Download Physiology Ch 76 p907-918 [4-25

Physiology Ch 76 p907-918
Thyroid Metabolic Hormones
-Thyroid is the biggest endocrine gland, secreting two major hormones: thyroxine and triiodothyronine,
commonly called T4 and T3 respectively.
-These hormones act to increase metabolic rate of the body
-Lack of thyroid hormones drop basal metabolic rate to 40-50% below normal, and excess increases to
60-100% of normal
-Controlled by thyroid-stimulating hormone secreted by the anterior pituitary gland
-Thyroid also secretes calcitonin depositing Ca on bones and decreasing plasma Ca
Synthesis and Secretion of Thyroid Metabolic Hormones – 93% of thyroid hormone is thyroxine (T4)
and 7% is triiodothyronine (T3)
-almost all T4 is converted to T3 in tissues
-function is almost the same, but they differ in rapidity and intensity of action
-Triiodothyronine is 4x as potent as thyroxine, but is present in blood in smaller quantities and doesn’t
last as long
Thyroid Gland – composed of large numbers of follicles filled with colloid substance lined with cuboidal
epithelial cells that secrete into the interior of the follicles
-colloid consists mainly of thyroglobulin containing the hormones
-must be absorbed through follicular epithelium into blood for action
Iodine is required for formation of thyroxine – 50 mg ingested iodine is required in the form of iodides
each year or 1mg/week
-iodides ingested orally are absorbed from GI into blood same as chlorides
-normally most iodides get excreted by kidneys but 1/5th is removed for thyroid gland use
Iodide Pump- Na-I Symporter – first stage in formation of thyroid hormones is transport of iodide into
thyroid gland cells and follicles
-basement membrane can actively pump iodine into the cell by a sodium-iodide symporter, which cotransports iodide and two sodium ions across the basolateral membrane into the cell using ATP form a
Na+/K+ ATPase pump pumping sodium out of the cell and establishing low intracellular Na and a
gradient for Na for facilitated diffusion into cel
Iodide trapping – process for concentrating iodide inside the cell, in a normal gland the iodide pump
concentrates iodide to 30 times its concentration in the blood
-a maximally active thyroid gland concentrates to 250 times
-rate of iodide trapping influenced by TSH which stimulates it (hypophysectomy dimishes)
-Across apical membrane, iodide is transported out into the follicle by a chloride-iodide antiporter called
pendrin.
-thyroid epithelial cells secrete thyroglobulin containing tyrosine amino acids to which iodide binds
Thyroglobulin and Thyroxine and Triiodothyronine Formation –
-Endoplasmic reticulum and Golgi apparatus synthesis and secrete thyroglobulin, a large glycoprotein
into follicles. Each thyroglobulin molecule has 70% tyrosine amino acids, which combine with iodine to
form thyroid hormones
-Thyroxine and triiodothyronine hormes are formed within thyroglobulin and remain a part of it
throughout synthesis and even afterward as stored hormones in the colloid
Oxidation of Iodide Ion – first step in formation of thyroid hormone is oxidation of iodide to I0 or I3-,
which can combine directly with tyrosine
-oxidation is promoted by the enzyme peroxidase and accompanying hydrogen peroxide which provide
system for oxidizing iodides
-peroxidase is either at the apical membrane or attached to it, oxidizing iodine just as thyroglobulin is
secreted from golgi to be stored in the colloid
Iodination of Tyrosine and Formation of Thyroid Hormones – binding of iodide with thyroglobulin is
called organification of thyroglobulin
-iodine will bind tyrosines almost immediately once thyroglobulin is released through apical membrane
-Successive iodination occurs in these steps
1. Peroxidase converts Tyrosine + Iodine  Monoiodotyrosine  diiodotyrosine
2. Monoiodotyrosine + Diiodotyrosine  3,5,3’-triiodothyronine (T3)
3. diiodotyrosine + diiodotytosine  thyroxine (T4) (MAJOR PRODUCT)
-reverse T3 can be formed but is not clinically relevant
Storage of Thyroglobulin – can store large amount of hormone after synthesis
-one thyroglobulin contains up to 30 thyroxine and a few triiodothyronine molecules, sufficient to
supply body with normal requirements for 2-3 months
Release of Thyroxine and Triiodothyronine – T4 and T3 must be cleaved off of thyroglobulin before
release into bloodstream.
-apical surface of thyroid cells sends out pseudopod extensions that close around small portions of
colloid to form pinocytic vesicles that enter the cell. The vesicles fuse with lysosomes where proteolytic
enzymesdigest thyroglobulin to release T3 and T4 which diffuse through capillaries into the blood
-3/4 of iodinated tyrosine in thyroglobulin never become thyroid hormones but remain
monoiodotyrosine and diiodotyrosine
-after lysosomal digestion of thyroglobulin, these iodotyrosines are cleaved by deiodinase
enzyme that makes all iodine available again for recycline
-congenital absence of this enzyme can cause iodine deficiencies
Daily Rate of Secretion of T3 and T4 – 93% synthesized is T4 and 7% is T3, but half of T4 slowly
diodinates to T3, therefore final delivery to tissues is mainly T3, a total of 35micrograms/day
Transport of T4 and T3 to Tissues – both T4 and T3 are bound to plasma proteins, mainly thyroxinebinding globulin and a little bit thyroxine-binding prealbumin, both synthesized by the liver
T4 and T3 are Released Slowly into tissues – because of high affinity of proteins for thyroid hormones,
thyroxine in particular is slow to be released into tissues
-half of thyroxine released to tissues in every 6 days, and half triiodothyronine released every day
-in the cells, both T4 and T3 bind intracellular proteins, with T4 binding stronger and stored in target cell
Thyroid Hormones Have Slow Onset and Long Duration – if human injected with T4, no change in
metabolic rate occurs for 2-3 days, suggesting a long latent period for activity to begin
-Once began, reaches a maximum in 10-12 days, then decreases with half-life of 15 days, persists weeks
-T3 occurs 4x as rapidly as T4, with latent period of 6-12 hours and max activity at 2-3 days
Thyroid Hormones Increase Transcription – activate transcription for a large number of genes, general
functional increase of a lot of transcription
-before acting on genes to increase transcription, one iodide is removed from almost all T4, forming T3.
Intracellular thyroid hormone receptors have a high affinity for T3, so 90% of all thyroid hormone is T3
Thyroid Hormones Activate Nuclear Receptors- thyroid hormone receptors attached to DNA strands or
next to them.
-receptor is usually a heterodimer with the retinoid X receptor (RXR) at specific thyroid hormone
response elements on DNA. When T3/T4 is bound, receptors activate transcription to form a lot of RNA
and followed by a lot of translation
-Not all proteins increased as much as RNA, some slightly, some 6-fold.
-Thyroid hormones can also have non-genomic effect on cells without affecting transcription, such as in
heart and pituitary, where they regulate ion channels and oxidative phosphorylation, and appear to
regulate activation of intracellular second messengers such as cAMP or protein kinases
Thyroid Hormones Increase Cellular Metabolic Activity – increase metabolic activities of almost all
tissues in body up to 60-100% above normal
-rate of utilization of foods is increased, protein synthesis increased, protein catabolism increased,
growth rate of young people is increased, mental processes excited, endocrine glands more active
-increases growth, CNS development, cardiac output, blood flow, heart rate, heart strength,
respiration, mitochondria, Na-K-ATPase, O2 consumption, glucose absorption, gluconeogenesis,
glycogenolysis, lipolysis, protein synthesis, BMR
Thyroid Hormones Increase # of Mitochondria – T3 and T4 stimulation increases the number and size of
mitochondria in the animal (total membrane surface increases), which would increase ATP formation,
though could be as a result of increased activity of cells and not T3/T4 stimulation
Thyroid Hormones Increase Active Transport of Ions – Na-K-ATPase activity increases with thyroid
hormone stimulation, which increases rate of transport of Na and K through membranes
-uses energy and increases body heat, this may be one mechanism by which thyroid hormone regulates
body’s metabolic rate
-T3 and T4 cause cell membranes to become leaky, causing influx of Na and activating pump to increase
heat production
Effect of Thyroid Hormone on Growth – manifests mainly in growing children; in those that are
hypothyroid, growth is retarded, and in hyperthyroid, growth is excessive.
-in hyperthyroid conditions, bones mature more rapidly and epiphyses close earlier, so duration of
growth is shortened
-Thyroid hormone promotes growth and development of the brain in fetal life and first few years,
because deficiency causes brain growth retardation and can cause mental deficiency if not treated
Effect of Thyroid Hormone on Specific Body Mechanisms
1. Stimulation of Carb Metabolism – rapid uptake of glucose by cells, enhanced glycolysis,
gluconeogenesis, increased GI absorption rate, increased insulin secretion
2. Stimulation of Fat Metabolism – all fat metabolic processes are increased, lipids mobilized rapidly
from fat tissue, decreases fat stores. Increases free fatty acid conc. In plasma and increases
oxidation of fatty acids by cells
3. Effect on Plasma and Liver Cells – increased thyroid hormone DECREASES concentration of
cholesterol, phospholipids, and triglycerides in the plasma and INCREASES free fatty acids
-DECREASED thyroid secretion INCREASES plasma cholesterol, phospholipids and triglycerides
-Hypothyroidism deposits fats on liver and can cause severe atherosclerosis
-Decreases cholesterol by increasing rate of cholesterol secretion in bile and loss in feces
-TH induces increased numbers of LDL receptors on liver, leading to LDL removal from blood
4. Increased Requirement for Vitamins – increase in enzyme quantity by thyroid hormone
necessitates increased vitamin requirement since vitamins are used as cofactors for many enzymes.
Relative vitamin deficiency can occur when excess thyroid hormone is secreted
5. Increased Basal Metabolic Rate – since thyroid hormone increases metabolism in all cells, excessive
hormone can increase basal metabolic rate 60-100% above normal. Can fall to 50% below normal if
no thyroid hormone is produced
6. Decreased Body Weight – increase thyroid hormone = decrease body weight and vice versa. Do not
always occur because thyroid hormone increases appetite and can counterbalance weight loss
7. Increased Blood Flow and Cardiac Output- more rapid utilization of oxygen than normal due to
metabolic demand causes vasodilation to increase blood flow
a. Blood flow around skin increases a lot to make up for heat expulsion
8. Increased Heart Rate – heart rate increases considerably under direct influence of thyroid hormone,
one of physical signs a physician uses to determine excessive or diminished thyroid production
9. Increased heart Strength – increased enzymatic activity caused by increased thyroid hormone
increases the strength of the heart when only slight excess of TH is secreted
a. If thyroid hormone dramatically increases, heart strength decreases due to increasing
protein catabolism
b. Severely thyrotoxic patients die of cardiac decompensation secondary to myocardial failure
10. Normal Arterial Pressure – mean arterial pressure remains normal, pulse is increased with systolic
pressure elevated in hyperthyroidism 10-15mmHg and diastolic pressure reduced
11. Increased Respiration – increased need for oxygen and large formation of CO2 activate mechanisms
that increase rate and depth of respiration
12. Increased GI motility – in addition to increased appetite and food intake, TH increases rates of
digestive secretions and motility of GI tract: Hyperthyroidism leads to diarrhea, hypo=constipation
13. Effects on CNS – thyroid hormone increases rapidity of cerebration but also often dissociates this.
Hyperthyroid individuals can have extreme nervousness and many psychoneurotic tendencies.
14. Effects on Muscles – slight increase in TH can make muscles react violently, but excess TH weakens
muscle due to protein catabolism
15. Muscle tremor – fine muscle tremor is characteristic of hyperthyroidism, can be observed by placing
sheet of paper on finger and noting degree of vibration
a. Caused by neuronal synapses in spinal cord controlling muscle tone
16. Effect on Sleep – Hyperthyroid subject has constant tiredness due to exhausting effect of thyroid
hormone on musculature, CNS, and metabolism. It is, however, difficult to sleep due to excitement
of synapses. Extreme somnolence characteristic of hypothyroidism
17. Effect on Other Endocrine Glands – increased thyroid hormone increases rates of secretions of
other endocrine glands and also increases need of tissues for hormones
a. increased T4 increases glucose metabolism everywhere in body, but also increased insulin
secretion by pancreas
b. increases rate at which adrenal glucocorticoids are inactivated by liver, feedback increase in
ACTH production in anterior pituitary and more glucocorticoid secretion by adrenal glands
18. Effect of Thyroid Hormone on Sexual Function – normal thyroid function is required for sexual
function. Hypothyroid = loss of libido in men, hyperthyroid = impotence. In women, lack of thyroid
hormone causes menorrhagia and polymenorrhea – menstrual bleeding
a. in other women, amenorrhea may occur and cause irregular periods
Regulation of Thyroid Hormone Secretion – TSH is an anterior pituitary hormone increases rate of
secretion of T3 and T4 in the following mechanisms
1. Increases proteolysis of thyroglobulin stored in follicles (MOST IMPORTANT)
2. Increases activity of iodide pump
3. Increases iodination of tyrosine
4. Increases size and secretory activity of thyroid cells
5. Increases number of thyroid cells plus change from cuboidal to columnar
cAMP Mediates Stimulatory Effect of TSH – most effects of TSH happen through the cAMP second
messenger system.
-TSH binds TSH receptors on thyroid cell, activates adenylyl cyclase which forms cAMP inside cell to act
as a second messenger and activate protein kinase for multiple phosphorylations
Anterior Pituitary Secretion of TSH is Regulated by Thyrotropin-Releasing Hormone from Hypothalmus
-TSH release controlled by thyrotropin-releasing hormone (TRH) from hypothalamus.
-From median eminence of hypothalamus, TRH transported to ant. pituitary by way of hypothalamichypophysial portal blood.
-TRH is a tripeptide amide, a pyroglytamyl-histidyl-proline-amide. Directly affects anterior pituitary to
increase output of TSH
-If blood portal system between hypothalamus and pituitary is blocked, TSH release diminishes but not 0
-TRH binds TRH receptors in anterior pituitary to activate phospholipase C production followed by
cascare of other second messengers including Ca ions and DAG which leads to TSH release
Effects of Cold and Other Neurogenic Stimuli on TRH and TSH – exposure to cold temperatures is best
stimuli for increasing rate of TRH secretion of hypothalamus and therefore increasing TSH secretion.
-exposure of rats for several weeks to severe cold increases output of thyroid hormones to more than
100% of normal and increases basal metabolic rate by 50%
Emotional Reactions can affect TRH and TSH and indirectly affect thyroid hormones, such as excitement
or anxiety that stimulate sympathetic nervous system, can acutely decrease TSH because these states
increase metabolic rate and decreasing TSH would have the inverse effect
-neither cold nor emotional responses are present if hypophysial stalk is cut
Feedback Effect of Thyroid Hormone to Decrease Anterior Pituitary Secretion of TSH – increased
thyroid hormone decreases TSH by anterior pituitary
-when rate of TH secretion is 1.75 times normal, TSH secretion goes down to 0
Antithyroid Substances Suppress Thyroid Secretion – thiocyanate, propylthiouracil, and high
concentrations of inorganic iodides
1. Thiocyanate Ions – same ion pump for iodide ions also pumps thiocyanate, which competitively
inhibits iodide transport (inhibiting iodide-trapping). Does not stop thyroglobulin production,
just its iodization.
a. Increases TSH secretion since there is no feedback, enlarges thyroid gland (goiter)
2. Propylthiouracil – decreases thyroid hormone function by preventing formation of thyroid
hormone from iodide and tyrosine, blocks peroxidase enzyme that is required for iodination of
tyrosine.
a. increases TSH secretion causing thyroid enlargement and Goiter
3. Iodides in High Conc. Decreases Thyroid Activity – at 100x normal conc. Iodides decrease
activity of thyroid gland in order to reduce trapping so that the rate of iodination of tyrosine to
form thyroid hormones decreases
a. normal endocytosis of colloid from follicles paralyzed by high conc. Iodides
b. Decrease in thyroid gland size
Hyperthyroidism – thyroid gland is increased 2-3x normal size in hyperthyroidism, and all cells increase
rate of secretion 5-15x normal
-Graves’ Disease- most common form of hyperthyroidism (autoimmune disease) where antibodies
called thyroid-stimulating immunoglobulin (TSIs) form against TSH receptor to cause continual activation
of cAMP to cause hyperthyroidism. The thyroid hormone suppresses TSH release from anterior
pituitary, so that the patient’s TSH levels are less than normal
Thyroid Adenoma – hyperthyroidism can occur due to a tumor that develops on thyroid and secretes
large quantities of thyroid hormone. As long as tumor is present, rest of thyroid is totally inhibited due
to negative feedback from anterior pituitary
Symptoms of Hyperthyroidism – high excitability, heat intolerance, sweating, weight loss, diarrhea,
muscle weakness, nervousness, fatigue but can’t sleep, hand tremors
Exophthalmos – protrusion of eyeballs seen with hyperthyroidism, can damage vision, autoimmune
Diagnostic Tests for Hyperthyroidism – direct measurement of free thyroxine in plasma using
radioimmunoassay. Other tests include: basal metabolic rate increased, TSH in plasma measured
(suppressed), TSI is measured
Treatment of Hyperthyroidism – surgical removal of most of gland, or administration of radioactive
iodine to destroy secretory cells of thyroid
Hypothyroidism – Opposite of hyperthyroidism, often initiated by autoimmunity against thyroid
(hashimoto disease) but immunity that destroys it rather than stimulates it.
-patients have thyroiditis which deteriorates the tissue and causes fibrosis, decreasing T3+T4
Endemic Colloid Goiter Caused by Iodide Deficiency – Goiter means enlarged thyroid, and if you have
an iodine deficiency in diet, it can cause endemic goiters. Lack of iodine stops production of T3 and T4,
no hormone is available to inhibit TSH by anterior pituitary which causes it to constitutively secrete TSH,
which stimulate thyroid to make excessive thyroglobulin colloid, gland grows really large but does not
secrete thyroid hormones.
Idiopathic Nontoxic Colloid Goiter – Enlarged thyroid goiter can occur in non-iodine deficient patients,
where thyroid hormone is secreted normally but the amount is depressed. Cause is not known, but
patients can show thyroiditis, which leads to increased TSH and growth of noninflamed portions of
thyroid
-in some people with goiter, thyroid has abnormality of enzyme system required for formation of T3+T4
1. Deficient iodide-trapping mechanism
2. Deficient peroxidase system
3. Deficient coupling of iodinated tyrosines
4. Deficiency of deiodinase enzyme
-some foods can also contain goitrogenic substances that have propylthiouracil type of antithyroid
activity to block formation of thyroid hormones
Physical Characteristics of Hypothyroidism – fatigue and extreme somnolence with heavy sleeping,
extreme muscular sluggishness, slowed heart rate, decreased cardiac output, decreased blood volume,
increased body weight, constipation, mental sluggishness, myxedema
Myxedema – develops in patient with lack of thyroid hormone, demonstrating bagginess under eyes
and swelling of face
-large quantities of hyaluronic acid and chondroitin sulfate bound with protein form excessive tissue gel
on interstitial spaces causing total amount of interstitial fluid to increase
Atherosclerosis – lack of thyroid hormone increases blood cholesterol because altered fat and
cholesterol metabolism in liver diminishes, can cause atherosclerosis
Diagnostic Tests in Hypothyroidism – same tests described for hyperthyroidism result in opposite
findings in hypothyroidism
Treatment of Hypothyroidism – Easy to maintain steady level of thyroid hormone activity in body by
oral administration of tablet containing thyroxine
Cretinism – caused by extreme hypothyroidism during fetal life, infancy or childhood.
-Characterized by failure of body growth and mental retardation
-Results from congenital lack of thyroid gland, failure of thyroid gland to produce thyroid hormone due
to genetic defect, or lack of iodine in diet
-Baby can be normal if mother ingests iodine, but after birth, baby’s movements become sluggish and
both physical and mental growth begin to be retarded
-Treatment involves adequate iodine or thyroxine can cause return of physical growth but not mental
growth unless treated at birth
-Children tend to be short, abnormal skeletal development, obese, stocky, tongue becomes large and
can obstruct swallowing and breathing