Theme 5: The Endocrine System (L14-18) Flashcards
1
Q
Name 4 different types of cellular communication
A
Endocrine
Autocrine
Paracrine
Synaptic
2
Q
What are the hormones of the adrenal glands?
A
Cortisol
Aldosterone
Catecholamines (adrenaline and noradrenaline)
Oestrogen
3
Q
What are the different endocrine glands?
A
Hypothalamus
Pituitary
Thyroid
Parathyroid
Adrenal
Pancreas
Ovaries
Testes
4
Q
What are the differences between the anterior and posterior pituitary?
A
Anterior has it’s own larger supply of blood to the lobe and creates its own hormones
Posterior receives hormones from the hypothalamus and cannot create it’s own
5
Q
What are the zones of the adrenal gland?
A
Glomerular
Follicular
Reticularis
6
Q
Which hormones are released from the zona Glomerulosa?
A
Aldosterone
7
Q
Which hormones are released from the zona Fasciculata?
A
Glucocorticoids (cortisol)
8
Q
Which hormones are released from the zona reticularis?
A
Catecholamines (adrenaline and noradrenaline)
9
Q
How is cortisol released?
A
Feedback from the hypothalamus releases corticotropin-releasing hormone
Then the anterior pituitary releases adreno-corticotropic hormones
This stimulates the cortex of the adrenal glands to release cortisol
10
Q
What is the mechanism of androgen receptor signalling?
A
Testosterone diffuses through the cell, this then forms dihydrotestosterone using alpha reductase
DHT binds the androgen receptor which sheds HSP90 after conformational change then homodimerises to enter the nucleus
Binding to androgen response elements which recruits coactivators
Increased expression through TXN
11
Q
What is the function of HSP90?
A
It allows the androgen receptor to remain stable in the cytoplasm when inactive
12
Q
What is the mechanism of testosterone production?
A
Hypothalamus: GnRH
Pituitary: LH
Testes: Testosterone -> prostate
13
Q
What is the structure of the androgen receptor?
A
Expressed on the q chromatid of the X chromosome
Protein contains N-terminal domain, DNA-binding domain hinge and ligand-binding domain
14
Q
What is the function of the NTD in AR protein?
A
Allows transcriptional activity
Binds to the LBD when inactive for stabilisation
15
Q
What is the function of the LBD in the AR protein?
A
It allows homo dimer binding
16
Q
What is the function of the DBD of the AR protein?
A
It contains zinc fingers which allow binding of a specific motif on DNA which provides specific binding
1st binds androgen response element
2nd allows dimerisation on DNA
Which is all stabilised by Zn2+
17
Q
What was one of the first treatments of prostate cancer?
A
1966 - the removal of testicles which causes a significant regression in PC due to reduction in the production of testosterone
18
Q
What is androgen deprivation therapy?
A
Reduced/interferes with androgens - block receptor activations
Slowing the growth of PC
Surgical and chemical castration
First line treatment of metastatic PC
Improvement of outcome and survival
Significant side effects
19
Q
What is the process of chemical castration?
A
LHRH, GnRH and antiandrogens which block the binding and inhibit synthesis of androgen at kidneys and testes
20
Q
What is the mechanism of GnRH antagonists in prostate cancer?
A
It involves the blocking of tRH receptors which causes a rapid drop in LH meaning less testosterone therefore decreased tumour stimulation
21
Q
What is the mechanism of androgen receptor antagonist in prostate cancer?
A
Enzalutamide binds ligand binding domain of AR which prevents binding of androgen
Inhibition of translocation of AR in to nucleus
So inhibition of TXN of AR target genes
22
Q
What are the side effects of androgen deprivation therapy?
A
Increase risk heart disease
Erectile dysfunction
Mood changes
Hot flushes
Memory problems
Brain fog
Bone loss
Fatigue
Sleep disruption
23
Q
What is castration resistance prostate cancer?
A
Within 18 month 90% of men eventually develop treatment resistance
AR remains active in resistant disease (more aggressive)
Valid therapeutic target
Inhibiting AR signalling at different part o the signalling circuit may prove therapeutic beneficial
24
Q
What is the mechanism of castration resistant prostate cancer?
A
Intratumoral & adrenal steroid synthesis (increase intratumoral androgens)
AR gene amplification (inc. expression and hypersensitivity at low levels)
AR mutations, gain-of-function (point T877A, W741C, F876L and T878A)
AR splice variants (truncated, LBD deficient without ligand)
AR coregulators (inc. coactivators dec. corepressors)
Alternative signalling (up regulate anti-apoptic pathways AKT and loss tumour suppressors PTEN inhibits AKT)
Upregulation GR
25
How do mutations alter castration resistant prostate cancer?
Point mutations T877A, W741C, F876L and T878A
Increase promiscuity, activation (flutamide, biclutamide, enalutaminde and progesterone)
26
What is AR-V7?
It is the splice variant of the androgen receptor
It is constitutively active without androgens as it contains NTD and DBD but no hinge and LBD
27
What is the AR coregulator KMT5A?
Lysine methyltransferase: mono-methylates H4K20 and non-histone proteins
It interacts with AR and is required for transcriptional activity
Regulates the oncogenic pathways e.g. CDC20 in PC
28
How can the Hippo pathway be used to target prostate cancer?
- Hippo controls the switching off of TXN programmes for cell growth
- Through kinase cascade signalling to phosphorylation and proteasome-mediated degradation of YAP
- YAP is associated with AR
- YAP stabilisation upregulates genes like c-Myc
- High levels of c-Myc unregulates TXN of c-Myc target genes like AR
- IKBE leads to YAP stabilisation, so increased AR signalling
- IKBE and YAP are often over expressed in cancers like PC
29
What is androgenic alopecia?
Male pattern hair loss
Excessive follicular sensitivity to androgens
Shrinks hair follicles, replaces hair terminal with vellus hairs
30
What is the treatment for androgenic alopecia?
Finasteride - 5-alpha reductase inhibitor
Blocks the conversion of testosterone to its active form DHT lowering DHT levels
31
What is the use of heat shock proteins in monitoring hormone levels?
They can be used as housekeeping genes to monitor expression
32
What is the process of nuclear hormone receptor binding?
- Steroid hormone diffuses through cell membrane
- Binds to receptor with HSP, conformational change sheds the HSP
- This allows translocation into nucleus which binds promotor and increases the level of expression
33
What are the properties of oestrogen?
Fertility:
Growth of ovarian follicles
Endometrial growth
Increase tubal motility & uterine contractions
Lactation:
Stimulation of duct growth
Inhibits milk let-down (prolactin)
Secondary sexual characteristics:
Breast development
Female habitus
Development of external genitalia
34
What are the properties of progesterone?
Fertility:
Endometrial receptivity
Decrease Fallopian tube motility
Decrease uterine contractions
Lectation:
Stimulation of lobuloaveolar development
Inhibits milk let-down (prolactin)
PMS (post menstrual syndrome - progesterone withdrawal)
35
What is the role of progesterone in the hypothalamic-pituitary-ovarian axis?
LH stimulates the production of progesterone and the maturation of the uterine lining
36
What is the role of oestrogen in the hypothalamic-pituitary-ovarian axis?
FSH produces aromatase which stimulates the conversion of androgen to oestrogen stimulating the growth in ovarian follicles
37
Where is GnRH released from?
Generated in hypothalamus and released to the anterior pituitary gland
37
What is the target of FSH?
Granuloma cells in ovarian follicles
This induces the expression of aromatase (androgen to oestrogen)
38
What is the target of LH?
Theca cells and later the corpus luteum
Theca cells produce androgens allowing oestrogen production and maintains the corpus luteum which produces progesterone
39
What is the negative feedback of oestrogen?
Follicular maturation
Proliferation of endometrium
Inhibition of FSH to regulate cycle
40
What is the negative feedback of progesterone?
Renders endometrium suitable for implanting fertilised ovum
Inhibition of further release of GnRH (hypothalamic arcuate nuclei), FSH and LH to regulate cycle and ovulation
41
What are the phases of the menstrual cycle?
Follicular phase
Ovulation
Luteal phase
42
What happens in the follicular phase of the cycle?
FSH increase from low ovarian production
FSH aids follicular development
Follicles produce development
High concentrations oestrogen
43
What happens during ovulation in the cycle?
Positive feedback from increase oestrogen initiates LH surge
LH surge induced ovulation
44
What happens during the luteal phase of the cycle?
Remainder of the ovulatory follicle becomes luteinised
Secreted progesterone and oestrogen
45
What happens during the cycle when not pregnant?
Corpus luteum regresses and decrease in oestrogen and progesterone
Endometrium not maintained - menstruation
Lack progesterone so GRH, FSH and LH secretion released which starts the cycle again
46
What happens during the cycle in fertilisation and implantation occurs?
Ovum secreted human chorionic gonadotrophin (HCG) stimulates CL continual progesterone
Maintain endometrium and pregnancy
Thicken cervical mucus
Inhibit further secretion of GRH, FSH and LH prevents further follicles developing
47
What are the important pharmacological targets in regulation of ovulation and pregnancy?
ER and PR agonists - GnRH, FSH and LH induce follicle formation and ovulation, inhibition of further follicle formation
PR antagonist - progesterone to maintain pregnancy
48
What are the different sex hormones in contraception?
Combined pill (progesterone and oestrogen)
Progesterone only
49
How does the combined pill work?
Oestrogen inhibit FSH via -ive feedback, prevents development of ovarian follicle and blocks ovulation - no FSH peak
Progesterone inhibits secretion of LH, blocks LH surge and makes cervical mucus less suitable for passage
50
How does the progesterone only pill work?
Inhibits LH thickening the mucus stopping sperm reaching egg
Blocks ovulation not cosistent
Taken continuously cause irregular periods
51
What are examples of emergency contraception?
Contragestation (abortion)
Mifepristone - progesterone antagonist
Terminates pregnancy at level of endometrium
Progesterone imperative for pregnancy maintenance
52
When are sex hormones targeted clinically?
Oral contraceptives/fertility control
Replacement therapy in menopause
Ovulation induction
Cancer chemotherapy
53
What type of drugs are used to treat breast cancer?
ER+ BC
Selective oestrogen receptor modulators (SERM) - tamoxifen
Aromatase inhibitor - anastrozole
54
What are hormone antagonists?
Used in tumours in hormone sensitive tissues (breast, endometrial, ovarian and prostate)
Growth inhibited: oestrogen/progesterone and androgen and inhibition of synthesis
55
What is the mechanism of tamoxifen?
Competitive inhibitor of estradiol binding to ER
Forms a dimer when bound
Transported to nucleus which binds to DNA and forms an unstable complex
Hormonal growth signal switched off and reduces cell proliferation
56
What is the mechanism of anastrozole?
Inhibits the conversion of androstenedione and testosterone to oestrodiol and oestrone
Switches normal signal off and reduces cell proliferation and cell survival (NOT PRE MENOPAUSAL)
57
57
Why is anastrozole not used pre-menopause?
Due to the ovaries still making oestrogen, using the drug it stimulates higher levels of oestrogen
Only used in combination (GnRH agonists + surgical oophorectomy)
58
Why is ER+ breast cancer more important than ER-?
As 75% breast cancers have over expressed oestrogen receptor signalling which plays an important role in BC
59
Which hormones are produced from the posterior pituitary?
Antidiuretic hormone (renal function)
Oxytocin (regulation uterine contraction)
60
What does the posterior pituitary contain?
Axons from supra tic and paraventricular nuclei of hypothalamus
Release peptide hormones into capillaries of hypophyseal circulation
Stores and secretes hormones
61
Which hormones does the anterior pituitary produce?
TSH, ACTH, FSH, LH, GH, PL
62
What does ADH do?
Regulates blood volume/pressure by controlling water reabsorption
63
What is the mechanism of ADH?
Binds V2 receptors on basolateral membrane of principle cells
Promotes conversion ATP to cAMP via adenylyl cyclase
Activated PKA
Promotes fusion of aquaporin2 into apical human enhancing permeability to H2O
Increased water permeability = concentrated urine
64
Which part of nephron is impermeable to H2O?
Ascending limb LoH, DCT and collecting duct
65
What are ADH hormone level stimulants?
Opioids, anti-depressants, nicotine and MDMA (repetitive habits and thirst)
66
What are ADH hormone level depressants?
Alcohol
67
What are the disorders of ADH - Syndrome of inappropriate ADH secretion (SIADH)?
Excessive secretion leading high urine osmolality, increase body water
Hyponatremia, hypo osmotic blood plasma and hypervolemia (inc. H2O)
68
What are the causes of SIADH?
Post operative (metabolic response)
Head trauma
Ectopic ADH production (tumours)
Drugs
69
What is the treatment of SIADH?
ADH V2 antagonist (Tolvaptan)
70
What is the mechanism of syndrome of inappropriate ADH secretion?
Increased ADH - increased water permeability in DCT and CD
Increased blood volume - more concentrated
Compensatory mechanism:
Kidney decreases Renin - decreased angiotensin II - decreased mineralocorticoid - decrease Na+ in blood - high Na+ in urine
Hyponatremia worse
71
What is a disorder of ADH - diabetes insipidus?
Non-functional ADH - excessive loss of water
Polyuria, polydipsia, hypernatremia and hypotension
72
What happens in neurogenic diabetes insipidus?
Failure ADH secretion - lesson hypothalamus/pituitary
Treatment - synthetic ADH
73
What happens in nephrogenic diabetes insipidus?
Failure principle cells response to ADH (V2 R mutation)
Treatment - restricted Na+ diet
74
What are the different treatments for too little and too much ADH?
Too little:
V2 agonists (lypressin, desmopressin)
Too much:
V2 antagonist (demeclocylcine, tolvaptan)
75
Where is aldosterone released from?
Zona glomerulosa in the adrenal cortex
76
Which hormones are released from the zone fasiculata?
Glucocorticoids
77
Which hormones are released from the zone reticularis?
Androgens (dihydrotestosterone)
78
Which hormones are released from the adrenal medulla?
Adrenaline and noradrenaline
79
Which enzyme is used to form glucocorticoids from cholesterol?
17α-hydroxylase
80
Which enzyme allows the conversion from cortisol to sex hormones?
17,20 lyase
81
What happens when aldosterone binds to its receptors?
Increased expression of ENaC channels in the apical membrane of the principle cell
Increased K+ channels
Increased basolateral Na+/K+ pump
Increased SGK1 (kinase) activated Na+/K+ pump
Therefore increase in Na+ reabsorption (increase water volume)
82
What are the properties of aldosterone?
Regulation Na+ and K+ balance - principle cell (DCT + CD)
From zona glomerulosa
MR specific to kidney - regulates DNA TXN
83
How is aldosterone regulated?
Directly - stimulated by low plasma Na+ or high K+
Indirect - angiotensin II
84
What is the indirect pathway of aldosterone regulation?
Renin production converts angiotensinogen to angiotensin I
Angiotensin I converted to angiotensin II using angiotensin converting enzyme
Aldosterone produced by adrenal retaining salt and increasing BP
85
What are the effects of angiotensin II?
Sympathetic activity
Tubular Na+, Cl- reabsorption K+ excretion and H2O retention
Aldosterone secretion
Arteriolar vasoconstriction
ADH secretion - H2O reabsorption
86
What are the different diseases of hyperaldosteronism?
Primary: Conn's syndrome - adrenal hyperplasia/tumour
Secondary: Chronic low BP - congestive HF=high renin= excess aldosterone
87
What are the symptoms of hyperaldosteronism?
Decreased Na+ - hypernatermia (thirst and odema), hypertension (headache, fatigue, confusion and chest pain)
Increased K+ - hypokalaemia (heart arrhythmia, constipation and weakness)
88
What is hyperaldosteronism treated with?
Sironolactone or eplerenone
89
What are the different diseases of hypoaldosteronism?
Primary: Addison's disease - autoimmune - destruction of Z.glomerulosa cells
Secondary: Renin deficiency - genetic predisposition
90
What are the symptoms of hypoaldosteronism?
Increased Na+ - hyponatermia (confusion, fatigue, seizure and coma), hypotension (vascular collapse, dizziness, fatigue and confusion)
Decreased K+ - hyperkalemia (heart arrhythmia, constipation and weakness)
91
What is hypoaldosteronism treated with?
MR agonist - fludrocortisone
92
What are the properties of glucocorticoids?
Cortisol - GR
HPA axis - increased metabolism
Anti-inflammatory/immunosuppressive
Disorders: hypercortisol - Cushing's syndrome
Metabolic dysfunction - cortisol synthesis
Antagonist - metyrapone
93
What are the affinities for GR and MR using aldosterone and cortisol?
Aldosterone: high MR, low GR
Cortisol: high MR, low GR
94
What happens at basal circulating plasma levels of cortisol?
MR receptors fully saturated
95
What is the function of 11-hydroxysteroid dehydrogenase?
It removes cortisol allowing aldosterone to act on the MR
96
What is carbenoxolone used for?
Oral and gastric ulcers due to lack of cortisol which can be caused by glycerrhetinic acid
97
What is the side effect of glycerrhetinic acid in pregnancy (licorice)?
Protects foetus from elevation in cortisol - baby weight and mental cognition side effects
Can cause oppositional defiant disorder - temper, argue, spiteful, defiant and intolerant
98
When is insulin required in T2D?
Relief of symptoms
Reduce risk of complications
When other treatments may be contraindicated
99
What is the educational programme provided for T1D?
DAFNE - dose adjustment for normal eating
100
What are the different types of insulin?
Animal (pigs and cows)
Human: short acting - actarapid and humulin S, intermediate - insulatard and humulin I
Insulin analogues: genetically engineered, very fast acting - humalog, novorapid, long duration - glargine, determir
101
What is the percentage of adults with T2D?
90%
102
How is treatment established in T2D?
HbA1C is measured
Reinforcement about diet, lifestyle and adherence to drug treatment
1st line treatment is metformin
103
What is the mechanism of action of metformin?
Suppresses glucose production in the lives
Inhibits mitochondrial respiratory-chain complex 1, reduce ATP, inc. AMP
AMP activate adenosine monophosphate activated protein kinase (AMPK) lowers BG in 2 ways:
1) Increased AMPK phosphorylates CBP&CRTC2 transcription factors, inhibits genes producing glucose
2) Inc. AMPK inhibits mitochondrial glycerol-3-phosphate dehydrogenase, inc cytosolic NADH, pyruvate to lactate and dec. gluconeogenesis
104
What are the different treatments of T2D?
Sulphonylureas
Pioglitazone
Dipeptyl peptidase 4 (DPP4) inhibitors and glucagon-like-polypeptide 1 (GLP-1)
Sodium glucose like transporter-2 (SGLT-2)
105
What is the mechanism of sulphonylureas?
Block the K+ sensitive channel in beta cells by binding to SUR1 receptor
Closes the K+ channels so depolarises the cells
Ca2+ rushes in via VGCC
Insulin is secreted to lower BG
106
What is the mechanism of thiazolidinediones?
Improve insulin sensitivity
Activate peroxisome proliferator-activated receptor gamma (PPAR-γ), found in fat cells
Activation increases expression of insulin-responsive genes enhancing the production of proteins in glucose and lipid metabolism
107
What are the benefits of thiazolidinediones?
Improved differentiation and function of adipocytes - enhances storage and stops release
Inc. glucose uptake muscle and adipose lower BG
Reduce hepatic gluconeogenesis, different regulatory mechanisms to metformin
108
What is the mechanism of GLP-1 agonists?
Synthetic analogue of glucagon-like-polypeptide 1 (GLP-1) resistant to break down by DPP-4 multiple actions:
Potentiates glucose-mediated insulin secretion
Suppression of postprandial glucagon release
CNS-mediated loss of appetite
Slowed gastric emptying by reduced parasympathetic tone
109
What is the mechanism of DPP-4 inhibitors?
dipeptyl peptidase-4 inhibitors stop the degradation of incretin GLP-1
This allows the potentiation of secretion of insulin via the pancreas
110
What is GIP?
Glucose-dependent insulinotropic polypeptide
Insulin secretion, less potent in type 2
Does not suppress glucagon like GLP-1
111
What are incretins?
Hormones released from the GI in response to nutrient ingestion
Potentiate glucose-stimulated insulin from beta cells in the pancreas
112
What is the mechanism of SGLT2 inhibitors?
Inhibits the Na-glucose co-transporter 2 in the kidney to increase glucose excretion and lower BG
Located in PCT and mediates ~90% of glucose reabsorption and also cardioprotective
113
What does the thyroid gland regulate?
Brain development
Metabolic control (muscle control, heart function and digestive function)
Bone maintenance
114
How is thyroxine and triiodothyronine produced?
Hypothalamus: TSH- releasing hormone (TRH)
Pituitary: Thyroid stimulating hormone (TSH)
Thyroid gland: T4/T3
115
Where is thyroglobulin found?
In the follicle surrounded by follicle cells
116
What regulates the thyroid?
The hypothalamic pituitary thyroid axis
117
What is the most active hormone in the thyroid?
Triiodothyronine (T3)
118
What is calcitonin?
It is involved in calcium homeostasis produced from the thyroid in conjunction with the parathyroid
119
What is the mechanism of T3&4 production?
Tyrosine residues thyroglobulin synthesised by follicular cells and released into colloid
Iodide from the blood is transported through follicle cells into colloid
Iodination occurs whereby iodine molecules attach tyrosine done using thyroperoxidase and coupling occurs (T1+T2/T2+T2) forming T3/4
120
What is T1/2?
Monoiodotyrosine (T1)
Diiodotyrosine (T2)
121
What are the different types of thyroxine receptors?
α1, 2 & β1, 2
122
What is the mechanism of binding for thyroid receptors?
TRα2 doesn't bind T3 but other receptors have higher affinity for T3 than T4
Key target is increased transcription of genes encoding mitochondrial uncoupling proteins
123
What is the function of thyroxine?
Metabolic - inc. basal rate: glycolysis, O2 consumption, thermogenesis and protein turnover
Growth and development - fetal neural development post-natal: bone growth and tooth development
Neurological - maintains emotional tone: increase alertness, memory, reflexes and wakefulness
Cardiovascular - inc. cardiac output and systolic pressure and enhances catecholamine actions
Reproduction - permissive role in males and females
124
What are the symptoms of hypothyroidism?
Weight gain
Decrease metabolic rate
Depressed function of CNS
Decreases SNS
Bradycardia
Low activity of GI and constipation
Decreased catecholamine sensitivity
125
What are the symptoms of hyperthyroidism?
Wight loss
Increase metabolic rate
Increased CNS
Increase SNS
Tachycardia
High activity GI tract and diarrhoea
Increased catecholamine sensitivity
126
When are synthetic thyroid hormones used?
Hypothyroidism
Diffuse non-toxic goitre (enlargement of thyroid gland)
Hashimoto's thyroiditis
Thyroid carcinoma
127
What are the treatments used for synthetic thyroid hormones?
Levothyroxine and Liothyronine sodium
128
What are the adverse effects of synthetic thyroid hormones?
Overdose - hyperthyroidism - thyrotoxicosis
Precipitation of cardiac arrhythmias, angina pectoris or cardiac failure
129
What are the treatments for hyperthyroidism?
Carbimazole/propylthiouracil - used to block thyroperoxidase
Carbimazole - most commonly used, decreases output of thyroid hormones 3-4 weeks normal
propylthiouracil - blocks T4 to T3 in peripheral tissues only reserved for no response to carbimazole
130
What are the diseases of hyperthyroidism?
Thyrotoxicosis - high metabolic rate, increase temperature, nervousness, tremor, increase appetite and wight loss, tachycardia
Diffuse toxic goitre (Grave's disease) -TSH receptors, increased thyroxine
Toxic nodular goitre (tumour)
131
What is the use of excess iodine treatment?
High doses inhibit thyroid hormones 10-14 days
Reduction in blood supply
Used in preparation for surgical resection
132
When is radioactive sodium iodide used?
Treat thyrotoxicosis at all ages - if drugs not tolerated or complications
Emits beta and gamma radiation therefore destroys thyroid tissue, T4 replacement therapy required
133
What are other different treatments for hyperthyroidism?
Propranolol hydrochloride - treat symptoms (tachycardia, arrhythmias and tremor)
Thyrotoxic crisis - IV fluids, propranolol, hydrocortisone, oral iodine and carbimazol/propylthiouracil
