Endocrinology Flashcards
Endocrine glands
- Function
- Vascularity
- Function: secrete hormones directly into the bloodstream upon stimulation
- Vascularity: highly vascularised
The three arrangements of endocrine tissue
1- Endocrine organ
2- Distinct clusters of cells within an organ
3- Individual cells scattered throughout an organ
Major hormone products of the hypothalamus
- RH and IF
- Examples
- Releasing hormones and inhibiting factors
- E.g. CRF, GnRH, GHRH, TRH, dopamine
Major products of the posterior pituitary (2)
- Anti-diuretic hormone (ADH)
- Oxytocin
Major hormone products of the anterior pituitary (6)
- ACTH
- GH
- P
- FSH
- LH
- TSH
- Adrenocorticotrophic hormone (ACTH)
- Growth hormone
- Prolactin
- Follicle stimulating hormone (FSH)
- Luteinising hormone (LH)
- Thyroid stimulating hormone
Major hormone products of the thyroid gland (3)
- Thyroxine (T4)
- Tri-iodothyronine (T3)
- Calcitonin
Major hormone product of the parathyroid gland
- Parathyroid hormone
Major hormone products of the adrenal gland (2)
- Adrenaline
- Cortisol
Major hormone products of the pancreas (2)
- Glucagon
- Insulin
Major hormone products of the gonads (3)
- Progesterone
- Oestrogen
- Testosterone
Modes of hormone action
- Autocrine and Paracrine
- Endocrine and Neuroendocrine
- Autocrine and Paracrine: Local diffusion
- Endocrine and neuroendocrine: Circulation
Chemical nature of hormones is related to …. (5)
- How they are….
- Nature of the H….
- Ability to b…..
- degradation
- How they are synthesised
- Nature of the hormone receptor they bind to
- Ability to bind to other proteins (e.g. transport proteins)
- How they partition in tissues
- How they are degraded
Steroid hormone examples:
- Prog…
- Gluco…
- Mineral…
- And….
- Oest…..
- Progestagens
- Glucocorticoids
- Mineralocorticoids
- Androgens
- Oestrogens
Non-steroid hormones
- Poly…
- Glyco…
- Eico….
- Pep….
- Ami….
- Polypeptides
- Glycoproteins
- Eicosanoids
- Peptides
- Amines
Peptide hormone structure:
- Chains of amino acids
Steroid hormone structure
- Cholesterol derived
Peptide hormone solubility
- Hydrophilic
Steroid hormone solubility
- Lipophilic
Peptide hormone synthesis
- Gene transcription and post-translational modification
Steroid hormone synthesis
- De novo biosynthesis
modification of cholesterol in mitochondria and ER
Peptide hormone storage
- Large amounts in secretory granules
Steroid hormone storage
- Not stored (cholesterol precursor stored as esters)
Peptide hormone secretion
- Exocytosis
Steroid hormone secretion
- Simple diffusion
Peptide hormone transport
- As a free hormone in the blood
Steroid hormone transport
- bound to transport proteins in the blood
Peptide hormone receptors
- Cell surface receptor
Steroid hormone receptor
- Intracellular receptor
Peptide hormone mechanism of action
- Activation of second messenger system to alter activity of existing proteins
Steroid hormone mechanism of action
- Activation of specific genes to produce new proteins
Hypothalamus-pituitary axis:
- Interface between central nervous system and endocrine system
Hypothalamus-pituitary axis controls homeostatic regulation of (7)
- S and I F
- R
- G and D
- W/E B
- E B/A C
- T
- S/W
- Stress and immune function
- Reproduction
- Growth and development
- Water/electrolyte balance
- Energy balance/appetite control
- Thermoregulation
- Sleep/wakefulness
Hypothalamus, anatomical boundaries:
- Anterior: OC
- Posterior: MB
- Superior: T
- Inferior: ME
- Anterior: Optic chiasm
- Posterior: Mammillary bodies
- Superior: Thalamus
- Inferior: Median eminence
Hypothalamus structure: (2)
- Divided into anatomical nuclei
- Contains hypothalamic neurosecretory cells
Action of the hypothalamus: (2)
- HNC R P F AT A to C
- I NI F BS, LS a HA, W R A
- Hypothalamic neurosecretory cells release peptides from axon terminals adjacent to capillaries
- Integrates neural inputs from brainstem, limbic system and hypothalamic areas, which regulate activity
Pituitary (hypophysis): two gland in one
- Posterior lobe: under DIRECT control
- Anterior lobe: under INDIRECT control
Tissue of the posterior lobe:
- Neural tissue: axons and nerve terminal endings of neurosecretory cells
Tissue of the anterior lobe:
- Glandular tissue: cells controlled by releasing hormones, delivered via hypophyseal portal system
Vascular supply of the pituitary gland:
- Anterior
- Posterior
- Drainage: CSS/IPS
- Anterior lobe: primary portal plexus transports releasing hormones to the secondary plexus
- Posterior lobe: a single plexus
- Drainage: cavernous sinus superior / inferior petrosal sinus
Posterior pituitary: blood supply and innervation (2)
- Blood supply from inferior/middle hypophyseal arteries
- Direct innervation from hypothalamus via pituitary stalk, releases neurohypophyseal hormones into systemic blood
Anterior pituitary: blood supply and innervation
- Blood supply from hypophysial portal system
- No direct innervation. Parvocellular neurones terminate in median eminence, releasing hypophysiotrophic hormones into portal blood
Posterior pituitary lobe: hormones secreted (2)
- Oxytocin
- Arginine-vasopressin (ADH)
Anterior pituitary lobe: hormones secreted (6)
Hormones with trophic action
- Follicle stimulating hormone (FSH)
- Luteinising hormone (LH)
- Adrenocorticotrophic hormone (ACTH)
- Thyroid stimulating hormone (TSH)
- Growth hormone (GH)
- Prolactin
Hormones with trophic action:
- They go on to regulate a third hormone
“Tripartite” neuroendocrine system:
- The idea that 3 separate hormones are involved in a system
1. Releasing hormone
2. Tropic hormone
3. Hormone (hits target cells)
Tripartite neuroendocrine system is prominent in control of major glands e.g. (3)
- Thyroid gland
- Adrenal gland
- gonads (ovary/testis)
What controls biorhythms?:
- The hypothalamic suprachiasmatic nucleus (SCN), the body’s master clock
Role of the hypothalamic SCN: (2)
- Partial control on …. Of …. Release from rhythm generators in the SCN
- Partial control on pulsatile patterns of hormone release from rhythm generators in the SCN
- E.g. paraventricular nucleus receives circadian input from SCN, regulating hypothalamus-pituitary-adrenal (HPA) axis activity and cortisol release
Polyuria:
Polydipsia:
- Excessive production and passing of urine
- Excessive thirst
What causes polyuria:
- In uncontrolled diabetes mellitus, osmotic diuresis (glucosuria) causes increased passive water loss
Principles of metabolic regulation:
- The flow of metabolites through pathways must be regulated to maintain homeostasis
- Homeostasis occurs when metabolite concentrations are at a steady state
Reasons why the levels of required metabolites may vary: (3)
Hint:exercise
- To increase the rate of glycolysis during exercise
- To reduce the rate of glycolysis after exercise
- To increase the rate of gluconeogenesis after exercise
What is the Km of a reaction:
- Rates are more sensitive to concentration near or below their Km
Km variation in glucose transporters:
- Different tissues have different glucose transport proteins present.
- The Km for each GLUT type varies due to its tissues function
GLUT1:
- Tissue/organ:
- Km
- Red blood cells
- 3 mM
GLUT 2:
- Tissue/organ
- Km
- Liver, pancreas
- 17 mM
GLUT3:
- Tissue/organ
- Km
- Brain
- 1.4 mM
GLUT4:
- Tissue/organ
- Km
- Muscle, adipose tissue
- 5 mM
Factors that affect rates of biochemical reactions:
- E S
- T of S G
- mRNA D
- mRNA T on R
- P D
- E S in S O
- E B S
- E B L
- E U P/deP
- E C with R P
- Extracellular signals
- Transcription of specific genes
- mRNA degradation
- mRNA translation on ribosome
- Protein degradation
- Enzyme sequestered in sub cellular organelle
- Enzyme binds substrate
- Enzyme binds ligand
- Enzyme undergoes phosphorylation
- Enzyme combines with regulatory proteins
Types of signalling: neuronal
- AP are ….
- AP reaches …..
- Action potentials are transmitted electrically along a nerve cell’s axon.
- AP reaches nerve terminal, causing the release of neurotransmitters onto adjacent cells
Contact-dependant signalling:
- A cell-surface-bound signal molecule binds to a receptor protein on an adjacent cell, no molecules are released
Paracrine signalling:
- Paracrine signals are released by cells into the EF, acting as a local mediator
Endocrine signalling:
- Hormones are secreted into the bloodstream and are distributed widely throughout the body
Cell surface receptors:
- Most signalling molecules….
- instead, they bind to …..
- Most signalling molecules are large and hydrophilic, they can’t cross the plasma membrane.
- Instead, they bind to cell-surface receptors which generate intracellular second messenger signalling molecules
Intracellular receptors:
- Some small hydrophobic…. pass through the target cells plasma membrane binding to ….
- That regulate, for example…..
- Some small hydrophobic extracellular signalling molecules pass through the target cells plasma membrane, binding to intracellular receptors.
- That regulate, for example, gene transcription
Effect of a signal molecule on different cells:
- The same signal molecule can induce different responses in different cells.
- Varies due to the various receptor and effector proteins in the cell
Apoptosis:
- A form of cell suicide that occurs when a cell does not receive the necessary signals to survive
Timescales of a cell’s response
- Fast
- Slow
- Fast: processes that rely on altered protein function; movement, secretion and metabolism
- Slow: processes that rely on altered protein synthesis; differentiation, growth and division
Ion-channel-coupled receptors:
- Signal molecules…..
- Causing a change in……
- Thus, a chemical change…..
- Signal molecules (acetylcholine) cause the receptors to open in response to binding,
- causing a change in the electrical potential across the membrane
- Thus, a chemical signal is transducer into an electrical signal
G-Protein coupled receptors are transmembrane proteins:
- Extracellular
- Intracellular
- Extracellular portion of a GPCr binds to signalling molecules
- The cytoplasmic portion binds to a G-protein
The two most common enzyme targets of G-proteins are:
- Adenyl cyclase action:
- Phospholipase C action:
- Adenyl cyclase catalyses the formation of the second messenger cyclic AMP (cAMP)
- Phospholipase C produces the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 promotes the accumulation of cytosolic Ca2+, another 2nd messenger
The effect of adrenaline on skeletal muscle:
- Adrenaline indicates a …..
- Adrenaline activates a …..
- The increase in cAMP activates…..
- Phosphorylase kinase activates……
- Adrenaline indicates a requirement for glucose in muscle
- Adrenaline activates a GPCR, activating a G-protein which activates cAMP
- The increase in cAMP activates protein kinase A (PKA), which phosphorylates, activating phosphorylase kinase
- Phosphorylase kinase activates glycogen phosphorylase, the enzyme that breaks down glycogen
GPCRs and cholera:
- Cholera toxin affects cells of the intestinal epithelium
- Modifies a G protein, preventing it from deactivating, so it continually activates adenylyl cyclase
- Causes continuous outflow of Cl- and H2O
- Causing diarrhoea, dehydration and death
Contents of the PCHR (red book):
- Family and birth info
- Routine screening
- Immunisations
- Growth
Growth hormone:
- Location
- Effect
- Action
- Anterior pituitary
- Causes growth in most tissues and promotes differentiation in some cell types
- Binds to GH receptor in target tissues
Effect of somatostatin on GH secretion:
- Somatostatin inhibits GH secretion
Effect of GRH dopamine on GH secretion:
- GRH dopamine increases GH release
GH secretion:
- Periodic secretion, affected by sleep
Feedback control of GH:
- SS
- GH
- GH stimulates somatostatin (SS), SS inhibits GH release
- GH also inhibits GHRH release and GH release
GH action: acute
- Protein
- Lipid
- Carbs
- Key effect
- Protein: Increased amino acid uptake and usage, increased protein synthesis.
Decreased protein catabolism - Lipids: decrease in lipogenesis
increase in lipolysis - Carbohydrates: decrease in glucose uptake and oxidation
Increase in blood glucose
-KEY EFFECT: PROTECTS PROETIN
Regulation of bone growth: IGF-1
- PM
- R of P C
- M of D S
- Pro-mitogenic
- Recruitment of precursor cells
- Maintenance of differentiated state
Regulation of bone growth: Glucocorticoids
- P
- Chronic effect
- Permissive: presence required for normal processes
- In chronic high doses leads to bone loss and catabolism
Regulation of bon growth: Androgens
- T S
- Testosterone surge during puberty accelerates closure of growth plates
Effects of an abnormal increased GH secretion:
- Gigantism (before epiphyseal growth plate has sealed)
2. Acromegaly (after growth plate closure)
Adrenal cortex zones: (3)
- g
- f
- r
- Zona glomerulosa
- Zona fasiculata
- Zona reticularis
Hormone produced in the zone glomerulosa:
- Aldosterone
Hormone produced by zona fasiculata:
- Cortisol (and androgens)
Hormone produced by zona reticularis:
- Androgens (and cortisol)
Hormones produced by the adrenal medulla
- Adrenaline
- Noradrenaline
Synthesis of adrenocortical steroids
- All based on cholesterol, synthesised as required
- Expression of key enzymes regulated
Cortisol (glucocorticoid):
- secretion:
- regulation:
- Secreted by zona fasiculata
- Release controlled by CRH/ACTH
CRH: Cortisol releasing hormone
ACTH: adrenocorticotrophic hormone
Circadian rhythm for Cortisol:
- Synchronisation
- Effect of stress
- CRH secretion synchronised with sleep cycle.
- Stress-induced CRH secretion increases glucocorticoid secretion approx. 20 fold
Cortisol actions:
- Metabolic effects
- Cardiovascular effects
- Other
- ME: Stimulates gluconeogenesis and glycogenolysis (provides fuel)
- CE: Maintains blood volume (protects CVS)
- OE: Anti-inflammatory, immunosuppressive
Cortisol action on CVS:
- Increases contractility
- Increases peripheral resistance
Amplifying the effects of noradrenaline and adrenaline
Cortisol effect on inflammatory/immune response: -INHIBITS . S of C . H R . P of I C . S of A
- Inhibits: . Secretion of cytokines . Histamine release . Proliferation of immune cells . synthesis of antibodies
Regulation of cortisol release: tripartite
1.
2.
3.
- Hypothalamus: releases CRH
- Anterior pituitary: releases ACTH
- Adrenal cortex: cortisol
CRH: corticotropin releasing hormone
ACTH: adrenocorticotropic hormone
Feedback control of cortisol
- Positive
- Negative
- Positive: stressors (physical/emotional)
- Negative: Pituitary, hypothalamus
Aldosterone:
- Secretion
- Half-life
- Zona glomerulosa
- 30 mins
What stimulates the release of cortisol?:
- Angiotensin 2
- Low Na stimulates renin release in kidney, renin cleaves angiotensin into Ang1
What does aldosterone stimulate?:
- Answer
- Effect
- aldosterone stimulates Na-K ATPase in renal collecting ducts
- Na reabsorbed in filtrate, K secreted into filtrate, Water retention
Corticosteroid receptors:
- two cytosolic receptors
- Glucocorticoid receptor (GR)
. Cortisol - higher affinity at GR
. Most cells have GR - Mineralocorticoid receptor (MR)
. Aldosterone - higher affinity at MR
. MR mainly in kidney and gut
Termination of action (adrenocorticoid):
- Half-life:
- Liver
- Kidney
- Half-life:
. Cortisol: 60 mins
. Aldosterone: 15 mins - Liver: cortisol and aldosterone inactivated
- Kidney: inactivated forms excreted in urine
Dysregulation of glucocorticoid release (2)
- Addison’s: too little cortisol
- Cushing disease: too much cortisol
Paths to dysregulation:
- Primary
- Secondary
- Tertiary
- Primary: failure of adrenal cortex to secrete cortisol
- secondary: failure of pituitary to secrete ACTH
- tertiary: failure of hypothalamus to secrete CRH
Addison syndrome: too little cortisol
-Symptoms(6)
Symptoms:
- Hypotension
- Hypoglycemia
- Hyponatremia
- Hypovolumia
- Hyperpigmentation
- Hyperkalemia
Addison’s disease :
- Main cause
- Other cause
- Main cause: autoimmune destruction of adrenal cortical cells (primary adrenocortical insufficiency)
- Other causes:
. Chronic glucocorticoid treatment
. Infection
Cushing’s SYNDROME:
- ACTH???
- Causes????
- ACTH low
- Adrenal neoplasm or hyperplasia
- Chronic glucocorticoid treament
Cushing’s disease:
- ACTH high
- Excessive and unregulated pituitary ACTH secretion
Glucocorticoid treatment:
- wanted effects
- unwanted effects
- Wanted effects:
- reduces inflammation and suppresses immune system
- Unwanted effects:
- Atrophy of the zona fasicula (cortex)
Cushing’s treatment:
- Remove or destroy source of ACTH or cortisol
Cushing’s treatment:
- Remove or destroy source of ACTH or cortisol
General thyroid and parathyroid anatomy:
- TG
- PTG
- Thyroid gland has lateral lobes connected by isthmus
- Parathyroid glands are located behind the lateral lobes of the thyroid
T4 and T3 synthesis:
-Location
- Active uptake of….. I
- Production of ….. Thy
- Iodination of …… tyr
- Reabsorption of….. thy
- Digestion by …..
- Occurs in the thyroid follicles
5 steps
1. Active uptake of iodide I-
2. Production of thyroglobulin
3. Iodination of tyrosine on thyroglobulin (in colloid)
4. Reabsorption of thyroglobulin
5. Digestion by lysosomal enzymes causes secretion of T4 and T3
Dietary iodide facts:
- Daily requirement:
- AVG. daily intake
- Efficiently absorbed
- Absorbed into….
- Removed from EP by ….
- Kidneys…
- Thyroid contains…..
- Daily requirement: >75 micro grams
- Avg. daily intake: 500 micro g
- Efficiently absorbed: only 15 micro g lost from gut in bile
- Absorbed into extracellular pool: 150 micro g.
- Removed from EP by thyroid or kidneys
- Kidneys excrete 485 micro gram/day
- Thyroid contains huge iodide store in colloid (8000 micro g)
Actions of thyroid hormones:
- TBG
- Method of action
- Target genes
- Target cells
- > 99% is reversibly bound to proteins - thyroid binding globulin (TBG)
- T4 and T3 operate through nuclear receptors regulating gene transcription (latency of several days)
- Genes regulating cell differentiation and metabolism
- Affects most tissues
Hypothyroidism: in early development
- Definition
- Symptoms (4)
- Cretinism: complete absence of thyroid hormone during development
- symptoms: Neurological deficits (retardation)
- Small stature and immature appearance
- Puffy hands and face
- Delayed puberty
Hypothyroidism in adulthood: symptoms (9)
- L BMR and C S
- B
- S S
- L
- W G
- C
- M A
- D T S
- S M F
- Low BMR and cold sensitivity
- Bradycardia (abnormally low resting HR)
- Slow speech
- Lethargy
- Weight gain
- Constipation
- Menstrual abnormalities
- Dry thickened skin
- Slow mental function
Hyperthyroidism symptoms:
- Nervousness
- High BMR, raised temp
- Tachycardia (abnormally high resting HR)
- Increased appetite/ weight loss
- Tiredness
Physiological role of calcium: (6) - B S - B C _ N E - M I T - E R - C
- Bone strength
- Blood coagulation
- Neuromusclular excitability
- Membrane ion transport
- Enzyme regulation
- Contraction
3 hormones of Ca regulation:
- PTH
- Calcitonin
- Vitamin D
Normal plasma calcium range:
- 2.2 to 2.6 mmol/L
Low Plasma Ca2+ response:
- Parathyroid glands (chief cells) secrete PTH, increasing plasma Ca2+
High plasma Ca2+ response:
- Thyroid parafollicular C cells secrete calcitonin, lowering plasma Ca2+
Hypocalcaemia:
- Cause
- Symptoms
- Increased N E
- T, M C, T
- C and D (severe)
- Caused by hypoparathyroidism, caused by accidental damage to parathyroid glands during thyroid surgery
- Symptoms:
- Increased neuromusclular excitability
- Twitching, muscle cramps, tetany
- Carpodeal spasm
- Coma and death (severe)
Hypercalcaemia:
- Cause
- Symptoms
- Associated with primary hyperparathyroidism and malignancy
- Symptoms of stones bones and groans
Insulin:
- Role:
- Secreted:
- Role: signals the fed state, lowers blood glucose levels
- Secreted by beta-cells in the pancreas
Insulin synthesis:
- Starts as preproinsulin, signal sequence….
- A and B peptides linked by ….
- Mature insulin leaves …..
- Starts as preproinsulin, signal sequence directs it into the endoplasmic reticulum
- A and B peptides linked by disulfide bonds, proinsulin cleaved twice by a protease, removing C peptide
- Mature insulin leaves Golgi network and enters a secretory vesicle
Insulin action:
- Insulin binds to ……… ………. ……… on the surface of muscle and adipose cells
- …… is activated, auto phosphorylating ……….
- Phosphorylated receptor binds to …..
allowing ….. to be converted to …….
- …….. activated ……. which activates Akt
- Activated Akt increases cell glucose uptake
- Insulin binds to enzyme-coupled receptors on the surface of muscle and adipose cells
- RTK is activated, auto phosphorylating tyrosines
- Phosphorylated receptor bind to IRS-1 allowing PIP2 to be converted to PIP3
- PIP3 activates PDK1, which activates Akt
- Akt ac
Effect of activated Akt on GLUT4 transporters:
- Activated Akt causes GLUT4 transporter vesicles to fuse to the cell surface membrane, increasing glucose uptake 15x
Glucose regulates insulin secretion from beta-cells:
- Glucose enters…..
- Glycolysis causes an…..
- ATP binds to …..
- Membrane depolarisation causes…..
- Causing more ….
- Triggering insulin release via …..
- Glucose enters the beta-cell via GLUT2
- Glycolysis causes an increase in ATP
- ATP binds to ATP-gated K+ channels, closing them
- Membrane depolarisation causes opening of Ca2+ channels
- Causes more Ca2+ to be released by the ER
- Triggering insulin release via exocytosis
Sulfonylurea drugs in treating diabetes:
- Binds to SUR1 subunit, closing K+ channel, causing insulin release
Insulin main aim:
- Stimulate the uptake of glucose into cells, lowers plasma blood sugar levels
Glucagon main aim:
- Glycogen breakdown, raises plasma blood sugar levels
Type 1 diabetes:
- Population UK
- Due to:
- Development:
- Treatment
- 375,000
- Due to failure to secrete or produce insulin, usually due to autoimmune destruction of b-cells
- Usually develops early in life
- Treated with insulin injections
Type 2 diabetes
- Population
- Due to
- Development
- Treatment
- > 2 million
- Due to failure to respond to insulin
- Usually develops late in adulthood / associated with obesity
- Controlled by diet and drugs
Diabetes symptoms:
- Mutual (2)
- Type 1 specific: ketoacidocis
- Elevated blood sugar
- Excessive urination and thirst
In type 1:
- Accelerated fat break down, increase in ketone bodies, some of which are ketoacids, raising [H+], causing ketoacidosis
Long-term effects of raised blood sugar:
- Hemoglobin becomes glycated, compromising O2 deliveries (especially to extremities)
Luteinizing hormone (LH) role:
- Stimulation of testosterone secretion
Follicle-stimulating hormone role: (2)
- Spermatogenesis
- Oestrogen synthesis
DHEA (Dehydroepiandrosterone) role:
- Weaker androgens, no effect in males
Testosterone role:
- Secondary male sexual characteristics
- Spermatogenesis
Oestrogen role: (2)
- Secondary sexual characteristic development
- Growth of ovarian follicles/proliferation of endometrium
Progesterone role:
- Prepares the uterus for ovulation, thickens wall lining etc.
