ERS03 04 05 Introduction To Endocrine System And Hormones + Physiological Action Of Hormones + Regulation Of Endocrine Secretion Flashcards
Components of Endocrine / Hormonal system
- Glands
- specialised group of ***cells that makes and secretes hormones
- not necessarily have to be an organ
- located throughout the body (brain, kidney, reproductive organs) - Hormones
- produced by glands
- released into bloodstream / extracellular fluid surrounding cells
- >50 kinds
- regulate biological processes (e.g. homeostasis, growth, metabolism, mood, sleep cycle) - Receptors
- recognise / respond to hormones —> trigger action
Location of major endocrine glands
- Hypothalamus, Pituitary gland
- Vasopressin, Oxytocin (hypothalamus —> posterior pituitary)
- GnRH, TRH, Dopamine, GHRH, CRH (hypothalamus)
- LH, FSH, TSH, Prolactin, GH, ACTH (anterior pituitary)
- other regulatory hypothalamic hormones —> regulate anterior pituitary secretion - Pineal gland
- melatonin - Thyroid, Parathyroid gland
- T3, T4, Calcitonin (thyroid)
- PTH (parathyroid) - Thymus (undergo involution with age)
- thymosins (regulate immune response) - Pancreas
- insulin
- glucagon - Adrenal gland
- **adrenocorticosteroid: aldosterone, cortisol, androgen (cortex)
- **adrenomedullary catecholamine: NE, E (medulla) - Placenta
- human chorionic gonadotropin (HCG, maintenance of corpus luteum during pregnancy) - Ovary, Testicle
- estrogen, progesterone, inhibin
- testosterone, inhibin
Mode of action of hormones
- Endocrine signalling:
- act on distant cells through bloodstream
- **ductless gland, secrete products into bloodstream
(vs Exocrine gland: secrete products into **ducts/channels, carry to outside of body / into body cavity) - Paracrine signalling:
- enter ***extracellular region and act on cells next to secreting cells
- without entering bloodstream - Autocrine signalling:
- act on same cell that secreted them
- the hormone regulate its own secretion
Structural classifications of hormones
- Amino acid derivatives
- from modifications of ***a.a —> Tyrosine (e.g. T3, T4, Epinephrine), Tryptophan (e.g. melatonin)
- small molecules
- t1/2: from mins to a few days (e.g. T4 bind to Thyroxine-binding globulin (vs T3) —> lower clearance —> longer t1/2) - Peptide / Protein hormones
- **chains of a.a. (e.g. Insulin)
- synthesised in **rER as precursors (contain signal peptide that direct them into ER)
—> post-translational processing into active hormone (e.g. cleave away signal peptide / further modification)
- water soluble
- **stored in intracellular vesicles in large amount before released via exocytosis
- **short t1/2 in blood: mins (∵ water soluble —> no need to bind to carrier protein)
- ***quickest effect - Steroid hormones
- derived from **cholesterol (e.g. cortisol)
- lipid soluble
- synthesised in **sER **on demand (∵ can pass through lipid membrane easily)
- most bind to carrier proteins (e.g. albumins, globulins)
- **longer t1/2: hours
- ***slowest effect
Mechanism of action of hormones
- Specificity
- A hormone can only trigger a reaction in specific target cells bearing specific receptor for that hormone (lock and key hypothesis)
- bind to receptors in a particular cells
—> receptor carries out instruction by hormones
—> alter cell’s existing proteins / turning on genes to build new protein - High affinity
- hormone receptors with high affinity (sensitivity) toward the hormone (∵ exist as trace amount in blood stream) - Hormone receptors: Surface of cell / Within cell depend on type of hormone
- Water-soluble (peptide / protein)
—> repelled by lipid membrane
—> bind to receptors on **cell surface (plasma membrane)
—> **2 responses: **Cytoplasmic response (e.g. trafficking of transporter / signalling transduction) + **Nuclear response (e.g. changing gene expression) - Lipid-soluble (steroid)
—> diffuse through plasma membrane
—> bind to receptors **within cell
—> **1 response ONLY: **Nuclear response (receptors are mainly **transcription factors: bind to target gene and regulate gene transcription)
Signal transduction of Steroid hormone receptors
Steroid receptors:
- ***Transcription factors (bind to promoter region)
- contain **DNA binding site + **Transcriptional activation site
Steps:
Binding of hormone to receptor
—> Dissociation of repressor protein
—> Without repressor protein
—> Hormone-receptor complex translocated to nucleus
—> Steroid receptors form dimers (2x Hormone-receptor complex) after binding to hormone
—> **Dimerised complex act as transcription factor
—> bind to a DNA sequence: **“Hormone Response Element” (HRE) on target gene promoter region
—> induce / suppress gene expression
—> ***slow response
Example: Estrogen receptor (reproduction, CVS function, bone integrity, cognition, behaviour)
MOA:
Upon binding estrogen
—> cytosolic ER undergo dramatic ***decrease in surface hydrophobicity
—> important for entering nucleus + recruit specific transcriptional co-regulatory proteins + binding to estrogen-response element in promoter region of estrogen-responsive genes
Drugs acting on steroid receptors are either Agonists / Antagonists:
- Antagonists: Tamoxifen for breast cancer (Estrogen stimulate of proliferation of mammary cells)
- Agonists: Raloxifene (selective agonist for estrogen receptor α) for prevention of osteoporosis in postmenopausal women (Estrogen inhibit bone turnover by ↓ osteoclasts-mediated bone resorption, ↑ osteoblast-mediated bone formation)
Conclusion:
When a receptor binds to hormone
—> receptor undergo conformational change
—> allow productive interaction with other components of cells
—> alteration in physiologic state of cell
Signal transduction of Peptide hormone receptors
Binding of hormone to receptor
—> Generation of ***2nd messengers within cells
Signal transduction depends on type of cell surface receptors involved:
- GPCR (e.g. PACAP, glucagon, oxytocin, vasopressin receptors)
- 7-transmembrane-spanning receptors: antiparallel
- N-terminal for binding to hormone + 3 extracellular loops + 3 intracellular loops + C-terminal for binding to intracellular signalling molecules
- respond to ligands by undergoing dynamic conformational changes in **TM domain
—> alter their ability to communicate with intracellular signalling partner
—> TM6 swings away to prevent steric hindrance
—> allow docking of intracellular signalling protein onto 3rd intracellular loop
—> **activation of associated G protein by **exchanging GDP bound to G protein (Gα) for GTP
—> **Gα subunit dissociate from β and γ subunits
—> the type of intracellular signalling pathways activated depends on type of Gα subunit
—> ***Gαs (↑ cAMP), Gαi (↓ cAMP), Gαq (activation of Phospholipase C)
- Enzyme-linked / Catalytic receptors
- Extracellular ligand binding domain
- Transmembrane helix
- Cytoplasmic domain: ***intrinsic enzyme activity / associate directly with enzyme (e.g. Tyrosine kinase, Tyrosine phosphatase, Serine/Threonine protein kinase)
MOA:
Upon ligand binding
—> receptor dimerised
—> conformational change transmitted via transmembrane region
—> activate enzyme activity intracellularly
—> **activate 2nd messenger (PI3K, PLC, Ras, JAK)
—> signalling cascades
—> changes in gene expression
—> **slow response (hours)
Conclusion:
Responses of Enzyme-linked receptor require ***many intracellular signalling steps
—> changes in cell proliferation, differentiation, survival, migration etc.
—> disorders in enzyme-linked receptor / abnormalities in signalling pathway are fundamental events in cancer
GPCR: Vasopressin receptor V2R
Binding of ADH at extracellular interface
—> conformation changes in TM6, 3rd intracellular loop
—> Gαs stimulation
—> ↑ cAMP
—> protein kinase A activation
—> Cytoplasmic response: ↑ insertion of AQP2 on apical membrane + Nuclear response: ↑ AQP2 expression and production
—> changing water permeability of collecting tubule cells
—> ↑ water reabsorption
Conclusion:
Hormones affect physiology of target tissue by inducing protein express (Nuclear response) / changes in membrane permeability (Cytoplasmic response)
Enzyme-linked receptor: Insulin receptor
- member of Tyrosine kinase family of transmembrane signalling protein
- 2 subunits linked by disulphide bond
—> α subunit (x2): ligand binding
—> β subunit (x2): protein kinase which catalyse phosphorylation of proteins - binding of insulin onto α-subunit
—> phosphorylation of β-subunit (autophosphorylation)
—> docking centre for recruitment of different substrate adaptors (e.g. insulin receptor substrate 1 (IRS-1))
—> nucleus for assembly of other signal transduction particles
—> activation of other enzymes ultimately mediate insulin’s effect - **2 main pathways of insulin signalling by Insulin receptor:
1. PI3K/AKT pathway - IRS-1
- ***metabolic effects of insulin (blood glucose regulation)
- Ras/ERK pathway
- ***cell growth and differentiation induced by insulin
- defective IRS-1 / hyperinsulinaemia —> direct to Ras/ERK pathway —> high risk of cancer
Conclusion:
Hormones can act via control of intracellular enzyme activity —> different pathways —> different responses within cell
Purpose of learning MOA of hormones
- Many steps after initial hormone binding to receptor
- potential places where REGULATION can take place - Hormonal signals can be AMPLIFIED along cascade
—> multiple intracellular signals are produced for every receptor that is bound - Create opportunities for target cells to INTEGRATE information it receives from different stimulus (e.g. receptor A / receptor B)
—> specific response elicited is determined by the cell rather than hormone
Hormone interaction at whole body level
Coordinated interplay of different body systems + Integration of multiple hormonal signals (overall effect can be greater/smaller than individual effect of hormone)
—> Maintain integrity of the internal environment upon exposure to changing external environment
4 ways of hormone interaction:
1. Redundant effect
- Reinforcement effects
- Antagonistic effects
- Permissive effects
- Redundant effect
- different hormones produce same effect
- ***safe-guard mechanisms for very important physiological functions (allow other mechanisms to compensate)
- produce ***synergistic outcome —> combined action to produce effects greater than sum of individual effects
e.g. epinephrine (a.a hormone), glucagon (peptide hormone), cortisol (steroid hormone)
—> all can ↑ blood glucose
—> act synergistically during prolonged fasting / flight/fight response to rapidly restore/↑ blood glucose level
—> actions are not identical though —> function with ***different time constant!!!
- Reinforcement effect
Same hormone act in different tissues to induce different responses
—> at the end reinforce each other at whole body level (e.g. Cortisol)
OR
Same hormone induced different responses in single cell
—> at the end reinforce each other (e.g. Aldosterone)
e.g. Cortisol
1. breakdown of proteins into a.a. in muscle —> ↑ a.a. supply to liver
2. breakdown of fat in adipose tissue —> ↑ glycerol supply to liver
3. ↑ production of glucose from a.a. + glycerol in liver
4. ↓ sensitivity to insulin
Overall effect: ↑ blood glucose level
e.g. Aldosterone (single cell molecular level)
- bind to mineralocorticoid receptor (MR) in distal tubule cells —> different gene expression:
1. Na/K-ATPase expression on basolateral membrane (Na back to circulation, K into cell)
2. Na channel (ENaC) expression on apical membrane (Na into cell)
3. K channel (ROMK) expression on apical membrane (K out into filtrate)
Overall effect: Na reabsorption + K excretion
- Antagonistic effect
- hormones acting to return body conditions to within acceptable limits from opposite extremes i.e. one hormone oppose action of another
—> dual control
—> more precise regulation than through negative feedback
e. g. Insulin vs Glucagon
- reduce glucagon cannot reduce blood glucose —> require insulin
- Permissive effect
Presence of one hormone at a certain concentration
—> enhance responsiveness of target organ to another hormone
—> i.e. one hormone control expression of receptor of another hormone
e.g. Estrogen induce expression of progesterone receptor in uterus during proliferative phase
—> Estrogen induces proliferation of uterine endometrium + endometrium to express progesterone receptor
—> once Corpus luteum produce Progesterone
—> Progesterone act on same cell to exert its effect:
—> development of uterine endometrium (maintain thickness), including blood vessels formation —> prepare for implantation
Rhythms of Hormone secretion (Pulsatile, Diurnal, Cyclic)
- Hormone concentration in blood plasma fluctuate
- Vary widely over course of a day
3 secretion rhythms:
1. Pulsatile secretion
- hormones released in **short bursts / episodic manner
- regulated by physiological stimuli (e.g. insulin, GnRH)
- **change pulse frequency —> change hormone response (e.g. low frequency GnRH —> stimulate FSH secretion, high frequency GnRH —> stimulate LH secretion)
(記: 低頻FSH, 高頻LH)
- pulsatile release to ***prevent dilution of hormone in blood (vs one-off dose)
- Diurnal secretion
- e.g. cortisol vs melatonin
- cortisol peak shortly after waking
- melatonin peak at night
- circadian clock —> coordinate behavioural, endocrine, metabolic function to adjust to time of day - Cyclic secretion
- secreted in complicated cycles with respect to some bodily events e.g. menstrual cycle
- cyclic changes in hormonal levels control —> orchestrate events of menstrual cycle - FSH induce Estrogen production by ovary (Proliferative phase)
- ↑ Estrogen level —> ↑ LH production —> ovulation
- Corpus luteum produces Estrogen + Progesterone
- Absence of fertilisation —> Corpus luteum decay —> ↓ Estrogen + Progesterone —> uterus lining shedding —> onset of menses
Regulation of hormone secretion (Humoral + Hormonal + Neural stimuli)
- Humoral stimuli
- release of hormone in response to **changes in extracellular fluids / blood-borne chemicals
- e.g. PTH secretion in response to **Ca level
- e.g. insulin secretion in response to high ***blood glucose
—> unstimulated state: pancreatic β cell ATP-sensitive K channel are open
—> keep resting membrane potential ~ -60mV
—> high extracellular glucose
—> glucose enters cell by diffusion through glucose transporter
—> ATP production
—> suppress and close ATP-sensitive K channel (also inhibited by Meglitinides, Sulfonylureas —> do not work in type 1 DM)
—> no K efflux
—> depolarisation
—> opening of voltage-gated Ca channel
—> ↑ cytosolic Ca
—> Insulin release - Hormonal stimuli
- one hormone secreted in turn stimulate secretion of another hormone
- e.g. ***Hypothalamic-pituitary axis
—> Releasing / Inhibiting hormone —> Tropic hormone —> Hormone from target endocrine cell)
- **Arcuate nucleus:
- GH-releasing hormone / Somatostatin —> GH (Somatotroph)
- GnRH —> FSH, LH (Gonadotroph)
- Dopamine —> inhibit Prolactin (Lactotroph)
- **PVN:
- Corticotropin releasing factor —> ACTH (Corticotroph)
- Thyrotropin-releasing hormone —> TSH (Thyrotroph)
- **Magnocellular neurons in PVN, SON:
- ADH (produced by Hypothalamus)
- Oxytocin (produced by Hypothalamus)
- Neural stimuli
- nervous system directly stimulate endocrine glands to release hormones
- e.g. NE/E secretion from adrenal medulla (innervated by SNS) in response to stress
—> ACh (Presynaptic neuron) bind to nicotinic receptor on Chromaffin cell (act as Postsynaptic neuron)
—> Ca influx —> Tyrosine hydroxylase —> Tyrosine —> DOPA —> Catecholamine release
Feedback system
- Positive feedback (closed loop)
- reinforce (increase) changes in controlled condition
- e.g. Oxytocin secretion during childbirth to cause contraction of uterine muscle
—> uterus contraction
—> nerve impulse send to hypothalamo-pituitary axis
—> posterior pituitary secrete oxytocin
—> stimulate uterus to contract more vigorously - Negative feedback (closed loop)
- consequence of hormone secretion act on secretory cell to inhibit further secretion
- e.g. glucose production by glucagon
—> ↓ blood glucose stimulate α cells of islets of Langerhans to release glucagon
—> ↑ blood glucose
—> ↓ glucagon secretion after restoration of blood glucose concentration
—> high blood glucose require antagonistic hormone (i.e. insulin) to work - Complex negative feedback system
- Long loop / Short loop / Ultra-short loop
- Allow fine-tuning of hormone secretion
- Minimise changes in hormone secretion even if one component not functioning normally
Hypothalamo-pituitary axis:
Long loop:
- Target organ —(-ve)—> Anterior pituitary
- Target organ —(-ve)—> Hypothalamus
Short loop:
- Anterior pituitary —(-ve)—> Hypothalamus
Ultra-short loop:
- Hypothalamus —(-ve)—> Hypothalamus
E.g. Thyroid hormone secretion
- TRH —> TSH (Anterior pituitary)
- TSH —> Thyroid hormone (Thyroid gland)
- TRH/TSH inhibited by too much Thyroid hormone
Closed loop negative feedback control:
- maintain condition at state of constancy near pre-determined set-point (i.e. homeostatic equilibrium)
- set-point can be **temporarily adjusted by changing demands from body
- set-point deviation mainly achieved by intervention of some additional signal from **outside (usually nervous system)
- e.g. Epinephrine can override glucose set point by inhibiting insulin secretion + stimulating glucagon secretion
—> stimulate stimulatory signal + removing inhibitory signal —> Push-pull mechanism
Feedforward system
Feed-forward control (open loop)
- ***Anticipatory response in later stage of pathway (positive / negative)
- Open loop: no feedback to control the input
- no regulatory method
e.g. Cephalic insulin response to meal ingestion
- ↑ insulin even before blood glucose ↑
- Presence of food in oral cavity stimulate Vagus nerve activation
—> Parasympathetic pre-ganglionic neuron
—> Vagus nerve
—> Activation of post-ganglionic neuron in pancreatic islets
—> Preabsorptive insulin response (prior to nutrient absorption in first 10 mins of food ingestion)
Conclusion:
- External factors operate via ***Open loop (Feedforward control mechanism)
- Internal factors operate via ***Close loop (Feedback control mechanism)
Regulation of hormone activity
- Conversion of hormone to active / inactive form
- Regulation of hormone receptors
- Priming effect
- Desensitisation - Hormone clearance
- Liver enzymes
- Kidney enzymes
- Enzymatic processes inside target cell
- Conversion of hormone to active / inactive form
Some hormones are secreted as ***prohormone (inactive precursor)
—> must be activated
e.g. Angiotensinogen —(Renin)—> Angiotensin I —(ACE)—> Angiotensin II (within circulation)
Hormone can also be converted to ***inactive form to decrease its activity
e.g. T4 (inactive) —> T3 (active) (within target cells)
—> Outer ring 5’ deiodination —(deiodinase I / II)—> active T3
—> Inner ring 5 deiodination —(deiodinase I / III)—> inactive T3 (reverse T3)
Deiodinase I: liver, kidney, thyroid
Deiodinase II: brain, anterior pituitary, thyroid
Deiodinase III: brain, placenta, fetal tissue
- Regulation of hormone receptors
Hormone-receptor interactions are saturable
—> ***receptor number is limiting factor (limited, finite number)
More receptors available to interact with hormone
—> more likely there will be a response
—> biological effect is proportional to amount of complex that forms
- Priming effect (receptor up-regulation)
—> hormone can induce more of its own receptors expression in target cells
e.g.
Low frequency GnRH —> ↑ FSH production
High frequency GnRH pulse —> stimulate more GnRH receptor in anterior pituitary —> higher response (↑ sensitivity of anterior pituitary) —> ↑ LH production - Desensitisation (receptor down-regulation)
- occur after long exposure to high levels of hormone
- internalisation of receptor-hormone complex
—> ↓ cell surface receptors
—> ↓ sensitivity of cells to hormone
e.g. growth hormone downregulates its own receptor
—> targeting receptor to internalisation
—> enzymatic degradation
- Hormone clearance
Hormone signals turned off after serving their purpose
—> prevent prolonged exposure of target cells to hormones
Process of lowering hormone levels in blood (little regulation):
- Degradation by liver enzymes + Excretion in bile
- peptide hormones: proteolysis
- steroid hormones: reduction, hydroxylation, oxidation, decarboxylation, esterification (conjugated to steroid hormones to enhance water solubility) - Degradation by kidney enzymes + Excretion in urine
- primary route of excretion of hormone degradation products - Removal by enzymatic processes inside target cell
- via internalisation of hormone-receptor complex
—> lysosomal degradation of hormone
**Theoretical calculation of metabolic clearance rate (MCR):
Metabolic clearance rate (ml/min)
= Rate of disappearance of a hormone from plasma / Concentration of hormone in plasma
= **Urine production x Conc in urine / Concentration in plasma
Hormone t1/2:
Lipid-soluble hormones: longer (∵ carrier protein)
Water-soluble hormones: shorter (fluctuation by pulsatile secretion)
Endocrine disorders
Too much / Too little hormone
Causes of endocrine disorders:
- Problems in secreting gland (e.g. tumour: too much, infection: too little) —> Primary disorder
- Problems in endocrine feedback system (mostly hypothalamic-pituitary axis) —> Secondary / Tertiary disorder
- Autoimmune disorder (e.g. Type 1 DM, Graves’ disease)
- Genetic disorders (e.g. Kallmann syndrome, Cretinism)
Testing for Endocrine disorders
Isolated hormone test is not accurate (∵ hormone levels fluctuate)
Stimulation / Suppression testing:
- a dynamic test
- substance measured before + after administration of another substance to determine if levels are stimulated / suppressed
Excess hormone suspected = Suppression test (睇下撳唔撳到)
- Dexamethasone suppression test
- Captopril suppression test
Deficiency hormone suspected = Stimulation test (睇下刺唔刺激到)
- ACTH stimulation test
- TRH stimulation test
General aspects considered when interpreting hormone measurements:
- Hormone levels should be evaluated with their ***appropriate regulatory factors (e.g. Releasing factors, Tropic hormones)
- Urinary excretion of hormone metabolites ***over 24 hours in individuals with normal renal function»_space;> one-time plasma-level measurement (in estimate of hormone secretion)
- Target hormone excess should be evaluated with appropriate tropic hormone to rule out ***ectopic hormone production
- **Simultaneous elevation of pairs —> a **hormone-resistance state / ***autonomous secretion by pituitary
Suppression test
- Dexamethasone suppression test
Normal:
administer Dexamethasone
—> suppress ACTH
—> ↓ Cortisol
Cushing’s syndrome:
- no ↓ Cortisol (adrenal cortex overproducing cortisol)
- low dose test: differentiate patient from normal people
- high dose test: distinguish Cushing’s disease (Pituitary hypersecretion of ACTH) from Cushing’s syndrome (Primary / Non-pituitary ACTH secreting tumour)
- Captopril suppression test
- measure plasma Aldosterone
Normal:
Captopril inhibit ACE
—> ↓ Aldosterone
Primary hyperaldosteronism (Conn syndrome): - no ↓ Aldosterone, but ↓ Renin level (∵ -ve feedback) (↑ aldosterone / renin ratio)
Stimulation test
- ACTH stimulation test
Normal: injected ACTH —> ↑ Cortisol
Adrenal insufficiency: no ↑ Cortisol - TRH stimulation test
Normal: injected TRH —> ↑ TSH
Secondary hypothyroidism (pituitary problem): no ↑ TSH
Tertiary hypothyroidism (hypothalamic problem): delayed ↑ TSH
***Level of Endocrine disorder
Pituitary hormone ↑, Target hormone ↓ —> Primary disorder (failure of target organ to secrete/produce hormone)
Pituitary hormone ↓, Target hormone ↓ —> Secondary disorder (anterior pituitary failure)
***Pituitary hormone ↑, Target hormone ↑ —> Autonomous secretion of pituitary hormone / Resistance to negative feedback from target hormone
Pituitary hormone ↓, Target hormone ↑ —> Autonomous secretion by target organ (e.g. tumour) (normal -ve feedback to pituitary)
Tertiary disorder: Hypothalamic disorder
Treatment for Endocrine disorders
- Medication
- synthetic hormones
- chemotherapy (for cancer of endocrine gland) - Surgery / Radiation therapy
