Lecture 16: Importance of Thyroid and Adrenal Hormones Flashcards
What is unique about thyroid hormones?
-Almost all cells have receptors except brain and heart
What is the thyroid gland?
-Located on both sides of the trachea, below the larynx
-2 lobes bridged by isthmus (a narrow passage ie trachea/esophagus)
-Heavily vascularized, it is the heaviest of pure endocrine glands (right by carotid)
-Composed of numerous follicles:
-Single layer of epithelial cells that release thyroid hormones
-Lumen filled with protein rich fluid (colloid)
-Between follicles, parafollicular cells (C-cells) secrete calcitonin
What is the synthesis of thyroid hormones?
- active uptake of iodine
-Iodine circulates I blood as iodide
-Actively transported through follicular cells (I/Na symport)
-Diffuses and accumulates in colloid as iodine (I2) - Iodination of thyroglobin (Tgb):
-Tgb, a glycoprotein with over 120 tyrosine residues, is released in the lumen
-Tyrosine peroxidase (TPO) binds I2 to tyrosine residues
-In colloid 10% of Tgb is iodinated
-Each tyrosine residue can be iodinated on possibly 2 sites: - I2 tyrosine= momoidodotyrosine
- I2 tyrosine= diiodotyrosine
- Tgb- I2 up-taken by endocytosis from colloid into cells, fused to lysosomes and split into third hormones
What happens after cleavage in follicular cell?
-When 2 diiodothyrosines are cleaved = tetraiodothronine or thyroxine (T4)
- 1 moniodityrosine + 1 diiodotyrosine = Triiodothyronine (T3)
-T3 and T4 represent 10 and 90% of thyroid hormones, respectively
-Lipophilic hormones –> diffuse across basal membrane into interstitial space then into blood capillaries
-In blood, binds to plasma proteins (carriers, TBG)
What is the difference between T3 and T4?
T4: inactive form, majority synthesized, need to be donated to become T3
T3: active form only about 10% of thyroid hormones, converted to T3 from T4 when the body needs it
What is the transport of thyroid hormone?
-TBG (thyroid binding globin) binds 70-80% of circulating thyroid hormones
-Remaining bound to other albumins
-Only 0.03% of T3 and T4 are free in blood and diffuse to tissues (only free hormone is active) thus there is several days of hormone available bound to TBG (small amount able to enter cell that is not bound to a carrier)
What are the actions of thyroid hormones?
-Main action os to increase basal metabolic rate by consuming O2 and glucose by:
-After diffusing in target cells, T4 is deiodinated to T3 (active form), binds to its nuclear receptor and actives gene transcription
-Affinity of receptor is higher for T3 than T4 (T4 5x more active)
-Thyroid hormones act on all cells of the body to increase basal metabolic rate, which will increase heat production and O2 consumption
-Areas where this doesn’t occur is the brain (doesn’t have storage), gonads (need specific temp for testes) and spleen
-During development thyroid hormones stimulate secretion of GH which is important for bone growth and tissue growth
-During the last phase of fetal development and early stage after birth, torpid hormones are caritas for normal maturation of brain function (lack of TH leads to cognitive problems)
-Thyroid hormones increase the number of adrenalin/noradrenalin receptors which boost sensitivity to Sympathetic system (reason why issues with hyperthyroid will cause a jumpy reaction in cats)
-Essential for gonadal normal function (lack results in reduced sperm production, irregular cycle)
-Increase nerve conduction velocity (faster reflexes)
Important piece* lots of receptors that are important for different results and almost all have TH receptors except a couple organs. The most important ones above are the BMR and the SNS effected by stress and enhances sensitivity)
How are Thyroid hormones metabolized?
-Deionization to reverse T3 in target tissues results deactivation
-After deactivation, diffuses out of target cell and is degraded in the liver (main organ for detoxification and deionization)
-The I2 release during metabolism can be recycled to the thyroid
How is TH regulated?
-TRH from HYPOTHAL increases TSH secretion form the ANTERIOR P
-TSH binds to its G-coupled receptor on membrane of follicular cells, stimulates cAMP pathway which in turn stimulates the endocytosis (bringing in more) of Tgb-I2 and the synthesis of TH (we can only control the synthesis)
-TH exert a negative feedback on both the pituitary and hypothalamus
-Exposure to cold for long period increase TRH release (bc BMR will create internal heat)
-If metabolites decrease (fasting) rapid decrease in TH (T3 and T4)
What are some thyroid pathologies?
-Hypothyroidism
-Goiter
-Hyperthyroidism
What is hypothyroidism?
3 different ‘types/causes’:
1. Primary hypothyroidism= In dogs most cases results from autoimmune disorder that destroy follicular cells (follicular cells destroyed)
2. Secondary hypothyroidism= low secretion of TSH, mainly due to injury to pituitary or hypothalamus (thyroid is fine but issue higher up chain with TSH or hypo)
3. Third hypothyroidism: Iodine deficiency
Most cell types affected by hypothyroidism:
-Reduced heat production and tolerance to cold
-Sluggish animal not feeding BUT gaining weight
-Impaired reproduction, constipation
Treatment: Thyroxine for the rest of life
What is Goiter?
-Enlarged thyroid gland
Several causes:
-Deficiency in iodine
-Tumor
-Inflammation
What happens: Lack of thyroid hormones increase TRH and TSH (problem with new feedback bc not hormones) stimulating multiplication (hyperplasia) and volume (hypertrophy) of follicular cells
-In costal areas good source of iodine, inland goitre more frequent in animals
What is hyperthyroidism?
-Over production of thyroid hormones
-Frequent in cats cause unknown
-Many target organs
Symptoms:
-Big appetites associated with weight loss (very skinny), excitable and nervous (increase response to catecholamines ie SNS), increase heart rate, increase respiration, increase digestive passage
Treatment: Surgery, radioactive I2 to destroy follicular cells
What is the structure of the adrenal gland?
adrenals= paired organs capping the kidneys
Consists of 2 layers:
-outer cortex: makes up 90% of the adrenal glands mass and has 3 layers
-inner medulla: part of the ANS (equivalent to a ganglion, but with post ganglion cells secreting catecholamines ie epinephrine/norepinepherine) that diffuse in the blood
What are the 3 areas of the cortex on the adrenal gland?
Cortex is composed of 3 layers:
1. Zona glomerulosa: outer most layer= secretes mineralcorticoids
2. Zona fasciculata: middle layer= secretes glucocorticoids
3.Zona reticularis: inner most layer= secretes androgens
What are the hormones of the adrenal cortex?
-Cortex produces steroid hormones (adrenocortical hormones) required for survival
-Hormones produced by stepwise conversion of cholesterol previously absorbed from blood lipoproteins
-Cytochrone-P450 are major enzymes in conversion
-Cells from each zone of the cortex have different enzymes –> formation of different hormones
*all need to know is all derived form stepwise action and end product depends on enzymes (P450)
What are mineralocorticoids?
-Produced in the zone glomerulosa (Outer layer, most potent is aldosterone) after diffusion, circulate loosely bound to cortisol binding globulin (CBG)
-Synthesis and secretion stimulated by angiotensin (BP losing fluid so stimulate production of angiotensin to reabsorb Na/K), and by direct action of K+ concentration on cortical cells
-ACTH from pituitary as minimal impact on aldosterone secretion
-Regulate metabolism of important inorganic ions
-Stimulate the reabsorption of Na+ and the secretion of K+ in the distal kidney tubes and collecting ducts
-In target cells, aldosterone binds to its receptor to modulate gene transcription which increases Na+ and K+ pumps in basolateral membrane and increase Na= channels in apical membrane
What are glucocorticoids?
-Primarily metabolic regulation but linked to stress (profs POV) in middle layer
-Regulate glucose metabolism
-Cortisol (mammals) is the most potent, corticosterone (birds) has weaker activity
-After diffusing into blood, cortisol binds to CBG (cortisol binding globulin)
-Free hormone portion enters target cells, binds to its receptor and stimulates or inhibits gene transcription
-All cells are potential targets:
-Permissive action: activates transcription of several enzymes that facilitate the acorn of other hormones (ex glucagon triggers relate of glucose from storage so increase glucose)
What is the stress hormone?
-Levels of cortisol increase during stress
-It enhances the effect of norepinephrine on blood pressure
-Stimulates gluconeogenesis and inhibits tissues glucose utilization which increases plasma glucose concentration (supposed to be acute response)
-At high level stimulates degradation of fat and protein leading to increase in plasma AA and fatty acid concentrations
-Cortisol also inhibits gene transcription in many tissues
-Combined with degradation of fat and protein –> growth inhibition effect
-Energy conserved for survival during high stress
What is the Anti-inflammatory effects?
-Inhibits formation of prostaglandins and cytokines
-Reduces number of lymphocytes migration
-Cortisol and gluco: shut off inflammatory response
-Block inflammation so can do flight to fight problem if its chronic stress prone to infections and everything falls apart
How is glucocorticoids regulated?
-Hypothalamus responds to internal and external stimuli (stress, circadian rhythm) by releasing ACTH-RH)
-ACTH-RH stimulates the release of ACTH by the anterior pituitary
-ACTH binds to its receptors on the cell surface in the adrenal cortex and increases intracellular cAMP levels
-Mobilization of cholesterol= more substrate for p-450
-ACTH: short loop negative feedback on hypothalamus ACTH-RH
-Glucocorticoids: long loop on hypothalamus and pituitary (long loop predominant bc not all have short loop)
What is addition’s Disease?
-Glucocorticoid deficiency
-In animals most common in dogs
-life threatening
-Major cause is auto immune disorders that destroy adrenal cortex cells (mount antibody response to own producing cells)
-Reduced BP -> dizziness
-Reduced appetite, sluggish, depression, vomiting
-Loss of negative feedback –> measurable increase in ACTH secretion
What is Cushing’s disease?
-Opposite to Addisions
-Glucocorticoid (cortisol) overproduction
-Common in dogs but can occur in Cats and horses
-Primarily due to pituitary and adrenal cortex tumours
-When cortisol continuously high
-Dogs eat and drink a lot, lose hair 9horse retain hair), muscle weaken
-Anti-insulin effects can lead to diabetes
What are androgens?
-Produced in the inner most layer of the adrenal cortex
-Similar to testosterone (male sexual steroid)
-Circulate partly sound to SHBG and albumin
-Much lower potency than testosterone, unknown role in male, in female transformed to estrogen in adipose tissue–> only source of estrogen after menopause
What are the hormones in the adrenal medulla?
-Medulla secretes catecholamines: epinephrine, norepinephrine (ratio depend on species; 4/1 in humans)
-Secretion party under the control of the preganglionic sympathetic nerves that release Acc
-Ach depolarizes cells from medulla, induces Ca+2 entry and exocytosis of hormones
-Effects slower but loner than sympathetic system
-Normal blood level of catecholamines is too low to exert an action
What is the role and action of catecholamines?
-Catecholamines bind to adrenergic receptors in target cells
-Two types of receptors, α and β both G-protein coupled receptors:
-α leads to an increase in Ca2+
-β leads to an increase in cAMP
-α receptors most common in target cells from sympathetic
-In arterioles and in sphincters of the GI tract, stimulation of α receptors constricts smooth muscle
-Activation of β1 receptors in heart leads to an increase in rate and contractility
-β2 receptors present in muscle from bronchioles leads to inhibition of contraction
-In arterioles of skeletal muscles, epinephrine have a dual effect on α and β receptors, low levels activate β receptors (relaxation) Whereas high levels activate α receptors (small contraction)
What is the action of stress on the body?
-Stress= factors that alter or might alter body internal environment
-Stress can be external (cold, exercise, injury) or internal (pain, psychological factors)
Response:
-Direct action of sympathetic system on unnerved organs
-Indirect action by stimulating release of catecholamines
-Increased cortisol secretion via action on ACTH-RH and ACTH
-Increased alertness, higher heart rate and blood pressure, increased blood glucose concentration, increased hormone secretion (thyroid)
- integration of all the systems
