Endocrinology: HPT axis (2b) Flashcards
Peripheral glands (further from the brain) include:
*Thyroid gland
*Parathyroid glands
*Adrenal glands
*Endocrine pancreas
read about: the role of parathyroids wrt calcium regulation
Thyroid gland
a discrete two lobed organ on the front of the trachea
*weighs about 20g
*Named after the greek word for shield
*Assymetrical right side bigger than left
*Larger in women than in men
*The gland is highly vascularised – so hormones can be carried in the blood stream and to take in iodine required for thyroid hormone synthesis
*Blood flow through thyroid is 4-6ml per minute per g of tissue – twice that of through the kidney
*Arranged in functional units called follicles
Epithelial cells surround a colloid filled lumen – colloid extracellular hormone storage site
Serves as extracellular storage site of hormones
*Follicles change appearance according to activity – small when active and larger when inactive due to storage
(see diagrams for thyroid histology)
Thyroid hormones
*Follicular cells produce two iodine-containing hormones derived from tyrosine (T4, T3)
*Reverse T3 is found in plasma at reasonable concentration but is biologically inactive
*C cells secrete peptide hormone calcitonin (not covered here)
*Tyrosil residues act as an acceptor for molecules for iodination
Thyroid hormone synthesis
*Basic ingredients:
- Tyrosine: Synthesised in sufficient amounts in the body
- Iodine: Obtained from dietary intake
Taken up from blood incorporated into tyrosyl residues of thyroglobulin
*Iodide pump in cells, Actively transport into colloid, needs ATP, Goes against steep conc gradient
*We can inhibit the pump using perchlorate, bromide or nitrite therapeutically to lower thyroid hormone synthesis
(see diagram)
Regulation of thyroid hormone secretion
- Controlled via HPT axis
*Thyroid gland activity is controlled by TSH from anterior pituitary
*TRH from the hypothalamus stimulates secretion of TSH from pituitary
*Thyroid hormones suppress TSH secretion by –ve feedback
*DA, SS, glucocorticoids, Oe, etc less important but have some influence on thyroid hormone secretion
Effect of TSH on follicular cells
*TSH stimulates cell metabolism, promotes a tropic response in cell size and activity
Causes increase in:
(Making and releasing)
*Transmembrane ion fluxes
*Iodination of thyroglobulin
*IC volume, number of colloid droplets, number form and activity of microvilli
*Cellular metabolism
*Protein synthesis and turnover
*Iodide influx into cell
*DNA synthesis
Metabolism of thyroid hormones
*Receptors for thyroid hormone bind T3 in preference to T4 (~10 fold)
*T4 is de-iodinated in target cells by specific deiodinases to produce T3 (40%) or reverse T3 (45%)
*Pathway is important for production of T3 in circulation
-80% T3 from peripheral deiodination
-20% T3 directly from thyroid gland
*T4 may be acting as a form of prohormone
*Serum iodothyronine concentrations remain constant from 3 days after birth, through life
-Prior to birth maternal hormone predominates
*In circulation thyroid hormones are strongly bound to serum proteins (not v. soluble)
Only 0.015% T4 and 0.33% T3 are in free solution
*3 main binding proteins
-Thyroxine binding globulin (TBG)
-Transthyretin (TTR)
-Serum albumin (relatively non- specific)
Time taken for metabolism
*Half-life of hormones relatively long
-T3 1-3 days
-T4 5-7 days
-Reverse T3 5 hours
*Total T3 present at much lower levels then T4 (about 2%)
*Preferential binding of T4 to serum proteins results in free T3 concentrations about 30% of T4
*T3 is 2 to 10x more active in the body than T4
*Amount of bound hormone can change it decreases in people with renal failure or in state of starvation and increases in pregnancy/ in women on the contraceptive pill
*Some drugs e.g. antiepileptics raise thyroid hormones a bit
Mechanism of action of thyroid hormones
*Thyroid hormones have receptors in the nucleus of target cells – like steroids can pass through membrane (lipophillic)
*Thyroid hormones are hydrophobic
-Most pass through plasma membrane by diffusion
*Some specific mitochondrial receptors exist
-Precise function unknown
-Small number of known non-genomic effects of thyroid hormones, mechanisms yet to be elucidated
Thyroid hormone receptors
*The hormone binds to receptor where it promotes formation of heterodimers or homodimers with receptors for retinoic acid
*Alternate receptors may modulate thyroid hormone activity
*The hormone receptor complex binds to DNA upstream of the regulated gene at the hormone responsive element (HRE)
*Interact with other transcription factors (repressors or activators) to regulate gene expression
Thyroid hormone function
*Widespread effects on virtually all cells in the body – general rather than tissue specific
*Main determinant of basal metabolic rate (BMR)
-Probably by increasing concentration of enzymes involved in catabolism
-Interacts with other hormones eg. T3 with catecholamines to increase heart rate and force of contraction
*Important in regulating “normal” growth and development
-Influences synthesis and degradation of carbohydrate, fat and protein (as in GH)
*Most of the effects are mediated by T3
*T4 is converted preferentially to T3 in target cells (80% T3 produced this way)
result of iodine deficiency: goitre
*Amount of iodine incorporated into thyroglobulin is directly related to amount of iodine reaching gland
*If dietary iodine insufficient little iodine incorporated into thyroglobulin
-More MIT formed
*When dietary iodine sufficient
-More DIT hence T4 formed
*Long term iodine deficiency - compensatory changes occur (less than 50 microgram per day)
-T3 secreted in preference to T4
-TSH secretion elevated to maintain circulating thyroid hormone levels
-Increased TSH induces thyroid enlargement & iodine uptake resulting in a GOITRE
A goitre is an enlarged (swollen) thyroid gland. Seen with underactive or overactive thyroid. There are various causes of goitre and treatment depends on the cause.
Normally a two month supply of T4 is stored in the thyroid, this reserve in the thyroid incase of short term iodine unavailability
Dietary iodine intake and hyperthyroidism
*Mild increases in dietary iodine intake associated with hyperthyroidism
*Iodine excess leads to inhibition of synthesis and release of thyroid hormone
Excess causes:
-Wolff-Chaikoff effect
-Adenylyl cyclase response to TSH inhibited
-Iodine incorporation into thyroglobulin is inhibited
*Paradoxical effect
*Reversed after several days but can be used therapeutically
Thyroid pathology: Hypothyroidism
What are the causes/ effects of low levels of thyroid hormones?
*Primary
- Dietary
- Autoimmune
- Hashimoto’s thyroiditis – high conc of antibodies against thyroid hormones
- Genetic errors in thyroid hormone synthesis
- Excessive iodine intake: Kelp, food supplements
- Iatrogenic: Lithium treatment for manic depression can cause low thyroid levels
- Treatment for Graves disease – overactive treatment can lead to underactivity due to damage
- surgery, iodine I^125
*Secondary
- Pituitary adenoma
- Pituitary loss due to surgery, trauma or disease
^can’t produce TSH and thyroid hormones requiring T4 treatment for life
*Tertiary
- Hypothalamic dysfunction
- Peripheral resistance to thyroid hormone
^ requiring T4 treatment for life
Treatment of hypothyroidism/ hyperthyroidism
*Hypothyroidism treated by oral administration of T4
*Dietary hypothyroidism is treated by addition of NaI to diet
*Dietary hyperthyroidism: By removal of I from diet/ body
Hyperthyroidism (excess thyroid hormone due to overactive thyroid)
*Also known as thyrotoxicosis:
Over activity of thyroid gland
Only in very rare cases is it secondary: due to over stimulation by TSH
2% women and 0.2% men suffer hyperthyroidism
*Hyperthyroidism results in an increased basal metabolic rate and increased beta-adrenergic activity
*Hyperthyroidism may be autoimmune origin (Graves disease) or non autoimmune
