Thyroid and Parathyroid Function
PHTY 615
Introduction
• Hormones secreted from the thyroid gland involved in controlling
metabolism
– Also work synergistically with other hormones to promote normal growth and
development
• Parathyroid glands essential in regulating calcium homeostasis and are
important in maintaining proper bone mineralization
• Problems with thyroid and parathyroid glands often treated by
pharmacologic methods
Function of the Thyroid Gland
• Gland on either side of the trachea in the anterior neck
– Bilateral lobes connected by a central isthmus
– Rich vascular supply and extensive nerve supply from the sympathetic
NS
• Thyroid gland synthesizes thyroxine and triiodothyroxine
Normal Thyroid Gland
Synthesis of Thyroid Hormones
• First step is adding iodine to the residues of AA tyrosine
• 2 iodinated tyrosines combine to create thyroid hormones
– Monoiodotyronsine + Diiodotyrsine = Triiodotyronsine (T3)
– Diiodotyronsine + Diiodotyrsine = Thyroxine (T4)
• Plasma levels of T4 much higher than T3 but:
– T3 may exert most of physiologic effects
– T4 may be precursor to T3
• T3 converted to T4 in peripheral tissue
– Both T4 and T3 required for normal physiologic function
Iodine uptake
• + -
Na /I symport protein controls serum I- uptake
• Based on Na+/K+ antiport potential
• Stimulated by TSH
• Inhibited by Perchlorate
Synthesis of Thyroid Hormones
• Thyroid follicle cells take up and concentrate iodide in the bloodstream
– Must be a sufficient amount of iodine in the diet to provide iodide needed for
thyroid hormone function
• Thyroid cells also make protein called thyroglobulin (TGB)
– 2 iodinated tyrosine residues combine with TGB to make T4 and smaller amounts
of T3
– TGB lysed from the iodinated tyrosines before released into the bloodstream
Regulation of Thyroid Hormone Release
• Controlled by hypothalamic-pituitary system
• Thyrotropin-releasing hormone (TRS) from hypothalamus
stimulates release of thyroid-stimulating hormone (TSH) from
the anterior pituitary
• TSH stimulates release of T3 and T4
• Negative feedback system controls TSH release from the
anterior pituitary gland
Thyroid Hormone Control
Control of T3 and T4 Release
Under normal conditions, decreases in T3/T4 cause TRH release from the hypothalamus (HPT) which
then causes TSH release from the pituitary (PIT).
TSH then stimulates:
1) T3/T4 synthesis and secretion
2) thyroid gland growth.
When T3/T4 levels increase, negative feedback shuts off TRH and TSH secretion.
Physiologic Effects of Thyroid Hormone
• Affect wide variety of peripheral tissue
• T4 and T3 may act directly on cell or facilitate function of other hormones
• Thermogenesis
– T4 and T3 increase basal metabolic rate and subsequent heat production
– Important in maintaining adequate body temperature during exposure to the cold
– Increase in thermogenesis achieved by thyroid hormone stimulating various
tissues
• Skeletal mm, cardiac mm, liver, kidneys
Physiologic Effects of Thyroid Hormone
• Growth and development
– Thyroid hormones facilitate normal growth and development
• Stimulate release of growth hormone and enhances its effect on peripheral tissue
– Thyroid hormones directly enhance development of many physiologic systems
• Especially skeletal mm and CNS
– When thyroid hormones not present:
• Severe growth restriction and mental retardation ensues
Physiologic Effects of Thyroid Hormone
• Cardiovascular effects
– Thyroid hormones increase heart rate and myocardial contractility
• Increase cardiac output
– Unclear how thyroid hormones increase myocardial sensitivity to other hormones
• Norepinephrine and Epinephrine
• Metabolic effects
– Increase intestinal glucose absorption
– Increase activity of several enzymes involved in carbohydrate metabolism
– Enhances lypolysis by increasing response of fat cells to other lypolytic hormones
Mechanism of Action of Thyroid Hormones
• Thyroid hormones enter the cell and bind to specific receptors in the cell
nucleus
– Thyroid hormone receptors act as DNA transcription factors that bind to specific
DNA sequences that regulate gene expression
– Alter protein synthesis in the cell
• Most if not all of thyroid hormone effects are secondary to altered protein
production
– Proteins may increase transport of specific substances across cell membrane or
new protein may be directly involved in metabolic pathway
Treatment of Thyroid Disorders
• Two primary categories
– Hyper and Hypothyroidism
• Several subtypes
– Hyperthyroidism
• Primary: Graves disease, thyroid adenoma
• Secondary: Induced by excessive hypothalamic or pituitary stimulation
– Hypothyroidism
• Primary: Genetic deficiency of enzymes that synthesize thyroid hormones
• Secondary: Hypothalamic or pituitary deficiencies, Cretinism (childhood hypothyroidism),
Myxedema (Adult hypothyroidism)
Hypothyroidism and its Treatment:
Hypothyroidism and its Treatment:
When the pituitary can't make TSH there is no signal to the thyroid gland to make T3/T4. Thus secondary
hypothyroidism is (i.e. pituitary- mediated) associated with decreased T3/T3 AND TSH and thyroid
atrophy.
Clinical Manifestations
• Hyperthyroidism
– Nervousness
– Weight loss
– Diarrhea
– Tachycardia
– Insomnia
– Increased appetite
– Heat intolerance
– Wasting
– Goiter
– Anorexia
• Hypothyroidism
– Lethargy/slow cerebration
– Weight gain
– Constipation
– Bradycardia
– Sleepiness
– Cold Intolerance
– Weakness
– Dry, course skin
– Facial edema
Hyper- thyroidism Features:
Hypo- thyroidism
Myxedema
Features:
Hyperthyroidism
• Thyrotoxicosis:
– Increased secretion of thyroid hormones
– Usually enlarged thyroid gland
• Toxic goiter = Graves disease
• Thought to be immune system problem
• Treatment
– Ablation of the thyroid gland
• Surgical removal or administration of radioactive iodine
Antithyroid Agents
• Directly inhibit thyroid hormone synthesis
• Propylthiouracil (Propyl-Thyracil), Methimazole (Tapazole)
• Drugs inhibit thyroid peroxidase enzyme needed to prepare iodide for
addition to tyrosine
• Also prevent coupling of tyrosine residues to thyroglobulin molecule
– Propylthiouracel also blocks conversion of T4 to T3 in peripheral tissue
• Adverse effects
– Skin rash and itching (mild)
– High doses may cause symptoms associated with hypothyroidism
Iodide
• Large doses of iodide (>6mg/day) causes a rapid decrease in thyroid
function
• In sufficient amounts, iodide inhibits virtually all steps involved in thyroid
hormone biosynthesis
– High iodide levels limit uptake of iodide into thyroid follicle cells, inhibits formation
of T4 and T3, and decreases secretion of completed hormones
• Effect of Iodide lasts ~2 weeks
– Iodide used temporarily for individuals awaiting thyroidectomy
Radioactive Iodine
• Selectively destroys thyroid tissue in Graves disease
• Radioactive iodine administered orally and rapidly sequestered
in thyroid gland
• Begins to emit beta radiation destroying thyroid follicle cells
• Patients must subsequently take thyroid hormone supplements
Beta-Adrenergic Blockers
• Adjunctive treatment to thyrotoxicosis
• BB do not lower thyroid hormone levels
• BB help suppress symptoms such as tachycardia, palpitations, fever,
restlessness
• BB may be helpful in severe, acute, exacerbations of thyrotoxicosis
• BB also administered preoperatively to control symptoms
• Acebutolol, atenolol, metoprolol, nadolol, propanolol, timolol
Hypothyroidism
• Many causes
– Idiopathic, autonomic, lymphocytic destruction, congenital impairment,
low dietary iodine intake, genetic
– Goiter may also occur but for different reasons
• Decrease dietary iodine
– TSH stimulates production of thyroglobulin
– Thyroid hormone incomplete
– No negative feedback and thyroglobulin production continues
– Primary treatment
• Thyroid hormone replacement therapy
Thyroid Hormones
• Natural or synthetic analogs necessary in most forms of hypothyroidism
• Administration of thyroid hormones especially important in infants and
children
– Adequate amounts needed for normal physical and mental development
• Thyroid hormone replacement is likewise necessary following
thyroidectomy or pharmacological ablation
• Thyroid hormone maintenance may be beneficial for patients in
preliminary or subclinical phase of hypothyroidism
– May prevent full blown hypothyroidism
• Main side effect is symptoms of hyperthyroidism
Hypothyroidism: Treatments
-Sodium levothyroxine (Synthroid®-T4)
-Sodium liothyronine (Cytomel®-T3)
-4-times as potent as T4, more rapid onset of action,
same efficacy
Parathyroid Gland Anatomy
• Four Parathyroid glands are usually found posterior to the thyroid gland
• Total weight of parathyroid tissue is about 150mg
• Parathyroid hormone (PTH) is made by these glands
Function of the Parathyroid Glands
• Parathyroid hormone (PTH)
– Polypeptide synthesized within cells of parathyroid glands
• Calcium concentration in bloodstream controls PTH release
• Decrease in CA2+ concentration increases PTH release and increased
CA2+ concentration decreases PTH release
• PTH increases blood CA2+ level by altering CA2+ metabolism in bone,
kidneys, and GI tract
Function of the Parathyroid Glands
• PTH increases bone resorption, liberating CA2+
– Enhances development and action of osteoclasts
• PTH increases renal resorption of CA2+
• PTH lastly increases absorption of CA2+ in the GI tract
– Caused by interaction between PTH and Vitamin D metabolism
– PTH increases conversion of Vitamin D to calcitriol
– Calcitriol stimulates CA2+ absorption from the GI tract
• PTH crucial in maintaining adequate levels of calcium in the body
• PTH works with Calcitonin and Vitamin D in regulating CA2+
homeostasis
Regulation of Bone Mineral Homeostasis
• Bone
– Provides rigid framework for body and readily available and easily interchangeable
CA2+ pool
– Balance between bone formation and resorption important
– CA2+ and phosphate needed for bone to maintain rigidity
– Excessive resorption of these minerals result in bone demineralization
• Bone at increased risk for failure (fracture)
– Balance between bone resorption and formation controlled by complex interaction
between local and systemic factors
– Several hormones regulate bone formation and help maintain adequate calcium
levels
Parathyroid Hormone
• Discussed previously
– Increase in PTH = Increase in blood CA2+ levels
– High PTH levels accelerates bone breakdown
– Low-Normal PTH levels may enhance bone formation
• May have implications for treatment of osteoporosis
Vitamin D
• Steroid like hormone from dietary sources or synthesized in skin from cholesterol
derivatives in the presence of ultraviolet light
• Vitamin D produces several metabolites important in bone mineral homeostasis
• Vitamin D derivatives such as 1,25 Dihydroxyvitamin D3 increases serum CA2+ and
phosphate levels by increasing CA2+ and phosphate absorption in GI tract and
decreases renal CA2+ and phosphate excretion
• Overall effect of Vitamin D is to enhance bone formation by increasing levels of
primary minerals (CA2+ and phosphate)
• Also suppresses synthesis and release of PTH
Synthesis, Release & Activity of Active Vitamin
D
• Vitamin D3 is may be obtained from the diet or made in the skin
• It is converted to the active form (1,25-OH-D3 by sequential enzymatic reactions in
the liver and kidney (stimulated by PTH)
• Vitamin D3 stimulates intestinal calcium uptake, increased bone calcium resorption &
increased kidney phosphate uptake
Calcitonin
• Secreted by cells located in the thyroid gland (C cells)
– Calcitonin is physiologic antagonist of PTH
• Calcitonin lowers blood calcium and stimulates bone formation
– Increases incorporation of CA2+ into skeletal storage
• Renal excretion of CA2+ also increased by Calcitonin effect on the
kidney
• Effect of Calcitonin on bone mineral metabolism relatively minor
• Calcitonin does have important therapeutic function
– Pharmacological doses may be helpful in preventing bone less
Calcium Metabolism:
Hormonal Regulation of Calcium and Phosphate Balance
• Decreased Plasma Calcium Causes:
• Increased PTH
• Resulting in mobilization of bone Ca & phosphate, increased renal phosphate excretion & Ca retention
and increased Vitamin D3 synthesis
• The outcome is a rise in plasma Ca levels & maintenance of normal phosphate levels
Summary
• PTH & calcitonin release are regulated by plasma Ca levels
• Bone Ca & phosphate serve as a ready reserve for
maintenance of plasma levels
• Bone, kidney & intestine participate in the regulation of plasma
calcium
• PTH, Vitamin D, & calcitonin balance plasma [Ca++] for bone
synthesis, muscle contraction, & cell signaling
• Endocrine diseases result from pathway or glandular hypo or
hyper secretion
Pharmacological Control of Bone Mineral
Homeostasis
• Blood CA2+ levels must be maintained within fairly limited range to
ensure adequate supply of calcium for various physiologic functions
– Normal range = 8.6-10.6 mg/100 ml
• Plasma levels 12 mg/100 ml depresses nervous system function
– Sluggish, lethargy, possible coma
Pharmacological Control of Bone Mineral
Homeostasis
• Chronic disturbances in CA2+ homeostasis can also produce problems
with bone calcification
• Various metabolic diseases can alter blood CA2+ levels leading to hypo
or hypercalcemia
• Pharmacological methods used to help control bone mineral levels in the
bloodstream and maintain adequate bone mineralization
Calcium Supplements
• Administered to ensure adequate calcium levels in the bloodstream
• Calcium supplements used to help prevent bone loss in conditions such as osteoporosis
– Can’t prevent osteoporosis alone but helpful when combined with other treatments such as
estrogen replacement
• Dose of calcium supplement should make up the difference between dietary calcium intake and
established guidelines
– Amount depends on amount to dietary calcium, age, gender, hormonal and reproductive status
• Excessive doses must be avoided to prevent hypercalcemia
– Constipation, drowsiness, fatigue, headache
– More pronounced: Confusion, irritability, cardiac arrhythmias, hypertension, nausea, vomiting,
muscle and bone pain
Vitamin D
• Precursor for other compounds that increase intestinal absorption and
decrease renal excretion of CA2+ and phosphate
• Used to increase blood CA2+ and phosphate levels and enhance bone
mineralization
• Vitamin D analogs such as calcitriol combined with CA2+ supplement to
help treat:
– Postmenopausal osteoporosis
– Bone loss with antiinflammatory steroids
Vitamin D
• Vitamin D is fat soluble
– Excessive doses can accumulate in body and lead to toxicity
• Early signs = headache, increased thirst, decreased appetite, metallic taste,
fatigue, GI disturbance
• Increased toxicity = Hypercalcemia, HTN, cardiac arrhythmias, renal failure,
mood changes, seizures
Bisphosphonates
• Inorganic compounds that appear to adsorb directly to CA2+ crystals in
the bone and decrease bone resorption
– Inhibits osteoclast activity
• Bisphosphonates often used in Pagets disease
– Help prevent excessive bone turnover and promote adequate mineralization
• Used to inhibit abnormal bone formation
– Heterotopic ossification
Bisphosphonates
• Treatment of choice for prevention and treatment of bone loss
during prolonged administration of antiinflammatory steroids
• Used in postmenopausal women
• Adverse effects
– Tenderness and pain over site of bony lesions in Pagets disease
– Fracture risk with excessive doses
– GI disturbances
Calcitonin
• Derived from synthetic sources to mimic effects of endogenous hormone
• Promotes bone mineralization
• Used to treat hypercalcemia and decrease bone resorption in Pagets
disease
• Used in postmenopausal and glucocorticoid-induced osteoporosis
• Aerosolized versions of Calcitonin now available
– Oral delivery difficult because absorbed poorly from the GI tract
Estrogen Therapy
• Critical in maintaining adequate bone mineralization in women
• Used with other adjunct treatments
– Calcium supplement, Calcitonin, Calcitriol, Bisphosphonates
• May increase risk of breast and uterine cancer
• Selective Estrogen Receptor Modulators (SERMS)
– Activates receptors in certain tissues and blocks effect in others
– Primary SERM used to prevent osteoporosis is Reloxifene (Evista)
• Binds to and activates estrogen receptors in bone
– Prevents bone loss and demineralization
• Reloxifene blocks estrogen receptors on breast and uterine tissue
Special Concerns for Rehabilitation Patients
• PTs need to be concerned with side effects of different drugs
• Thyroid disorders
– Excessive doses can cause opposite disorder
• Bone disorders
– Hypercalcemia can be detected by ECG
• Can prevent life threatening disorder
• Exercise
– Helps to stimulate bone formation