5. Endocrine System Flashcards
1
Q
Give examples of endocrine glands
A
-Pituitary
-Thyroid
-Parathyroid
-Adrenals
-Pancrease
-Ovaries and Testes
-Pineal
2
Q
Is the hypothalamus a gland?
A
-No, it is better described as a neuroendocrine organ, as it integrates the nervous and endocrine systems.
-but it does produce releasing and inhibiting hormones that regulate the pituitary gland
3
Q
Give some hormones that the hypothalamus releases
A
-Thyrotropin releasing hormone (TRH)
-Corticotropin releasing hormone (CRH)
-Gonadotropin releasing hormone (GnRH)
-Growth hormone releasing hormone (GHRH)
-Somatostatin
-Dopamine
-Vasopressin and Oxytocin
4
Q
Describe how the pituitary gland is divided?
A
Into two main lobes:
-Anterior pituitary (adenohypophysis): Releases hormones in response to signals from the hypothalamus
-Posterior pituitary (neurohypophysis): Stores and releases hormones produced by the hypothalamus
5
Q
Give hormones released by the anterior lobe of the pituitary gland
A
-Growth Hormone (GH)
-Thyroid stimulating hormone (TSH)
-Adrenocorticotropic hormone (ACTH)
-Luteinising hormone (LH)
-Follicle stimulating hormone (FSH)
-Prolactin
6
Q
Give hormones released by the posterior lobe of the pituitary gland
A
-Oxytocin
-ADH/Vasopressin
7
Q
Give the hormones released by the thyroid gland, and their functions
A
-T4 and T3, both involved in increasing metabolism and energy production, body temperature regulation, growth and development and heart rate and digestion
-Calcitonin, involving in lowering blood calcium levels by inhibiting bone breakdown and promoting calcium storage in bones
8
Q
What regulates the activity of the thyroid gland?
A
-Hypothalamus release of TRH leads to stimulation of TSH release
-TSH stimulates the thyroid gland to release T3 and T4
-High T3 and T4 inhibit TRH and TSH release through negative feedback
9
Q
Give the hormone that the parathyroid gland releases, and their functions
A
-Parathyroid hormone
-Plays a crucial role in calcium homeostasis, acting on the bones, kidneys and intestines
10
Q
Give the hormones that the pancreas releases, and their functions
A
-Insulin, lowering blood glucose levels
-Glucagon, increasing blood glucose levels
-Somatostatin, inhibits insulin and glucagon release to prevent extreme fluctuations in blood glucose levels
-Pancreatic polypeptide, regulating pancreatic enzyme secretion
11
Q
Give the hormones that the adrenal glands release, and their functions
A
-Cortisol (glucocorticoids) regulating metabolism and immune response, helping the body respond to stress
-Aldosterone (mineralocorticoids) regulating sodium and potassium reabsorption, controlling blood pressure
-Androgens acting as precursors to sex hormones
-Catecholamines as part of fight or flight stress response
12
Q
Give the hormones that the testes release, and their functions
A
-Testosterone, involved in development of male reproductive tissues, promoting secondary sexual characteristics and promotes spermatogenesis
-Inhibin, involved in the inhibition of the secretion of FSH, regulating sperm production
-Estradiol in small amounts, involved in sperm maturation
13
Q
Give the hormones that the ovaries release, and their functions
A
-Oestrogen, involved in development of female reproductive tissues, promoting secondary sexual characteristics, regulates the menstrual cycle and aids in maturation of oocytes
-Progesterone, involved in preparing the uterus and regulating the menstrual cycle. Helps prevent further ovulation during pregnancy.
-Inhibin, involved in inhibition of FSH and works in controlling number of eggs maturing in each cycle
14
Q
Describe simply endocrine communication
A
Hormones are secreted into the bloodstream and bind to target cell receptors
15
Q
Give the sections of the adrenal glands
A
-Adrenal cortex (outer layer)
-Adrenal medulla (inner layer)
16
Q
Give the sections of the adrenal cortex
A
-Zona glomerulosa (outermost layer)
-Zona fasciculata (middle layer)
-Zona reticularis (innermost layer)
17
Q
Give the hormones secreted by each section of the adrenal cortex
A
-Z Glomerulosa secretes mineralocorticoids (aldosterone)
-Z Fasciculata secretes glucocorticoids (cortisol)
-Z Reticularis secretes androgens (DHEA)
18
Q
Give the hormones secreted by the adrenal medulla
A
-Adrenaline
-Noradrenaline
19
Q
Describe the mechanism of action by which steroid hormones act
A
-Lipid soluble hormones (eg thyroid hormones) bind to carrier proteins until they reach target tissues
-Diffuse easily through the cell membrane due to fat solubility
-Bind to intracellular receptors inside the cell
-Hormone receptor complex enters the nucleus and binds to promoters to regulate the transcription of target genes
-These genes are translated and carry out specific cellular effects
20
Q
Describe the mechanism of action by which water soluble hormones act
A
-Peptides, proteins and catecholamines are hydrophilic, meaning they cannot pass through the cell membrane
-They bind to specific receptors on the plasma membrane of the target cell
-This signal is transducer through an intracellular signalling pathway (often involving second messengers)
-The second messengers activate protein kinases, which in turn alter the activity of other proteins
-Eliciting a cellular response
21
Q
How does androgen receptor signalling begin?
A
-Hypothalamus releases gonadotropin releasing hormone (GnRH), stimulating the anterior pituitary to secrete LH and FSH
-LH acts on the testes to stimulate the production of testosterone
22
Q
Describe what occurs after testosterone enters the prostate cell?
A
-Testosterone is converted to DHT by salpha reductase
-DHT binds Androgen receptor-HSP90 duplex, allowing for HSP90 dissociation
-DHT-AR forms a duplex with another DHT-AR, which translocates to the nucleus, binding to the promoter region (androgen response elements)
-Leading to transcription and translation of Prostate specific antigens (amongst others)
23
Q
Describe the gene on which the androgen receptor protein is encoded
A
-Regulated by a promoter region
-Composed of 8 exons and 7 introns
-Located on the X chromosome (Xq11-12)
24
Q
Describe the androgen receptor protein
A
-N terminal domain (encoded by exons 1 and 2) is involved in transcriptional activation
-DNA binding domain (encoded by exon 3) contains two zinc finger motifs, allowing androgen responsible element binding in the DNA
-Hinge region (encoded by exon 4) connects the DBD to the LBD
-Ligand binding domain (encoded by exons 5-8) is responsible for binding androgens (testosterone or DHT), undergoing a conformational change upon binding
25
Where do most mutations occur in the androgen receptor gene, leading to cancers?
The Ligand Binding Domain
26
What is androgen deprivation therapy?
-ADT is a cornerstone of prostate cancer treatment, targeting androgen signaling to slow or halt cancer progression
-ADT aims to reduce the levels of androgens in the body or block their action on androgen receptors (AR) in prostate cancer cells, thereby inhibiting cancer growth.
26
Describe the two forms of castration used in androgen deprivation therapy
-Surgical Castration (orchiectomy) involves removal of the testes to reduce the primary source of testosterone production
-Medical castration involves LHRH agonists and antagonists reducing the production of testosterone
27
Describe two forms of chemical castration used in the treatment of prostate cancer
-LH releasing hormone agonists (leading to desensitisation of the pituitary and reduced LH/FSH production) reduce testosterone production,
-LHRH antagonists, directly inhibit the release of LH and FSH from the pituitary, reducing testosterone production
28
Give examples of drugs used in the treatment of prostate cancer
-LHRH agonists (desensitises the pituitary)
-LHRH antagonists (inhibit LH release from the pituitary)
-Enzalutamide (competes for LBD of AR, and inhibits translocation of the AR)
-Ganirelix (GnRH antagonists)
29
Describe the mechanisms through which Enzalutamide blocks AR signalling
-Competitive antagonism of the LBD of androgen receptor, preventing binding of androgens
-Prevents the translocation of the AR to the nucleus by disrupting its conformational change
-Prevents the AR to bind to the androgen-responsible elements in the DNA
30
Describe the mechanism of action of Ganirelix in the treatment of prostate cancer
-Antagonism of the GnRH receptor in the pituitary gland, preventing the pituitary from releasing LH and FSH
-Testes are unable to produce testosterone without the initial surge in testosterone
31
Give side effects associated with Androgen deprivation therapy
-Erectile dysfunction
-Mood changes
-Hot flushes
-Memory problems
-Brain fog
-Bone loss
-Fatigue
-Sleep disruption
-Increased risk of heart disease
32
What is Castration Resistant Prostate Cancer?
-Advanced form of prostate cancer
-Continues to grow despite the suppression of testosterone
-Cancer cells are resistant to the effects of testosterone
-AR remains active in resistant disease, and remains a valid therapeutic target
33
Describe mechanisms by which castration resistant prostate cancer may develop
-Intratumoral steroidogenesis, maintaining AR signalling and therefore growth
-AR gene amplification, making them hypersensitive to low levels of circulating androgens
-AR mutations eg T877A allow AR to bind alternative ligands, increasing promiscuity
-Upregulation of antiapoptotic pathways eg AKT
-Increased AR coactivators eg SRC1 and decreased corepressors NCoR
34
Describe how splice variants may lead to the development of castration resistant prostate cancer
-AR splice variants, such as ARV7 cause truncated forms of the ligand binding domain
-This may lead to constitutive activation, driving prostate cancer cell growth without need for androgen binding
-These are also resistant to AR targeted therapies that aim to block the ligand binding and AR activation
35
Describe the function of KMT5A in AR signalling
-Histone methyltransferase, regulating androgen receptor activity in prostate cancer
-May act as a positive coactivator of AR signalling, increasing AR transcription
-This helps cancer cells to maintain AR activity even under low androgen level conditions
36
Describe the mechanism of the HIPPO pathway in the context of prostate cancer
-Downregulation of Hippo kinases can result in inactivation of YAP phosphorylation, allowing it to translocate to the nucleus
-YAP associates with the AR, causing up regulation of c-Myc, which up regulates AR
-IKBKE stabilises YAP, ultimately increasing AR signalling
37
Describe the cause of androgenetic alopecia
-DHT is produced from testosterone by 5⍺ reductase in the hair follicles
-DHT binds AR in scalp hair follicles, leading to miniaturisation of hair follicles, decreased hair density and thickness, and replacing terminal hairs with vellum hairs
38
What may be given to treat androgenetic alopecia?
5⍺ reductase inhibitors, eg Finasteride
39
Name female sex hormones
-Oestrogen
-Progesterone
40
What is the main goal of the follicular phase of the menstrual cycle?
-Preparation of a follicle for ovulation
-Rebuilding the uterine lining
41
What is the main goal of the luteal phase of the menstrual cycle?
Maintain and build the uterine lining for possible implantation
42
Describe the phases of the menstrual cycle
-Menstrual phase (1-5)
-Follicular phase (1-14)
-Ovulation (~14)
-Luteal phase (15-28)
43
Describe the hormonal changes and effects during the follicular phase of the menstrual cycle
-FSH rises, stimulating ovarian follicle growth (only the dominant fully matures)
-Oestrogen gradually rises, stimulating proliferation of the endometrial lining, and suppresses FSH through negative feedback, preventing multiple follicles maturing
-LH surges at day 12-14, due to high oestrogen levels, inducing ovulation, releasing an egg
44
Describe the hormonal changes and effects during the luteal phase of the menstrual cycle
-High levels of progesterone are secreted, thickening and stabilising the endometrial lining, increasing body temperature
45
What changes occur during the menstrual cycle if no pregnancy occurs?
-Corpus luteum degenerates between days 24-28 as there is no hCG to sustain It
-Progesterone and oestrogen drop, leading to shedding of the uterine lining and removal of hormonal suppression (FSH rises)
46
What changes occur during the menstrual cycle if pregnancy occurs?
-Embryo releases hCG, maintaining the corpus luteum
-Progesterone remains high, preventing menstruation and supporting early pregnancy
47
What roles does oestrogen have in the body?
-Fertility
-Lactation
-Secondary sexual characteristics
48
What roles does oestrogen have in fertility?
-Regulates the menstrual cycle (stimulating follicular growth during the follicular phase, and triggering LH surge)
-Prepares the uterus for implantation (stimulates endometrial proliferation, and increases vascularisation)
-Enhances fallopian tube function and uterine contractions
49
What roles does oestrogen have in lactation?
-Inhibits milk production before birth
-During pregnancy promotes growth of ductal tissue and increases prolactin secretion
-After birth, oestrogen drops sharply, removing the inhibition on prolactin, allowing milk production to begin
50
What roles does oestrogen have in secondary sexual characteristics
-Stimulates growth of mammary ducts and fat deposition in the breasts
-Promotes fat storage in the hips, thighs and buttocks
-Increases collagen production in the skin
-Maintains bone density and ends height growth after puberty
51
What is the role of progesterone in fertility?
-Before pregnancy it maintains the endometrial lining, suppresses further ovulation and reduces uterine contractions
-During pregnancy, the CL continues producing progesterone until the placenta takes over, suppresses the mother's immune system rejecting the foetus, and relaxes smooth muscle preventing early labour
52
What is the role of progesterone in lactation
-Stimulates the growth of alveoli and lobules (that produce milk)
-Inhibits lactation during pregnancy by suppressing the effects of prolactin
53
Describe how progesterone can lead to premenstrual syndrome?
PMS is caused by fluctuations in progesterone
-Progesterone drops, it fails to enhance GABA, triggering irritability, anxiety and low mood
-Drop also causes fatigue and low energy
-Fluctuations also slows digestion and causes bloating
54
Describe feedback loops in the hypothalamic-pituitary-ovarian axis
Negative feedback:
-Low oestrogen and progesterone increases GnRH, stimulating FSH and LH
-High progesterone (during luteal phase) decreases GnRH, suppressing FSH and LH
Positive feedback:
-High oestrogen prior to ovulation leads to LH surge, causing ovulation
54
What are the components of the hypothalamic-pituitary-ovarian axis?
-Hypothalamus: releases pulsatile Gonadotropin releasing hormone signalling the pituitary gland to release hormones, with frequency and amplitude changing which hormones are signalled to be released
-Pituitary gland: Responds to GnRH pulses by secreting FSH or LH
-Ovaries: Respond to FSH and LH by producing oestrogen and progesterone
55
Where does the GnRH pulse come from in the hypothalamic-pituitary-ovarian axis?
The arcuate nucleus of the hypothalamus
56
Where does FSH act on the ovaries in the hypothalamic-pituitary-ovarian axis?
-FSH stimulates granulose cells within the Graafian follicle
-Activating aromatase, which converts androgens into oestrogen
57
Where does LH act on the ovaries in the hypothamic pituitary-ovarian axis?
LH stimulates the corpus luteum to secrete progesterone
58
What are the primary targets of oral contraceptives?
-Oestrogen receptors (ER) agonists
-Progesterone receptors (PR) agonists
59
Describe the mechanism of action of oral contraceptives
-Progestins (PR agonists) inhibit ovulation by suppressing LH secretion (surge is required), as well as thickening cervical mucus reducing the ability of sperm and making it less receptive to implantation
-Oestrogens (ER agonists) inhibit FSH secretion, preventing ovulation by halting follicle development
Oral contraceptives often contain these in combination
60
Describe the mechanism of action of replacement therapies in menopause
-Oestrogen (ER agonists) restore hormonal balance, relieving vasomotor symptoms (eg hot flushes) by binding to ERs in hypothalamus, prevent vaginal atrophy and protect bone density
-Progestins (PR agonists) help to regulate menstrual like bleeding, and protect the endometrium
61
Describe the mechanism of action of drugs aiming to induce ovulation
-Clomiphene citrate is a selective oestrogen receptor modulator (SERM), which increases the release of GnRH, FSH and LH by blocking the negative feedback of endogenous oestrogen
-Increased FSH promotes follicular maturation, with the LH surge triggering ovulation
62
Describe what clinical targeting of female sex hormones can be used for?
-Oral contraceptives/fertility control
-Replacement therapy in menopause
-Ovulation induction
-Cancer chemotherapy
63
Describe ovulation predictor kits used to aid conception
-Aim is to detect LH surge, occurring 24-36 hours before ovulation
-Sex should happen 12-24 hours after the LH peak to increase the chance of pregnancy
64
Describe estradiol tests used to aid conception
-Monitors oestrogen/estradiol levels during the follicular phase, identifying the oestrogen peak that typically occurs just before ovulation
-At around day 12
65
Describe progesterone tests used to aid conception
-Monitors progesterone levels post ovulation
-Peak in level 7-days post ovulation signifies that the corpus luteum has formed and the luteal phase is functioning properly
66
Describe the mechanism of action of emergency contraceptions (such as mifepristone)
-Competitive progesterone antagonists
-Disrupting the normal function of the endometrium, making it inhospitable for a fertilised egg
-Can be used for medical abortions and mergency contraception
67
Give examples of ER breast cancer treatments
-Tamoxifen (SERMs)
-Anastrazole (aromatase inhibitors)
68
Describe the mechanism of action of hormone antagonists used to treat cancers
-Tumours arising in hormone sensitive tissues such as breast, endometrial, ovaries, prostate, may be hormone dependent
-So their growth may be inhibited by oestrogen, progesterone, androgen receptor antagonists or agents that inhibit the synthesis of oestrogen, progestogen or testosterone
69
What risk does tamoxifen carry?
Endometrial cancer
69
Describe the mechanism of action of tamoxifen
-Acts as an E2 antagonist at the ER⍺ receptor in breast cancer cells, causing a conformational changes that prevent the normal activation of the receptor
-Preventing the recruitment of coactivators such as SRC1, CBP, PGC) that lead to transcriptional activation of oestrogen-responsive genes
-This leads to cell cycle arrest at G1 phase
70
Describe the mechanism of action of anastrazole
-Selectively binds to the heme group in Aromatase/CYP19A1, preventing its enzymatic production of oestrogen
-This reduces oestrogen driven cancer cell proliferation in ER-positive cancer
71
In which group is anastrazole used?
-In post menopausal women
-As aromatase inhibitors are less effective because the Hypothalamic-Pituitary-Gonadal axis is still active, with feedback increasing ovarian oestrgoen production anyway
72
Give some vital functions of the kidneys?
-Filtration and Excretion of waste
-Regulation of fluid and electrolyte balance
-Blood pressure regulation
-Acid base homeostasis
-Glucose homeostasis
73
Name some key characteristics of the posterior pituitary gland
-Neural origin (extension of the hypothalamus)
-Does not produce hormones but stores and releases hormones
-Action potentials sent by hypothalamic neurosecretory cells trigger hormone release
-Vascular supply by the inferior hypophyseal artery facilitates rapid hormone transport into circulation
74
Describe the function of the hormones released by the posterior pituitary gland
-ADH/Vasopressin: Allows water reabsorption (reducing urine output), causes vasoconstriction (increasing blood pressure), aiding in osmoregulation
-Oxytocin: Stimulates uterine smooth muscle contraction (inducing labour), Contracts myoepithelial cells in mammary glands (leading to milk ejection) and allows for social and emotional bonding
75
Where do neuronal projection extend from in the hypothalamus to the posterior pituitary?
Extend from the supraoptic and paraventricular nuclei
76
Where are ADH and oxytocin stored in the pituitary gland?
Neurosecretory vesicles
77
What feedback loops are present regulating the posterior pituitary
-Water reabsorption feedback loop, regulating plasma osmolarity and volume
-Vasoconstriction feedback loop, regulating blood pressure
78
Describe the water reabsorption feedback loop regulating the posterior pituitary
Stimulus:
-Increased plasma osmolarity (dehydration, high sodium) is detected by hypothalamic osmoreceptors OR decreased blood volume detected by baroreceptors
Response:
-ADH secretion from the posterior pituitary, which binds V2 receptors, inserting aquaporin-2 into collecting ducts, increasing water reabsorption, concentrating urine and increasing blood volume
Negative feedback:
-Increased blood volume and dilution of plasma osmolarity inhibits further ADH release
79
Describe the vasoconstriction feedback loop regulating the posterior pituitary
Stimulus:
-Hypotension or low blood volume detected by baroreceptors
Response:
-ADH secretion increases, which bind V1 receptors on vascular smooth muscle, vasoconstriction, increasing systemic vascular resistance, increasing blood pressure
Negative feedback:
-As blood pressure stabilises, baroreceptors inhibit further ADH release
80
Describe the actions of the water reabsorption and vasoconstriction feedback loops when integrated into the renin-angiotensin-aldosterone system
-Low blood volume leads to release of renin from kidneys. This stimulates Angiotensin II formation, which stimulates ADH release and vasoconstriction to restore blood pressure
-High blood volume stimulates atrial natriuretic peptide (ANP), inhibiting ADH release to promote diuresis
81
Describe the mechanism of action of ADH in the nephron
-ADH binds V2 receptors on the basolateral of principal cells
-Promoting conversion of ATP to cAMP via adenylyl cyclase
-Activating protein kinase A
-Promoting fusion of aquaporin 2 into the apical luminal membrane, enhancing permeability to water
-Increasing permeability in distal convoluted and collecting duct, resulting in concentrated urine
82
Give some clinically important stimulants of ADH
-Opioids
-Antidepressants (SSRIs, TCAs)
-Nicotine
-MDMA
83
Give a clinically important depressant of ADH
Alcohol
84
Describe the pathophysiology of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
-Increased ADH secretion (promoting insertion of aquaporin 2 channels)
-Leading to excessive water retention, leading to dilution hyponatremia as sodium is not retained proportionally.
-Suppressed RAAS (aldosterone) leads to increased sodium excretion, worsening hyponatremia
-Despite normal plasma osmolarity, the kidney fails to excrete dilute urine
-DEVELOPS HYPONATREMIA, HYPOOSMOTIC BLOOD PLASMA AND HYPERVOLEMIA
85
Give some causes of Syndrome of Inappropriate ADH secretion
-Post surgery (especially brain/lung)
-CNS disorders (increasing hypothalamic ADH release) such as stroke, head trauma
-Malignant tumours leading to ectopic ADH secretion (eg small cell lung carcinoma)
-Drugs (eg carbamazepine, TCAs, NSAIDs)
86
Give the pharmacological treatment of syndrome of inappropriate ADH secretion
-Vasopressin receptors antagonists (eg tolvaptan)
-Preventing ADH action, increasing free water excretion
87
Give some key types of diabetes insipidus and its effect on ADH secretion
Neurogenic diabetes insipidus:
-Caused by deficiency of ADH secretion due to damage to the hypothalamus or posterior pituitary
-Leading to inability of the kidneys to retain water
Nephrogenic diabetes insipidus:
-Caused by the kidneys failing to respond to ADH, often due to genetic mutations, CKD, etc
-Normal or high ADH levels but the kidney does not respond
88
Describe the treatment for neurogenic diabetes insipidus
-Synthetic ADH
-eg Desmopressin
89
Describe the treatment for nephrogenic diabetes insipidus
-Low sodium diet
-Thiazide diuretics (paradoxically reduces urine output)
90
Simply, what is used to treat too little ADH or too much ADH?
Too little?: V2 agonists eg lypressin, desmopressin
Excess?: V2 antagonist eg Tolvaptan, Demeclocylcine
91
Which part of the adrenal gland releases mineralocorticoids (eg aldosterone)?
Zona glomerulosa
92
What is a precursor of aldosterone?
Cholesterol
93
Give examples of steroid hormones
-Cortisol
-Aldosterone
-Androgens
-Oestrogens
94
How do mineralocorticoids alter cellular function?
-Increasing apical ENaC
-Increasing apical K channels
-Increasing basolateral Na/K ATPase pump
-SGK1 activates Na/K ATPase pump, blocking ubiquination
95
What does aldosterone act on?
-Mineralocorticoid receptors found in distal tubules
-Nuclear steroid receptor
96
Describe the action of aldosterone on Na/K balance
-Increases Na reabsorption
-Increases K secretion
97
Describe what directly and indirectly regulates aldosterone secretion
-Directly (less important): stimulated by low plasma Na+ or high K+
-Indirectly (most important): stimulated by angiotensin II
98
Describe how RAAS contributes to hypertension
-Renin release converts angiotensinogen into angiotensin I, which is converted to ACE
-Angiontensin II leads to vasoconstriction (raising BP), aldosterone release (increasing sodium retention, raising BP), increasing ADH (increasing water reabsorption, raising BP), and enhancing Noradrenaline release (increasing HR and BP)
99
What is hyperaldosteronism
-Excessive secretion of aldosterone
-Leading to hypernatremia leading to hypertension, hypokalaemia, and metabolic alkalosis
100
Describe primary causes of hyperaldosteronism, and give an example
-Primary causes occur due to dysfunctional adrenal glands
-Conn's syndrome: caused by adrenal hyperplasia/tumour affecting zona glomerulosa
101
Describe secondary causes of hyperaldosteronism, and give an example
-Secondary causes occur due to pathology outside of the adrenals
-Chronic low blood pressure leads to congestive heart failure, increasing renin and leading to excess aldosterone
102
Give symptoms of hypokalaemia or hyperkalaemia
Similar symptoms
-Heart arrhythmia
-Constipation
-Weakness
103
How is hyperaldosteronism treated?
-MR antagonists
-eg Spironolactone or Eplerenone
104
Describe primary causes of hypoaldosteronism, and give an example
-Primary causes occur to dysfunctional adrenal glands
-eg Addison's disease, an autoimmune disorder destroying the zone glomerulosa cells
105
What is hypoaldosteronism?
-Deficient aldosterone production or action
-Leading to hyperkalemia, hyponatremia, hypotension, and metabolic acidosis
106
Describe secondary causes of hypoaldosteronism, and give an example
-Secondary causes occur due to pathology outside of the adrenals
-Renin deficiency due to genetic predispositions
107
Give symptoms of hyponatremia
-Confusion
-Fatigue
-Seizure
-Coma
108
What is hypoaldosteronism treated with?
-MR agonists (replacement therapy)
-eg Fludrocortisone
109
Describe the relative affinities of aldosterone for Mineralocorticoid and glucocorticoid receptors
High affinity for MR : Low affinity for GR
110
Describe the relative affinities of cortisol for Mineralocorticoid and glucocorticoid receptors
High affinity for MR : Low affinity for GR
111
Describe the relative concentrations of cortisol and aldosterone, and the potential effect of this?
[Cortisol] > [Aldosterone]
-MR will be fully saturated by cortisol, meaning MR will not respond to changes in aldosterone
112
Describe how the differential concentrations of cortisol and aldosterone are overcome in target cells for aldosterone?
-MR are distributed in specialised tissues (kidney, colon, bladder), of which high levels of 11β hydroxysteroid dehydrogenase-2
-This metabolises cortisol, allowing aldosterone to act on the MR
113
Describe the licorice effect in MR regulation
Glycyrrhetinic acid (in licorice) inhibits 11β-HSD2, allowing cortisol to activate MR, mimicking hyperaldosteronism (causing sodium retention and hypertension).
114
Describe the effect of liquorice in pregnancy?
-Glycyrrhetinic acid (in licorice) inhibits 11β-HSD2, preventing cortisol metabolism
-11β-HSD2 protects foetus from elevation in cortisol from the maternal bloodstream
-Cortisol affects behaviour (increasing temper, spite, defiance
115
What are the main types of diabetes mellitus
Type 1 - Insulin Hyposecretion
Type 2 - Insulin receptor hyposensitivity
116
Describe insulin replacement therapy for diabetes mellitus
-Cornerstone for management of type 1 and advanced stages/insulin dependent type 2
-Mimics normal insulin secretion in order to maintain blood glucose levels within the target range
-Often done with a basal-bolus insulin regimen, with basal covering insulin needs over 24 hours, and bolus given before meals to manage glucose spikes postprandially
117
Give types of insulins used in the treatment of diabetes mellitus
-Animal insulins (extracted from pancreas of pigs and cows)
-Human insulins (recombinant)
-Insulin analogues
118
What are the priorities for treatment of type 2 diabetes?
-Education
-Diet and lifestyle advice
-Blood glucose management
-Medication
119
Describe Haemoglobin A1c testing in type 2 diabetes
-Provides an average of blood glucose over the past 2-3 months
-However does not reflect daily fluctuations and is influenced by anaemia and haemoglobinopathies
-Aim for HbA1c level of 53mmol/mol
120
What is the first line of action for pharmacological treatment of type 2 diabetes, and the following treatments?
-METFORMIN
-SGLT2 inhibitors, then the following are all equally used
-Dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon like polypeptides (GLP1)
-Sulphonylureas
-Pioglitazone
121
Describe the mechanism of action of metformin
-Activates AMP-activated protein kinase, which inhibits enzymes involved in gluconeogenesis (eg G6P)
-Enhances insulin sensitivity, aiding translocation of GLUT4 to the cell surface, aiding glucose uptake into muscle and fat cells
-Inhibits mitochondrial respiratory chain (complex I), reducing ATP production
-Inhibits mitochondrial glycerol-3-phosphate stimulating conversion of pyruvate to lactate, decreasing gluconeogenesis
THESE CONTRIBUTE TO LOWER BLOOD GLUCOSE LEVELS
122
Give side effects associated with metformin
-Hypoglycaemia due to reduced blood glucose
-Rash
-Muscular cramps and acidosis due to lactate
122
Describe the mechanism of action of sulphonylureas in the treatment of diabetes mellitus
-Binding to sulphonylurea receptors (SUR1), closing ATP-sensitive potassium channels in pancreatic beta cells
-This decreases potassium efflux, depolarising the beta cell membrane
-This opens voltage gated calcium channels, allowing Calcium influx, triggering insulin release
123
Describe the mechanism of action of Thiazolidinediones in the treatment of diabetes mellitus
-TZDs bind PPARγ, a nuclear receptor increasing expression of insulin responsive genes INCREASING glucose metabolism, insulin sensitivity, lipid metabolism
-This leads to improved differentiation and function of adipocytes (enhancing ability to store fat), increase glucose uptake in muscle cells and adipose tissue, increasing glucose uptake in muscle and adipose cells and reduced hepatic gluconeogenesis
124
Describe the mechanism of action of GLP1 agonists
-Synthetic analogue that activate GLP1 receptors located on pancreatic beta cells, but also in brain, heart and GI
-Enhancing insulin secretion and improving insulin sensitivity
-Inhibiting glucagon secretion
-Delaying gastric emptying and increasing satiety
-Suppressing appetite by acting on the hypothalamus
125
How do GLP1 agonists differ from endogenous GLP1
They are DPP4 resistant
126
Give examples of GLP1 agonists
-Semaglutide (ozempic, wegovy)
-Exenatide
-Liraglutide
127
Describe the mechanism of action of Dipeptidyl peptidase 4 inhibitors
-Inhibits DPP4, preventing breakdown of endogenous incretin hormones GLP1 and GIP
-Allowing them to stimulate insulin secretion, inhibit glucagon secretion, slow gastric emptying and promoting satiety
128
Describe the mechanism of action of SGLT2 inhibitors
-Inhibits the Na-Glucose cotransporter 2 in the kidney to reduce glucose reabsorption, resulting in increased urinary glucose excretion and lower plasma glucose
-SGLT2 is expressed in the proximal tubule and mediates reabsorption of filtered glucose
-This leads to increased urinary glucose excretion, reducing blood glucose
-AS WELL AS REDUCING HYPERTENSION
129
Describe the structure of the Thyroid gland
-Butterfly-shaped endocrine organ located in the anterior neck, just below the larynx and wrapping around the trachea
-Consists of two lobes (left and right) connected by the isthmus
-Highly vascularised
-Composed of thyroid follicle functional units, lined by follicular cells
-Follicles are filled with colloid
130
Describe the functions of the Thyroid gland
Hormonal production of triiodothyronine (T3) and thyroxine (T4), and calcitonin
131
Describe the production and function of calcitonin from the thyroid gland
-Secreted by Parafollicular (C cells) in response to high serum calcium levels
-Lowering blood calcium by inhibiting inhibiting osteoclast activity (reducing bone resorption) and increasing calcium excretion via the kidneys
-Plays a minor role in calcium homeostasis compared to parathyroid hormone (PTH)
132
Describe hormonal synthesis of T3 and T4 by the thyroid gland
-Thyroid actively absorbs iodine from the bloodstream via the sodium-iodide symporter
-Follicular cells produce thyroglobulin and store in colloid
-Iodine is attached to tyrosine residues in thyroglobulin via thyroid peroxidase, forming monoiodotyrosine (1 iodine) and diiodotyrosine (2 iodine), combining to form T3 or T4
133
Describe regulation of the thyroid gland by the Hypothalamic-Pituitary-Thyroid Axis
Hypothalamic-Pituitary-Thyroid Axis tightly controls the activity
-Thyrotropin Releasing Hormone (TRH) is secreted by the hypothalamus, stimulating the AP to release TSH
-TSH binds to TSH receptors on thyroid follicular cells, stimulating iodine uptake, thyroglobulin production and thyroid hormone synthesis and release.
134
Describe negative feedback in thyroid regulation
-High levels of T3 and T4 inhibit TRH and TSH secretion, reducing thyroid activity.
-Low thyroid hormone levels trigger increased TRH and TSH release to restore balance.
135
Describe the physiological functions of the thyroid gland
-Metabolic regulation (increasing BMR, thermogenesis, glucose metabolism, protein metabolism)
-Cardiovascular regulation (increasing CO and decreasing peripheral vascular resistance)
-Growth and development (Essential for fetal brain development, skeletal growth)
-Neuromuscular function (regulates neuromuscular excitability)
-Plays a role in GI and reproductive systems
136
Describe thyroid follicular cells
-Cuboidal/Columnar epithelial cells lining the thyroid follicles
-Involved in iodine uptake, thyroglobulin synthesis, thyroid hormone synthesis and hormonal release
137
Describe thyroid colloid
-A gel-like, protein-rich substance that fills the central lumen of thyroid follicles.
-Acts as a storage reservoir for thyroid hormones in the form of thyroglobulin-bound T3 and T4.
-Stores iodine and thyroglobulin, facilitates hormone synthesis, regulates thyroid activity
138
Name the thyroid hormones
-Thyroxine (T4)
-Triiodothyronine (T3)
-Calcitonin
139
What does iodination produce in the thyroid?
Iodination produces T1 and T2 via thryroperoxidase
140
What does coupling produce in the thyroid?
T3 and T4
141
What type of receptor are thyroid hormone receptors?
-TRα and TRβ are nuclear receptors belonging to the steroid hormone receptor superfamily.
-These receptors function as ligand-activated transcription factors
Regulating gene expression in response to thyroid hormones (T3 and T4).
142
Describe Thyroid hormone receptor alpha isoform distribution
-TRα1: Highly expressed in the heart, skeletal muscle, and central nervous system (CNS), regulating cardiac function, metabolism, and neurodevelopment.
-TRα2: A non-T3-binding isoform that can act as a dominant-negative regulator of thyroid hormone action.
143
Describe Thyroid hormone receptor beta isoform distribution
-TRβ1: Found mainly in the liver, kidney, and brain, regulating metabolic processes, lipid metabolism, and thermogenesis.
-TRβ2: Predominantly in the pituitary and hypothalamus, playing a crucial role in feedback regulation of thyroid-stimulating hormone (TSH) and thyroid hormone levels.
144
Describe the mechanism of action of Thyroid Hormone Receptors (TRα & TRβ)
-Thyroid hormones enter target cells (T4 is converted to T3 by deiodinases) and bind to TRα or TRβ, forming a ligand-receptor complex
-In the absence of T3, TRs form heterodimers with retinoid X receptors (RXRs) and bind to thyroid hormone response elements (TREs) in the promoter regions of target genes.
-When T3 binds to TR, it induces a conformational change that dissociates co-repressors and recruits co-activators (e.g., SRC-1, CBP).
-This promotes the recruitment of RNA polymerase II and the initiation of transcription.
145
Describe the symptoms of hyperthyroidism
-Weight loss due to increased BMR
-Tachycardia, palpitation/arrhythmia, increased BP
-Neurological and psychological symptoms (anxiety, tremors)
-Heat intolerance and sweating
-GI diarrhoea
-Muscle and Skin changes
145
Describe the symptoms of hypothyroidism
-Weight gain due to decreased BMR
-Bradycardia, hypotension, reduced CO
-Neurological and psychological symptoms (Fatigue, memory impairment)
-Constipation
-Dry, rough skin
146
Describe the primary treatment for hypothyroidism
-Treatment does not involve augmentation of thyroxine synthesis, instead on synthetic analogues
-Levothyroxine (synthetic T4)
-Liothyronine sodium (synthetic T3)
147
Give effects of overdose of synthetic thyroid hormones
-Thyrotoxicosis
-Precipitation of cardiac arrhythmias, angina pectoris or cardiac failure
147
When are synthetic thyroid hormones used?
-Hypothyroidism (myxoedema)
-Diffuse non toxic goitre
-Hashimoto's thyroiditis
-Thyroid carcinoma
148
Give some causes of hyperthyroidism
-Thyrotoxicosis
-Diffuse toxic goitre (Graves disease)
-Toxic nodular goitre (benign tumour)
149
Describe first line treatment for hyperthyroidism
-Thioureylenes, eg:
Carbimazole or Propylthiouracil
-Inhibit thyroid peroxidase, blocking T4/T3 synthesis
150
Name some treatments for hyperthyroidism
-Thioureylenes
-Iodine/Iodide
-Radioactive sodium iodide
~Propanol
151
Describe iodine in the treatment of hyperthyroidism
-High doses of iodine saturate the thyroid gland, inhibiting thyroid peroxidase, reducing thyroid hormone release, and decreasing thyroid blood flow temporarily
-Used typically to prepare for thyroidectomy
152
Describe propranolol in the treatment of hyperthyroidism
-Used for treating symptoms
-eg tachycardia, arrhythmias, tremor
-Does not actively treat hyperthyroidism
152
Describe radioactive iodine therapy for hyperthyroidism
-Radioactive iodine (I-131) accumulates in the thyroid
-Its radioactive decay damages follicular cells, with β-particles causing localised cell death of follicular cells, without damage to other tissues
-Used for Graves' disease, toxic nodules
-Require T4 replacement therapy following this
153
How are thyrotoxic crisis/thyroid storms treated?
-IV fluids
-Propranolol hydrochloride
-Hydrocortisone
-Oral iodine solution
-Thioureylenes
