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Science
Medicine
Phys TT3 - Endocrinology
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Terms in this set (129)
Environmental changes are controlled by (3)
1. Constant monitoring of the composition of blood
2. Responding to changes in blood composition
3. Most response systems operate in a negative feedback manner
via neurotransmitters and hormones
Nervous System VS Endocrine System Internal Communication
NS
- Utilizes electrical or chemical signals to for cell-to-cell communication via synaptic transmission
- Rapid response time (<2 sec)
Endocrine
- Chemical messengers transported in extracellular fluid s
- May act over extended time peroids (mins to months)
-re-program tissues
Endocrine Physiology
The study of hormones and their actions
the study of how endocrine glands regulate the physiology and behaviour of animals
Endocrine Glands
Any tissue which releases (secretes) hormones into the bloodstream to effect change in another tissue
What makes a chemical a hormone?
Molecules secreted by endocrine glands
Levels of effect of Hormones
- Autocrine
- Paracrine
- Endocrine
Classes of Hormones (4)
-Amino Acid Derivatives
- Peptides
- Proteins
- Steroids
Amino Acid Derivatives Egs
- Epinephrine
- Thyroxine
- Melatonin
Peptides Egs
- Hypothalamic hormones
- Insulin
Proteins Egs
- Growth Hormone
- Prolactin
Steroids Egs
-Glucocorticoids
- Mineralocorticoids
- Gonadal steroids
Modes of Secretion
...
Overproduction = ____ secretion
hyper
Underproduction = ____secretion
hypo
Hormones are just one category of ______ molecules
regulating
Regulating Molecules
-Hormones
- Pheromones
- Neurotransmitters
- Cellular growth factors
- ANgiogenesis-regulating molecules
- Cytokines (interleukins, interferons)
All exert their effects on target cells by binding to receptors
Hormone Receptors
-Hormones bind non-covalently to receptors in/on target cells
- The receptors for most hormones are found in the plasma membrane of target cells
- The receptors for steroid and thyroid hormones are found in the cytoplasm/ nucleus of the target cells
Transmembrane receptor types use ______ systems
second messenger systems
Transmembrane Receptor types
1. G-protein linked receptors
> Adenylate cyclase-cAMP
> Phospholipase C-Ca2+
2. Tyrosine kinase receptors & Cytokine receptors
G-protein linked receptors
- Adenylate cyclase-cAMP
- Phospholipase C-Ca2+
Downstream effects promote phosphorylation + activation of enzymes responsible for carrying out hormones effect
Phospholipase C-Ca2+ Egs
Norepinephrine + epinephrine alpha 1 receptors
Phospholipase C-Ca2+ Messenger System Steps
1. Hormone binds to receptor
2. Alpha subunit dissociates from G proteins
3. Alpha subunit activates phospholipase C
4. DAG and IP3 is formed
5. IP3 enters endoplasmic reticulum
6. Stored Ca2+ diffuses into cytoplasm
Adenylate cyclase-cAMP Messenger System Steps
1. Hormone binds to receptor
2. Alpha subunit dissociates from G proteins
3. Alpha subunit activates adenylate cyclase
4. cAMP is formed
5. cAMP activates protein kinase
6. Protein kinase phosphorylates various enzymes in the cell
Adenylate cyclase-cAMP Egs
Norepinephrine and epinephrine (catecholamines) beta and alpha 2 receptors
Tyrosine kinase receptors & Cytokine receptors
Directly phosphorylate + activate enzymes responsible for carrying out hormone's effect
Tyrosine kinase receptor Eg
Insulin
Tyrosine kinase 2nd messenger system steps
1. Two half receptors form dimer prior to insulin binding
2. Insulin binding causes autphosphorylation of receptor
3. Active tyrosine of receptor phosphorylates insulin receptor substrate
4. Active signalling molecule causes cascade of effects --> Glucose uptake and anabolic reactions
Cytokine receptors Egs
Growth Hormone Receptor
Cytokine 2nd messenger system
1. Hormone binds to receptor
2. JAKs are activated
3. Activated JAK proteins translocate to nucleus to influence gene expression
Nuclear Hormone Eg
Steroid hormones
Nuclear Hormone Receptor Steps
1. Steroid hormone transported bound to plasma carrier protein
2. Steroid hormone binds to receptor in cytoplasm
3. Translocates to nucleus, binds to DNA (acts as a transcription factor)
4. Stimulates gene transcription
5. Protein products
6. Hormone response
Steroid receptors have a ______ binding domain and a _____ binding domain
hormone, DNA
DNA binding domain binds to ___________ in DNA
Hormone response elements (HRE)
**binding causes dimerization of receptor. Stimulation of gene transcription
Nuclear hormone receptors Eg
Thyroid Hormones
Nuclear hormone receptor steps
1. Thyroxine hormone (T4) usually bound to carrier protein
2. T4 is converted into T3 (Triiodothyroxine)
3. T3 uses binding proteins to enter nucleus
4. Hormone-receptor complex binds DNA
5. New mRNA
6. Protein synthesis
7. Hormone response
Nuclear hormone receptors within the nucleus .....
- T3 receptor forms a heterodimer with the RXR receptor when each binds its ligand
- Heterodimer receptor binds to HRE
- Stimulation of gene transcription
The biological relevance of HPTC axes
- Links the endocrine system to the environment via teh brain
- Step wise increase in signal from hypothalamus --> pituitary gland --> peripheral target tissues
- Adjustments can be made at several different levels of each axis
The anterior and posterior lobe have the same origin in embryonic development (T/F)
False, anterior from Rathkes pouch. Posterior from neuroectoderm
Pars distalis
Anterior lobe (endocrine part of pituitary gland)
Pars tuberalis
Wraps around infundibulum
Infundibulum
Funnel-shaped structure
Pars intermedia
"middle lobe"; mainly secretes melanocyte-stimulating hormone (MSH)
Magnocellular
Neurosecretory cells; ADH/oxytocin
Parvocellular Neurosecretory cells
AP-hormone regulating hormones
Posterior Lobe
Neural part of the pituitary gland (pars nervosa)
Importance of the Anterior Lobe
- Function of target glands is dependent upon adequate stimulation by anterior pituitary (AP) hormones
- Hypothalamic hormones are secreted into the portal enules that bring them to the AP
- Endocrine cells respond to hypothalamic hormones and secrete OR inhibit release of AP hormones
Endocrine cells of the AP
-Acidophils (Eosin +)
- Basophils (Hematoxylin +)
- Chromophobes (-/-)
AP Acidophils
- Lactotropes: Secrete prolactin
- Somatotropes: Secrete GH
AP Lactotropes
Secrete prolactin
Acidophils
AP Somatotropes
Secrete GH
Acidophils
AP Basophils
- Thyrotropes: Secrete TSH
- Corticotropes: Secrete ACTH
- Gonadotropes; Secrete LH/FSH
AP Thyrotropes
Secrete TSH
Basophil
AP Corticotropes
Secrete ACTH
Basophil
AP Gonadotropes
Secrete LH/FSH
Basophil
AP Melanotropes
Secrete MSH (pars intermedia)
Chromophobes
AP Chromophobes
-Melanotropes: secrete MSH (pars intermedia)
Pre-hormones
Inactive hormones are converted after secretion to become active
Pre-horomone Egs
- Vitamin D3 is converted to 1,25-dihydroxyvitamin D3 in target tissue
- T4 is converted to T3 in target tissue
Pro-hormone
Many hormones are derived from a precursor molecule
Pro-opiomelanocortin (POMC)
- A pro-hormone for many hormones
- Precursor for ACTH, MSH, LPH, and endorphin
- In AP, POMC is produced and cleaved into ACTH and B-liptropin
- In pars intermedia, POMC is produced and cleaved to produce MSH, CLIP, gamma-lipotropin, and beta-endorphin
Melanocortin Receptors
G-protein coupled, binding upregulates cAMP production
- MC1-R
- MC2-R
- MC3-R
- MC4-R
- MC5-R
MC1-R
- Primarily binds alpha-MSH
> Melanocytes: cell proliferation and melanin synthesis
> Immune cells: Anti-inflammatory actions
- Weakly bind to ACTH
MC2-R
- Primarily binds ACTH
> Adrenal cortex: stimulation of glucocorticoid and androgen synthesis
> Adipocytes: Stimulates lipolysis
MC3-R
- Primarily binds gamma-MSH
>CNS: hypothermia
> bradycardia and hypotension
MC4-R
- All MSH isoforms and ACTH
> CNS: Inhibition of feeding behaviour + appetite
Deficiency has been associated with obesity, increased fat mass, and insulin resistance (#1 genetic associated deficiency)
MC5-R
- Primarily binds ACTH and alpha-MSH
> Expressed in several organs
> May play several roles in metabolism and exocrine gland activity
Growth Hormone Facts
- Protein hormone
- Binds to cytokine receptors
- Half life: 6 - 20 mins
- Mostly transported bound to a binding protein (GHBP)
- Most abundant AP hormone (~10x)
- Impt role in growth
- Synthesized, stored, and secreted by somatotropes in the AP
GH secretion pattern
- Pulsatile secretion
- Basal levels highest early in life
- Amplitude is greatest during pubertal growth spurt and then decline throughout adult life
- GH and IGFs remain essential regulators of tissue renewal and metabolism
When is the largest GH peak?
~ 1 hour after onset of sleep (circadian pattern)
Sleep I/D the regulation of GH secretion?
Increase
Exercise I/D the regulation of GH secretion?
Increase
Hypoglycemia I/D the regulation of GH secretion?
Increase
Hyperglycemia I/D the regulation of GH secretion?
Decrease
High dietary protein I/D the regulation of GH secretion?
Increase
Sex steroids I/D the regulation of GH secretion?
Increase
GlucocorticoidsI/D the regulation of GH secretion?
Decrease
Endocrine disrupters I/D the regulation of GH secretion?
Decrease
Ghrelin (hunger hormone) I/D the regulation of GH secretion?
Increase
IGF-1 & Somatostatin I/D the regulation of GH secretion?
Decrease
IGF-1
-Mainly produced in liver
- Low at birth
- High at sexual maturity
- Lower later in life
- Needed for skeletal and extra skeletal devlpmnt, adipocyte differentiation
IGF-2
- Produced in many dvlping tissues
- Prominent during embryonic/fetal growth
- Can bind to insulin receptor (lower Sp)
IGFs modes of action
Autocrine
Paracrine
Endocrine
GH and IGF-___ appear to exert _____ actions in some tissues, which suggests that they have ________ roles
1, opposite, independent
GH is a ______ factor
diabetogenic factor
meaning it opposes the actions of insulin carbohydraet + lipid homeostasis
GH and IGF-___ exert similar ______ actions on protein homeostasis
1, anabolic
most of the anabolic actionsof GH are via IGF-1
What GH and other growth promoters are used in USA?
- rBST (increase milk prod)
- Estradiol, testosterone, progesterone, and synthetic hormones approved by FDA for beef cattle
What GH and other growth promoters are used in Canada?
- Estradiol, testosterone, progesterone, and synthetic hormones approved by FDA for beef cattle
-rBST NOT allowed in dairy cows
What GH and other growth promoters are used in EU?
NONE; all hormonal growth promoters are banned substances
What problems are associated with GH use?
- Increase stress due to high milk prod
> Increased risk of mastitis
- Adverse effects on repro
> 21 health problems have been ID'd
- Unclear affect on human health
GH-related disorders (pre-sexual maturity)
1. Underproduction or reduced sensitivity
> Dwarf GSD
> Dwarf rabbit
> Pygymy goat
2. Overproduction
> Gigantism
Giantism
- Hyper secretion of GH before sexual maturity
- Influences IGF release from the liver and therefore stimulates extensive bone growth
- Usually caused by a tumour on the anterior pituitary gland
-GH-related disorders (pre-sexual maturity)
GH-related disorders (post-sexual maturity)
1. Underproduction or reduced sensitivity
> Alopecia
> Cushings Syndrome
2. Overproduction
> Acromegaly
Acromegaly
- Thickening of bones/joints in skin, enlargement of internal organs (tongue, liver, spleen)
- Usually affects "middle-aged" animals
- hyper secretion of GH after epiphyseal plate closure
- >90% of cases is due to benign pituitary tumour
Hormones in thyroid axis
- TRH
- TSH
- Thyroxine (T4)
- Triiodothyronine (T3)
Thyroid releasing hormone (TRH)
Peptide hormone with a G-protein coupled receptor (IP3)
Thyroid stimulating hormone (TSH)
Protein hormone with G-protein coupled receptors (both cAMP and IP3)
Thyroxine (T4)
Amino acide hormone, cytoplasmic receptor
Triiodothyronine (T3)
Amino acid hormone, nuclear receptor
Thyroid follicles
Where T4 and some T3 are produced
Follicular cells/ thryocytes
surround thyroid follicles and uptake iodide (I-) from surrounding blood vessels
Filled with colloid, which contains thyroglobulin and enzymes to synthesize T4 and T3
Parafollicular cells
Dispersed throughout thyroid gland and synthesize calcitonin
How is thyroid hormone produced?
1. Iodide enters colloid and is converted from iodide to iodine by thyroid peroxidase
2. Once oxidized, iodine can bind, one at a time, to tyrosine residues on thyroglobulin (called organification)
3. Monoiodotyrosine (MIT) = 1 Iodine + 1 tyrosine
Diiodotyrosine (DIT) = 2 Iodines + 1 tyrosine
4. Thyroglobulin brings bound MIT and DIT molecules together
5. Lysosomal enzymes in the colloid modify the structures of MIT and DIT to make thyroid hormones (T3&T4)
6. TSH stimulation induce follicle cells to take up bound T3 and T4, hydrolyze them from thyroglobulin, and secrete hormone into the blood
Wolff-Chaikoff Effect (Autoregulation)
Any excess of iodide (>2mg/day in humans) inhibits the activity of iodide trapping irrespective of TSH levels; prevents hyperthyroidism
Humans/dogs secrete T4:T3 at what ratio?
4:1
Increased T3 indicates ______
hyperthyroidism
T3 is less potent than T4 (T/F)?
False; its 3 -5 x more potent
What % of T3 is produced by peripheral conversion of T4 in the liver and kidneys by deiodinases?
60 - 75%
What is the T4:T3 ration in plasma?
20:1
What is the half life of T4 and T3?
T4: 6 - 7 days
T3: 1 day
main effects of thyroid hormone
Regulation of metabolic rate (glucose consumption + ATP production in cells) and thermogenesis (heat production)
Thyroid hormones I/D the synthesis of GH and glucocorticoids
Increases
Physiological effect of thyroid hormones on CNS
Dendritic and axonal growth, myelin formation, synapse formationn, neuronal migration (crucial in early devlpmnt)
Physiological effect of thyroid hormones on blood
Supports normal RBC production
Physiological effect of thyroid hormones on fat tissue
Lipolysis
Physiological effect of thyroid hormones on gonads
Supports normal gonadal development and function (including seasonality of breeding)
Physiological effect of thyroid hormones on bones
Supports bone growth + remodelling/turnover
Physiological effect of thyroid hormones on muscles
Supports muscle growth
Hypothyroidism + Primary hypothyroidism
Serum levels of T4/T3 are abnormally low
- Primary thyroidism: Immune-mediated (dogs) or idiopathic atrophy (cats)
commonly affects dogs 4 - 10yrs old
Clinical signs of hypothyroidism
- Lethargy
- Weight gain
- Exercise intolerance
- slower HR
- Heat seeking
- Dry skin
- Alopecia
Causes of hypothyroidism
- Insufficient dietary iodide*
- Anti-thyroid factors in diet (goitrogens)*
- Congenital abnormalities (mutated receptors or transport proteins)
- TSH deficit
- Impaired thyroid hormone synthesis*
- Autoimmune disorder
- Hyperthyroid medications
Associated with goiter formation
Hyperthyroidism + Primary hyperthyroidism
Serum levels of T4/T3 are abnormally high
- Primary: thyroid adenoma (cats), thyroid carcinoma (dogs)
Usu. affects middle aged to old cats
Clinical signs of hyperthyroidism
-Weight loss
- Excitability
- Increased HR
- Increased thirst/urination
- Increased appetite
- Vomiting
Causes of Hyperthyroidism
- Primary: Thyroid tumours
- Secondary: Pituitary adenoma*
- Graves disease
*associated with goiter formation
Graves Disease
Form of hyperthyroidism
Autoimmune condition: Abs bind to TSH receptor
Mimic activity of TSH to induce production/secretion of thyroid hormones
Goiters in Hypothyroidism
Low iodide intake --> Low plasma thyroid hormone (leads to clinical signs) --> High TRH --> High plasma TSH --> Enlarged thyroid gland
Euthyroid sick syndrome (ESS)
- Changes to serum levels of T4, T3 or rT3 that are NOT associated with a defective tyroid
- Serious illness and certain drugs may lead to decreased T3&T4, and increased rT3 levels
- Complicates a true diagnosis of hypothyroidism
Diagnosing Thyroid Disorders
1. Behaviour history, weight changes
2. CBC and thryoid hormone panel
> Serum [] of total T4, T3, free T4, and TSH
> Presence of thyroglobulin auto-anti-body
3. Imaging and/or biopsy of thyroid tissue
4. TRH/TSH stimulation test
5. Differentials: ESS, adrenal hyperfunction
Treating Hypothyroidism
Levothyroxine; treatment for life
Treating Hyperthyroidism
- Reactive iodine
- Thyroidectomy
- Methimazole (frequent rechecks)
- Nutritional changes (Iodine-deficient diet)
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