- Parathyroid hormone and vitamin D together regulate calcium and phosphate. The
major targets of regulation are the gastrointestinal system (absorption), kidney
(reabsorption), and bone (deposition and resorption).
Calcium and phosphorus exchange and distribution
- Plasma calcium concentrations are normally maintained within 10 mg/100 ml. Three
sites for regulation are involved in maintaining this homeostasis.
- Regulate absorption from the small intestine.
- Regulate re-absorption from the glomerular filtrate.
- Regulate rate of exchange between body fluids and bone (bone formation and
resorption).
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Average daily intake of calcium in adult men is 1000 mg/day. Only about 100-200 mg
are retained. More than 1/2 of the ingested calcium is absorbed by the small intestine.
- The largest deposition of calcium in the body is in bone (1200 gm).
- There is not much calcium in body fluids. (99% in bone)
- Calcium exchange at the level of the bone is perhaps the most important exchange
interface for the overall regulator of plasma calcium.
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Three hormones regulate blood calcium:
- Parathyroid hormone (PTH) - secreted by parathyroid gland.
- Calcitonin - produced in the parafollicular cells of thyroid gland.
- Vitamin D.
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Phosphorus distribution is like that of calcium (i.e. most is in bone).
- The minimum requirement for phosphorus is 400 mg/day.
- The average daily ingestion is 800-900 mg/day.
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Calcium and phosphorus loss is primarily by the kidney.
- PTH increases proximal tubule reabsorption of calcium.
- A corresponding decrease in phosphorus reabsorption (also mediated by PTH)
occurs. This leads to reduced plasma phosphorus which, in turn, promotes bone
resorption.
- Only 50% of plasma calcium is in the free, ionized form and hence biologically active,
almost 85% of plasma phorphorus is in the free form. Most plasma phosphorus is
present as phosphate. As physiologic pH, phosphate exists as HPO4= and H2PO4=, for
simplicity, these ions are referred to collectively as phosphate.
Parathyroid hormone (PTH)
- PTH is released from parathyroid glands in response to a decline in circulating
calcium levels.
Regulation of parathyroid hormone (PTH) synthesis
- Secretion is regulated directly by the circulating level of calcium via a feedback mechanism.
- Increase plasma calcium, decrease PTH, calcium is deposited in bone.
- Decrease plasma calcium, increase PTH, calcium is mobilized from the bone.
Physiological actions of parathyroid hormone (PTH)
- PTH increases blood calcium and decreases blood phosphate by acting on two tissues,
bone(骨) and kidney(腎臟).
bone
- The action of PTH in stimulating bone resorption is indirect, through its action
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on osteoblasts(骨母細胞).
The production of osteoclast activating factor is stimulated by PTH.
The osteoclast activating factor acts on osteoclasts to stimulate bone matrix
resorption.
PTH also inhibits osteoblast functions and collagenase(膠原酶) biosynthesis.
kidney
- PTH acts to increase phosphate excretion and decrease calcium excretion.
- PTH may inhibit the reabsorption of phosphate and increase phosphate secretion
into the tubules, while increasing the reabsorption of calcium.
Vitamin D
- Historically, vitamin D is the name applied to two fat-soluble substances,
cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). In the following
discussion the term vitamin D is sometimes used to refer to 1,25-(OH)2D3.
Biosynthesis of 1,25-(OH)2D3
- The major starting material is cholecalciferol (Vit D3).
- Vitamin D3 is aquired in the diet or produced in the skin by UV irradiation of 7dehydrocholesterol (provitamin D3 )
- Vitamin D3 is converted in the liver to 25-(OH)2D3 which has some degree of
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biological activity (significantly less than 1,25-(OH)2D3)
- The second hydroxylation forming 1,25-(OH)2D3 occurs in the kidney. This step is
the critical one to the overall scheme of regulation and to the biological effectiveness
of vitamin D.
- The enzyme (1 -hydroxylase) is regulated by PTH.
- PTH and Vit D act together on bone to stimulate bone resorption.
Regulation of biosynthesis of 1,25-(OH)2D3
- The formation of 1,25-(OH)2D3 in the kidney is regulated by plasma calcium and
phosphate via a negative feedback mechanism.
- The formation of 1,25-(OH)2D3 is fascilitated by PTH.
Low plasma calcium --> Increase PTH secretion
- When the plasma calcium is high, the kidney produces 24,25-(OH)2D3 (inactive
metabolite) instead.
- Low plasma phosphate level --> Increase 1,25-(OH)2D3 production.
- High plasma phosphate level --> Decrease 1,25-(OH)2D3 production.
- Estrogen & prolactin
Increase renal 1 -hydroxylase activity --> Increase 1,25-(OH)2D3
production.
- Metabolic acidosis and insulin deficiency --> Decrease 1,25-(OH)2D3
production.
Physiological actions of vitamin D
- Increase serum calcium and phosphate levels by increasing gastrointestinal (GI)
calcium (and phosphate) absorption.
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The primary target organs for vitamin D in the regulation of calcium-phosphate
balance are the gut and bone. The action on the kidney are minimal.
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The intestinal mucosal epithelium contains a calcium-binding protein called calbindin
that facilitates calcium and phosphate transport from the mucosal surface to the
serosal surface. Synthesis of this transport protein is regulated by 1,25dihydroxycholecalciferol. If vitamin D is deficient, GI calcium and phosphate
absorption are impaired, which prevents normal bone mineralization.
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1,25-Dihydroxycholecalciferol synergizes with PTH on bone and therefore increases
osteoclastic activity. PTH has little effect on bone in the absence of vitamin D.
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1,25-Dihydroxycholecalciferol is essential for normal bone mineralization because it
provides for adequate GI absorption of calcium and phosphate and therefore
ultimately provides the high bone fluid calcium and phosphate concentrations
necessary for bone mineralization.
Vitamin D deficiency
- Results in impaired bone mineralization. In children this is seen as rickets(佝僂病) and in
adults it is seen as osteomalacia(軟骨病).
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Rickets (in children)
- Poor intestinal absorption of calcium leads to hypocalcemia(低血鈣), resulting in failure
of the mineralization of new bone protein. Due to:
- inadequate intake of the provitamins,
-inadequate exposure to sun,
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-failure of the kidneys to produce normal amounts of 1,25-(OH)2D3.
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