Endocrinology Flashcards
(235 cards)
1
Q
Major Endocrine glands
A
Hypothalamus and Pituitary Gland, Thyroid, adrenal cortex and gonads, Pancreas and parathyroid glands
2
Q
Hypothalamus secretion
A
Releasing and inhibiting hormones
3
Q
Pituitary gland secretion
A
Anterior lobe- trophic hormones
Posterior lobe- Oxytocin and vasopressin (ADH)
4
Q
Thyroid gland secretion
A
Thyroxine, tri-iodothyronine
5
Q
Adrenal gland secretion
A
Cortex- Cortisol, aldosterone
Medulla- Adrenaline/noradrenaline
6
Q
Gonads secretion
A
Oestrogens, androgens, progestogens
7
Q
Pancreas secretion
A
insulin, glucagon
8
Q
Parathyroid gland secretion
A
Parathyroid hormone
9
Q
Other secretions
A
Kidney(Vit.D, EPO), CVS(ANP, endothelins), pineal(melatonin), thymus(thymic hormone), bone(phosphate), adipose tissue(leptin)
10
Q
Main signalling mechanisms
A
Endocrine, paracrine, autocrine, intracrine
11
Q
Endocrine signalling
A
Hormones released by an endocrine cell into the general circulation and acting on distant target sites
12
Q
Paracrine signalling
A
Hormones released by an endocrine cell which act locally on adjacent cells
13
Q
Autocrine signalling
A
Hormones released by a cell which act back on the same cell
14
Q
Intracrine signalling
A
Conversion of an inactive hormone to an active hormone that acts within that cell
15
Q
General Functions of hormones
A
Reproduction, Growth and development
Maintenance of internal environment
Energy production, utilisation and storage
16
Q
Reproduction, growth and development
A
sex steroids, thyroid hormones, prolactin, growth hormone
17
Q
maintenance of internal environment
A
aldosterone, parathyroid hormone, vitamin D
18
Q
Energy production, utilisation and storage
A
insulin, glucagon, thyroid hormones, cortisol, growth hormones
19
Q
Chemical classification of hormones
A
Protein/peptide hormones, Steroid hormones(cholesterol), Amino acid derivatives(tyrosine/tryptophan), Fatty acid derivatives
20
Q
Protein/peptide hormones eg
A
Hypothalamic hormones, pituitary hormones, insulin, PTH, Calcitonin
21
Q
Steroid hormone eg
A
Cortisol, aldosterone, oestrogens, androgens, progestogens, Vitamin D
22
Q
Amino acid derivatives
A
Adrenaline, noradrenaline(tyrosine), thyroid hormones(tyrosine), melatonin(tryptophan)
23
Q
Fatty acid derivatives
A
Prostaglandins, thromboxanes, prostacyclin
24
Q
Half lives and transport
A
proteins and peptides: Minutes and mainly unbound
Tyrosine derivatives and Thyroid hormones: Seconds (CA’s), Hours (thyroid) and thyroid hormones bound to plasma proteins
Cholesterol: Hours-Days and bound to plasma proteins
25
Magnocellular hormones
In the hypothalamus, synthesise and release posterior pituitary hormones
26
Other neurosecretory cells
In the hypothalamus, release their hormones into the portal capillaries in which they are transported directly to endocrine cells of the anterior pituitary gland
27
Glands controlled by the hypothalamic pituitary axis
Hypothalamus -- (releasing/inhibiting neurohormones)--> anterior pituitary gland--Trophic hormones-->TSH(Thyroid), ACTH(Adrenal cortex), LH/FSH(Gonads)
28
How are the main ways disorders are caused?
Excess or deficiency of hormones, impaired synthesis, transport and mechanism of hormones, resistance to hormone action
29
Control of cortisol secretion
Hypothalamus-> CRH->Anterior pituitary->ACTH->Adrenal cortex->cortisol
30
Cortisol functions
Glycogenesis, Protein mobilisation, fat mobilisation, anti-inflammatory effects
31
Lack of/excess Cortisol =
Lack off= Addison's disease
| Excess= Cushing's Disease
32
Homeostasis
The maintenance of an internal steady state in the face of changing external and internal conditions.
33
Components of a feedback system
Regulated/controllable variable(set point, error signal), detector/sensor (afferent path), comparator/control centre(determines set point of variable; intrinsic: local= cell or tissue, extrinsic: endocrine), effector(returns variable to set point(efferent path)), response
34
Eg of regulated factors/controlled variables
Physical entities, blood pressure, core temperature, Circulating concentrations of chemical substances, Ions: Na+, Ca2+, Nutrients: blood glucose concentration, hormones
35
Regulation of body temp:
Shivering, vasoconstriction, increased metabolism, vasodilation, sweating
36
Benefits of an increased body temperature
Inhibits bacterial growth, speeds up metabolic reactions, increases delivery of white blood cells to infection sites
37
How does body temp increase and why?
Pyrogens (bacterial or viral infections) change the site point to a higher level resulting in fever.
Blood flow shifted to core conserve heat- increased muscle activity (shivering), chills stop when high temp reached
38
Time course of a typical fibril attack
The actual body temperature lags behind the rapid shift in set point and though regulation is maintained during the fever it is less precise.
39
Role of vasopressin
Vasoconstriction = increased arterial pressure
| Renal fluid reabsorption-> increased blood volume -> vasoconstriction
40
Following a haemorrhage
Blood volume and hence blood pressure are reduced. To help restore blood pressure several homeostatic controls systems activated:
The baroreceptor reflex to increase cardiac output and total peripheral resistance
Stimulation of vasopressin (ADH) secretion to increase blood volume
41
Integrated feedback
Loops in the control of sodium balance, blood pressure and fluid volume
42
Negative feedback
Increase in a controlled variable results in decrease in a controlled variable
43
Positive feedback
Increase in a controlled variable results in a increase in controlled variable.
44
+ feedback control: Haemostasis
Less common physiologically ( due to less control)
| The response of the effector output reinforces the stimulus e.g. blood clotting, ovulation, childbirth
45
+ feedback: Control of uterine contractions in labour by oxytocin
1) In labour, oxytocin stimulates contraction of uterine muscles
2) Cervix dilates and activate stretch receptors
3) Action potentials signal to hypothalamus
4) Stimulates further release of oxytocin
46
Peptides and Proteins
Water soluble, made large precursor molecules-prohormones
47
Steroids and iodinated tyrosines
Lipid soluble, made from low molecular weight precursors
48
Synthesis of Protein/peptide (transcription)
1- Transcription of DNA to RNA
2- Post transcriptional processing: RNA-> mature RNA- excision of introns, modifications of 3' and 5' ends
3- Translation of mature RNA into protein using tRNA to transfer amino acids
4- Post-transcriptional processing cleavage of large pre-prohormone, folding of proteins, additions of sugars (glycosylation)
49
Synthesis of Large precursor proteins -> active hormone
Pre-prohormone (signal sequence + prohormone) = signal, hormone, peptide sequence(s)( these sequences get cleaved)
Prohormone (hormone + peptide sequence(s)) = hormone + peptide sequence(s)
50
Synthesis of insulin
1- Transcription of RNA
2- Excision of introns to mRNA
3- Removal of signal sequence and formation of disulphide bonds in RER
4- Pre-proinsulin-> proinsulin
5- Transfer to golgi apparatus, excision of C peptide and packaging into secretory granules
51
Thyroid
Thyroid stimulating hormone ( TSH) stimulates Thyroid to release T3 and T4
52
Adrenal Cortex
ACTH stimulates adrenal cortex to release cortisol/aldosterone
53
Gonads
LH/FSH stimulates gonads to release oestrogen/testosterone
54
Control of Steroid synthesis from Cholesterol
1- cholesterol bound to sterol carrier protein transported to mitochondria
2- StAR protein transports cholesterol to inner mito. membrane (rate limiting)
3- Cholesterol to pregnenolone by side chain cleavage enzyme, P450scc (rate limiting)
4- Between mito. and SER steroids synthesised by hydroxylase enzymes
55
Synthesis of Thyroid hormone
1- Active uptake of iodine into follicular cell
2- Transport across the apical membrane
3- Oxi of iodine to iodinated intermediate , by thyroid peroxidase (TPO), which is activated by H2O2
4- Iodination of tyrosine residues of thyroglobulin
5-Coupling of iodinated tyrosine residues
6-Storage of T3 and T4 in colloid
7- Uptake of thyroglobulin droplets into follicle cell
8- Release and secretion of T3 and T4 stimulated by TSH
56
Signalling pathways for receptors with tyrosine kinase activity
Raf/MEK ERK Pathway
PI3-Kinase/Akt Pathway
JAK STAT Pathway
57
Steroid Hormone Receptors
A family of transcription factors
58
Domains
Different functional regions of the receptor
59
C domain
The DNA binding region is made up of 2 zinc fingers which can slot into the helix of the DNA
60
Pro and pep disorder
```
Obesity class III>- 40 BMI
type 1: autoimmune destruction of the pancreatic islets: absolute insulin deficiency
type 2: insulin resistance, partial loss of insulin production( insulinopaenia) - often associated with obesity
```
61
Protein and peptide disorder
```
Obesity class III>- 40 BMI
Diabetes
type 1: autoimmune destruction of the pancreatic islets: absolute insulin deficiency
type 2: insulin resistance, partial loss of insulin production (insulinopaenia) - often associated with obesity
```
62
Steroid hormone disorder
Aromatase deficiency
Men: unable to synthesise oestrogens from androgens -> no epiphyseal closure -> long stature
Women: Virilisation of XX fetuses, Clitoromegaly, Ambiguous genitalia
Girls develop male-type characteristics
Boys show early sexual development due to excess androgens
63
Steroid receptor disorder
Inactivating mutations of steroid receptors e.g. androgen receptor (nuclear receptor)
Androgen insensitivity syndromes (AIS)
64
Resistance to hormone action
When you cannot respond to steroid hormones
65
Thyroid hormone disorder
Goitre- Enlargement of thyroid gland
causes: Lack of iodine in the diet leads to deficiency in T3 and T4 (hypothyroidism), Graves disease (hyperthyroidism), Thyroid adenoma
66
Thyroid hormone disorder Graves' Disease
Autoantibodies to the TSH Receptor act on the thyroid gland, stimulate excess thyroid hormones and can cause disease
67
Proptosis
Bulging of eye
68
Thyroid hormone Cancer
Activating mutation of the TSH receptor- a G protein coupled receptor
69
Signalling
Any physiological function can be analysed in molecular terms as a succession of interactions occurring either in a solution or in a membrane system. The key mechanism in the ordering of the cascade is the conformational recognition of the two partners at each step. Each interaction results in the change of conformation of a recognized protein that in turn becomes a recognizer for the following molecule.
70
Neuroendocrine cells
Neurosecretory cells that release signal molecules (hormones) from their synaptic terminals into the blood.
controlled via synaptic transmission (neuroendocrine integration)
71
Embryology of the Pituitary gland
Evagination of floor of 3rd ventricle (neural ectoderm), Evagination of oral ectoderm (Rathke's pouch), Ratheke's pouch pinched off
72
Hypothalamus
Composed of various nuclei (cell clusters)
73
Parvocellular nuclei
Neurosecretory cells release hormones to capillaries of median eminence (supplied by superior hypophysial artery); conveyed by portal veins to anterior pituitary
74
Magnocellular Nuclei
Project to posterior pituitary and release to capillaries supplied by inferior hypophysial artery
75
Posterior pituitary hormones
Oxytocin and vasopressin
PP is an extension of the hypothalamus with hormones stored in hypothalamic neuron terminals. Released under neural control into hypophysial capillaries, inferior hypophysial vein
76
Growth hormone functions
Growth and development (anabolic)
| Couples growth to nutritional status
77
Secretion of Growth hormone
GH (Somatotropin) synthesised and secreted by somatotropes of the anterior pituitary
78
Ghrelin
'hunger hormone' secreted by endocrine cells of the stomach
79
GH-releasing hormone
Hypothalamic neurosecretory cells
80
Somatostatin
Hypothalamic neurosecretory cells
81
GH Negative feedback control by:
GH in circulation, IGF-1 (released by liver in response to GH)
82
Insulin Tolerance Test
Monitor blood every 30 min for 2 hr after insulin injection. Insulin will lower blood sugar, GH (and cortisol) will rise in response, if pituitary function is normal.
83
Partial list of factors controlling GH secretion
```
Stimulatory
GHRH
Ghrelin
Hypoglycemia
Decreased fatty acids
Fasting
Exercise, sleep
Stress
```
```
Inhibitory
Somatostatin (GHIH)
GH
Hyperglycemia
Increased fatty acids
IGF-1
```
84
GH action
Stimulates production of IGF-1 by liver
Increases lipolysis: raises free fatty acids (FFA)
Increases gluconeogenesis: raises blood sugar
Increases amino acid uptake into muscle, protein synthesis and lean body mass
Stimulates chondrocytes: linear growth
Stimulates somatic growth: increased organ/tissue size
85
XS GH : Acromegaly
Most common due to pituitary adenoma: increase in GH secreting somatrophs
Less commonly secondary: tumour elsewhere secretes GHRH
Diagnosed with glucose tolerance test. Monitor blood GH every two hours following 75 g glucose in oral solution. GH levels should be supressed, but doesn’t occur in acromegaly.
Excess GH leads to insulin resistance
Many patients will have impaired glucose tolerance and hyperinsulinemia. Also hypertriglyceridemia due to inhibition of lipoprotein lipase.
86
Endocrine signalling
Hormone secreting gland cell -> blood -> target cell (just taken up by capillaries and vessels)
87
'Neurocrine' signalling
Nerve cell -> Nerve impulse -> neurotransmitter -> neuron or effector cell (synaptic transmission)
88
Neuroendocrine signalling
Nerve cell -> neurotransmitter-> neurohormone -> blood -> target cell (mixture of both)
89
Local Endocrine signalling
Local cell -> paracrine agent -> target cell
or
local cell -> autocrine agent ->back to the local cell
90
Neuroendocrine reflex
Initiated by stimulation of sensory neurons that cause a release of a neurohormone from the neurosecretory cells. It is the simple neural reflex that controls the neuroendocrine reflex. The natural progression of events in this system is sensory nerves respond to a stimulus, be it thermal, tactile, or visual. These sensory nerves then synapse with interneurons in the spinal cord. Where efferent neurons, or neurons conducting impulses outwards from the brain or spinal cord, travel to the hypothalamus where the hypothalamic neurons release neurohormones. These neurohormones then enter the blood and activate the target tissues, such as the anterior lobe of the pituitary, mammary glands, or the epididymis.
91
pH of liquid
-log10 its hydrogen ion concentration
92
normal pH range of bodily fluids
7.35-7.45, corresponds to a hydrogen ion concentration of ≈0.00000004 moles per litre, or 40 nM
93
Carbon dioxide dissolves in the aqueous environment of the body to produce carbonic acid:
CO2 + H2O ↔ H2CO3
94
Carbonic acid is a volatile acid that readily dissociates into hydrogen ions and carbonate ions:
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
95
3 complementary tactics of maintaining pH
ECF&ICF Buffers, Respiratory excretion, retention of CO2, Renal excretion, retention, synthesis of HCO3-
96
3 main buffering systems in the blood
Biggest: Bicarbonate
H+ + HCO3- ↔ H2CO3 ↔ CO2 + H2O
Second: Phosphate
H+ + HPO42- ↔ H2PO4-
Third: Protein (inc haemoglobin)
H+ + Pr- ↔ HPr
All these systems work together
97
Bicarbonate Buffer System
Henderson-Hasslebalch Equation : Can calculate pH using pK and log10 of the bicarbonate ion conc/ CO2 ion conc
Is the most important buffer
Plasma(CO2) proportional to partial pressure of CO2 (pCO2) in plasma
math constant to covert pCO2 (mmHg) to [CO2] mmol/L is 0.03 = pH 6.1 + log[24mmol/L] / 0.03 x [40mmHg]
measured clinically = 20.1
measure pH w/ arterial blood gases (ABG)
98
+/ -'s of Bicarbonate Buffering
-
@ 6.1 the pK of CO2-HCO3 buffer not close to desired plasma pH of 7.4 = purely from a chemical POV, it is x
```
+
Abundant source of CO2 from metabolism
Alveolar ventilation controls PCO2
Kidneys Control [HCO3]ECF
the last two have (independent regulation) = physiologically it is really ✓
```
99
Renal control of acid-base levels
```
Kidneys control acid-base levels by excretion of acidic or basic urine
Primary renal mechanisms involved:
'Re-absorption' and secretion of HCO3-
Formation of 'new' HCO3-
Secretion of [H+] into tubular fluid
Buffer secretions within tubule that react with secreted [H+] are:
HCO3-:H2CO3
HPO42-:H2PO4-
NH3: NH4+
```
100
PCT
85-90% of filtered HCO3- 'reabsorbed'
| Great capacity to secrete [H+]
101
Intercalated cells of late DCT & Collecting duct
In distal part of nephron [HCO3-] is low and H+ react with other buffers
H+ATPase pump most important
102
(other buffers)-Phosphate
Further H+ secreted into lumen buffered by HPO42-
Very effective buffer because pK=6.8 (close to pH of filtrate)
Cl-HCO3- exchanger predominant within intercalated cells
103
(other buffers)- Ammonia
Tubular epithelium produces NH3 from glutamine with the enzyme glutaminase
Excretion of ammonia salts increases tenfold during metabolic acidosis- from 30-50mmol/day to 300-500mmol/day
Urinary excretion of ammonium salts
1 glutamine molecule gives rise to 2HCO3-
104
Role of Respiratory System
Chemosensitive area in medulla oblogata regulates respiration
Monitors [H+] of plasma indirectly, via CSF
Charged ions can not cross BBB, but CO2 can
105
Metabolic acidosis
Characterised by low pH as a result of increase ECF [H+] or decrease ECF [HCO3-]
caused by:
severe sepsis or shock = lactic acid
uncontrolled diabetes = overprotection of 3-OH-butyric acid & other ketoacids
Diarrhoea = loss of HCO3 from GI Tract
106
Metabolic Alkalosis
Characterised by high pH cause by increase ECF [HCO3-] or decrease ECF [H+]
```
caused by:
excessive diuretic (thiazide0 use= chronic loss of Cl-, Na+ & K+ = increase H+ secretion
Vomiting = loss of H+ from GI tract
Ingestion of alkaline antacids
Hypokalaemia
```
107
Kidney to Ureter pathway
Urine from all collecting ducts of all nephrons -> empty into renal pelvis -> urine enters ureter
108
Urine in ureter
Urine enters- distends it and smooth muscles around contract.
Peristaltic waves in ureter occur @ freq 1-6 contractions/minute
Ureters squeeze urine to pressure of 10-20mmHg
109
Ureter to bladder
Ureter open obliquely into bladder. Prevents reflux of urine back into ureters by passive flap-valve effect
Ureteric peristalsis is myogenic in origin and not under CVS control
Coordination required between peristalsis and changing urine volume.
110
Bladder
Can hold up to 400ml without much increase in pressure => spherical structure
111
Sphincters of bladder
Internal Sphincter: Extension of detrusor muscle => Not under voluntary control
External Sphincter: Two striated muscles(compressor urethrae & bulbocavernosus) surrounding urethra => these muscles are responsible for continence
112
Female bladder & Urethra
Short Urethra-only carries urine
External sphincter less developed
More prone to incontinence particularly after childbirth
113
Male Bladder & Urethra
Carries urine and semen
| Urine elimination aided by contraction of bulbcavernosus muscles in penis
114
Bladder summary
```
Bladder:
Lining- transitional epithelium
Bladder muscle- detrusor
Impermeable to salt& water
Permeable to lipophilic molecules
```
Outlet of bladder intro urethra:
Internal sphincter- smooth muscle, involuntary
External sphincter- striated muscle, voluntary
115
Kidney stones (renal calculi)
Most common disorder of urinary tract
Develop from crystals that separate from urine within urinary tract
Normal urine contains inhibitors (citrate) to prevent this
Calcium is present in nearly all stones (80%), usually as calcium oxalate or less often as calcium phosphate
Others made up of uric acid (<10%), struvite(<10%), cysteine(<5%)
more common in men because of testosterone
116
Kidney stones causes
```
XS dietary intake of stone-forming substances
Poor urine output/obstruction
Altered urinary pH
low conc of inhibitors
infection
```
117
Ureterolithiasis
Kidney stones can form anywhere in the urinary tract
symptoms:
Dysuria (painful urination)
Haematuria
Loin pain/back pain
Reduced urine flow
Urinary tract obstruction: pressure reaches 50mmHg-causes considerable pain 'renal colic'
If stone approaches tip of urethra- intense pain can inhibit micturition- 'strangury'
118
The bladder circuits
Neural circuits in brain & SC co-ordinate activity of the bladder & sphincters
Circuits act as on-off switches to alternate between storage & elimination.
119
The nerves in the bladders
Sympathetic (hypogastric nerve)
Parasympathetic (pelvic nerve)
Somatic (pudendal nerve)
120
The types of innervation
Sensory(afferent): gives sensation (awareness) of fullness and also pain from disease
Motor(efferent): causes contraction and relaxation of detrusor muscle and external sphincter to control micturition
121
Motor innervation
Parasympa. neurons:
Contract detrusor via Ach(muscarinic) & ATP(purigenic R)
Relax internal sphincter via NO(cGMP) & Ach(nicotinic R)
THEY ALL ENCOURAGE MICTURITION
Sympa. neurons:
Relax detrusor: Indirectly via NA(α-R), directly via NA(β-R)
Contract internal sphincter via NA(α-R)
Somatic neurons:
Contract external sphincter via Ach (nicotinic R)
SYMPA. + SOMATIC INHIBIT MICTURITION
122
Types of afferent (sensory) nerve fibre
'A Fibres': sense tension in detrusor
i. filling of bladder
ii. detrusor contraction
=> bladder fullness, discomfort
'C Fibres': respond to damage & inflammatory mediators
=> PAIN (urgent desire to micturate)
123
Afferent sensory innervation
Main afferent pathway is via pelvic nerve (parasympathetic):
Small myelinated Aδ–fibres = micturition reflex
Stretch receptors = signal wall tension
Volume receptors = signal bladder filling
Unmyelinated C fibres = endings in/near epithelium
Nociceptors = pain (e.g. during infection of bladder lining – cystitis; excessive distension)
Hypogastric (sympathetic) & Pudendal (somatic) pathways
Nociceptors
Flow receptors (external sphincter)
124
Bladder filling
Initially – bladder empty
Sphincters closed
(tonic activity sympathetic & somatic nerves)
Bladder pressure low
```
Arrival of urine
Detrusor relaxes progressively
(sympathetic activity inhibiting parasympathetic transmission)
Little increase in pressure
Sphincters still closed
= ''RECEPTIVE RELAXATION'
```
125
Bladder emptying (micturition)
1. Micturition is an autonomic reflex
e. g. in babies (<18months), adults with spinal cord transected above sacral region
2. Reflex is modified by voluntary control
Inhibited or initiated by higher centres in the brain
Maturation of bladder complete by >6 years
3.Basic circuits act as on/off switches to alternate between 2 modes of operation: storage and elimination
4.Disease/injury/ageing to nervous system in adults disrupts voluntary control of micturition
bladder hyperactivity & urge incontinence
stress incontinence
126
Micturition reflex
1. filling bladder: receptors in bladder wall 'fire off' as tension increases
2.Aδ-fibre afferent signals to the SC, which will return via parasympathetic efferent
stimulation
3. = contraction of detrusor muscle and also relaxation f the internal sphincter
4. = urine begins to leave the bladder = Urine flow activates flow receptors in urethra = pudendal afferents excited
5.Tonic contraction of external sphincter removed by inhibition of somatic input
Sacral reflex is important to reinforce micturition till bladder is empty
127
Modification of micturition reflex by higher centres
The activation pattern during micturition superimposed on averaged MRI scans.
A widespread involvement of cortical and subcortical areas including specific pontine micturition centre (PMC).
128
Voluntary Modification of reflex
Higher centres can modify micturition reflex for a while:
Contract external sphincter & levator muscle consciously
Increase sympathetic firing to bladder and internal sphincter (voluntary??)
Interferes with positive feedback to bladder emptying by inhibition of parasympathetic transmission
Tightens internal sphincter
Urine stream can be halted by “strangury” (urethral pain) due to urethritis (inflammation of urethra from STI or renal calculi)
Pinching glans penis can inhibit micturition
At night, if bladder fills to capacity, recognised by PMC and arousal centre wakes you up
129
Voluntary control of micturition
The bladder is contained in the floor of the abdominal cavity
By contracting abdominal muscles:
The increased intra-abdominal pressure is transmitted to the bladder and urethra.
Reflex contraction of peri-urethral striated muscles also helps compress the urethra ⇒ micturition reflex aided
130
Importance of bladder emptying
Urine
Normally sterile
Occasional bacterial entry
Complete emptying restores sterility
Bacteria in retained urine seeds fresh urine
Retained urine = clinical infection (UTI)
Repeated infections can destroy renal function if ascend to kidney
131
Urinary Tract Infections (UTI's)
Can happen anywhere along the urinary tract
UTIs have different names, depending on area of infection:
Bladder -- an infection in the bladder is called cystitis or a bladder infection
Kidneys -- an infection of one/both kidneys is called pyelonephritis
Ureters -- rarely the site of infection
Urethra -- an infection of the urethra is called urethritis
132
UTI Risk factors
More common in women because of short urethra
Common in men over 40 due to prostatic disease, causing bladder outflow obstruction
Some risk factors:
Diabetes mellitus; long-term catheterisation; pregnancy; enlarged prostate; prolonged immobility; kidney stones; bowel incontinence; advanced age
133
Problems of aging bladder 1
```
Slow urine stream:
Prostate enlargement (BPH -benign prostatic hyperplasia): most common cause of lower urinary tract symptoms in men (25% of men > 40yrs)
```
Slow urine stream → incomplete emptying → infection
134
Problems of aging bladder 2
Incontinence
Causes
Weakening of sphincters (e.g. stress incontinence): common in women after child-birth, weakened pelvic floor muscles
```
Failure of nervous control
Overactive bladder (OAB) – detrusor contracts spastically – results in sustained high bladder pressure – urge incontinence
```
Consequences
Socially embarrassing
Diminishes self-esteem
Reduces quality of life
135
Treatments
Anti-muscarinics relax smooth muscle & ↓ detrusor contraction
(eg non-specific muscrarinic receptor antagonist Oxybutynin – wide ranging side effects)
Bladder retraining (used for stress & urge incontinence): Timetable & Kegel exercises
Surgery:
Bladder neck suspension
botulinum toxin/collagen injections into muscles around urethra → relaxes bladder (OAB)
Sacral Nerve Stimulation (SNS):
implanted neurostimulation system
electrical impulses to sacral nerve
Stem cell therapy
cultured stem cells into bladder wall= 90% no leakage
Limited by supply of stem cells (bone marrow)
Tissue engineered bladder
Synthetic and natural scaffolds to form 3D structure using human tissue.
Currently in phase II trials.
136
Stored and circulating nutrients
```
Circulating:
Glucose
Fatty acids
Amino acids
Ketone bodies
Lactate
```
Stored:
Glycogen
Triglycerides
Body proteins
137
Plasma glucose
constant = 5mmol/L
brain depends of glucose metabolism
<2.5mmol/L is critical (hypoglycaemia- ultimately coma and death)
(hyperglycaemia- chronic exposure to raised glucose concentrations leads to protein damage via non-enzymatic glycation)
138
How much glucose?
60/40/20
60% of body weight is water
40% of body weight is intracellular water
20% of body weight is extracellular water
e.g. 70kg male, 14L extracellular water gives total of 14x5 = 70mmol glucose
brain:30mmol/hr
skeletal muscle(exten.): 300mmol/hr
139
2 sources of plasma glucose
Diet, Organs that can export glucose into the circulation
140
What prevents plasma glucose surging after a meal and plummeting between meals?
Hormones regulate the integration of carb ,fat, and protein metabolism to maintain constant plasma glucose level
141
2 phases of metabolism
Absorptive (fed state) and fasting(between meals, also called post absorptive phase)
142
Hormones and met.
regulate metabolic pathways promoting energy storage or release
143
Insulin and met.
Promotes storage, decreases plasma glucose
144
Counter-regulatory hormones
Promote nutrient release, raise plasma glucose:
glucagon
adrenaline (epinephrine)
cortisol, growth hormone (somatotrophin)
145
Major effects of insulin
STIMULATES nutrient storage:
uptake of glucose by skeletal muscle, adipose, and other tissues
Glycogen synthesis in liver, skeletal muscle
Uptake of FA and amino acids
INHIBITS nutrient release
inhibits release of glucose from liver(hepatic glucose production)
Inhibits fat and protein breakdown (lipolysis and proteolysis
146
Major effects of counter-regulatory hormones
glucagon: principle effects in liver- stimulates hepatic glucose production
Adrenaline (and sympathetic NS): stimulates hepatic glucose production
stimulates liposis: release of FA from adipose tissue stores
Growth hormone: stimulates hepatic glucose production, lipolysis
Cortisol: stimulates hepatic glucose production, lipolysis, stimulates proteolysis: release of amino acids from the body protein (skeletal muscle)
147
Metabolic pathways serving energy storage
```
Glycogenesis
lipogenesis
Triglyceride synthesis
Glycogenolysis
Gluconeogenesis
Lipolysis
Beta-oxidation
Ketogenesis
```
148
glycogenesis
synthesis of glycogen from glucose
149
lipogenesis
synthesis of FA from acetyl CoA
150
Triglyceride Synthesis
esterification of FA for storage as TG
151
Glycogenolysis
release of glucose from glycogen stores
152
Gluconeogenesis
De novo synthesis of glucose from non-carbohydrate substrates
153
Lipolysis
Release of FA from TF breakdown
154
Beta-oxidation
FA to Acetyl Co A
155
Ketogenesis
Production of ketone bodies from Acetyl CoA
156
Defences against HypOglycaemia
ST:
glucagon, epinephrine, sympathetic NS
Medium term: ketogenesis: fat reserves can provide a partial substitute for glucose, spring muscle tissue from the destruction that would otherwise be needed to provide amino acid substrates for gluconeogenesis
LT: Cortisol stimulates proteolysis to supply amino acid substrates for gluconeogenesis
157
Defences against HypERglycaemia
Insulin: stimulates glucose uptake by tissues, inhibits hepatic glucose production
Lack of insulin action = hyperglycaemia, diabetes mellitus
Type 1: insulin deficiency
Type 2: insulin insufficiency combines with insulin resistance
158
Plasma glucose regulation locations
Liver, skeletal muscle adipose tissue
159
How does glucose get into cells? I
Sodium-Glucose cotransporters (SGLTs)
Secondary active transport
SGLT1: Glucose absorption from gut
SGLT1,SGLT2: Glucose reabsorption from kidney (PCT)
160
How does glucose get into cells? II
Family of glucose transporters (GLUTs)
GLUT 1, GLUT 2, GLUT 3
GLUT 4(muscle and adipose tissue)-medium affinity for glucose. Insulin dependent transporters = insulin- dependent uptake of glucose into cells
161
Islets of Langerhans
Clusters of endocrine cells surrounded by exocrine pancreas
162
Islets of Langerhans: What they release
alpha cells- glucagon
beta cells- insulin
delta cells- somatostatin
163
Synthesis of insulin pathway
Original transcript: pre-pro insulin
Signal sequence removed: proinsulin (in rough endoplasmic reticulum)
Transfer to Golgi apparatus
Peptidases break off the C peptide leaving an A and B chain linked by disulphide bonds
One mole of C-peptide is secreted for each mole of insulin
164
Release of insulin into the circulation
Pancreas supplied by branches of the coeliac, super mesenteric, and splenic arteries.
The venous drainage of the pancreas is into the portal system.
Half of the secreted insulin is metabolized by the liver in it’s first pass; the remainder is diluted in the peripheral circulation
C-peptide is more accurate index of insulin secretion in peripheral circulation (not metabolized by liver)
165
Factors regulating insulin secretion
Plasma glucose (+ incretin hormones), amino acids, glucagon , parasymp
ALL INCREASE
somatostatin, alpha adrenergic
ALL DECREASE
= BETA CELLS = INSULIN
166
Factors regulating glucagon secretion
Plasma glucose, somatostatin, insulin
ALL DECREASE
Amino acids, Beta-adrenergic, parasymp
ALL INCREASE
=ALPHA CELLS = GLUCAGON
167
insulin and glucagon secretion
insulin and glucagon secretion are exquisitely sensitive to blood glucose levels.
Insulin: Glucagon ratio varies over physiologically significant range of glucose concentrations
168
How do beta cells sense rise in glucose?
No glucose receptor,
GLUT2/ Glucokinase can be thought of as the sensor
Effector is rise in ATP due to glucose oxidation
169
Thyroid Function
Development: essential for normal development, esp. CNS & bone
Metabolic: essential for normal metabolism of many body tissues
170
Anatomy of the thyroid gland
Rich blood supply: more blood per unit weight than kidney
Inferior thyroid artery from subclavian
Superior thyroid artery from carotid
171
Histology of the Thyroid gland
Follicular cells, colloid(mainly thyroblobulin), C-cell(parafollicular cell),
172
Follicular cells
Synthesise and secrete TH
173
C cells
secrete calcitonin
174
Where are thyroid hormones derived from?
2 iodinated tyrosine molecules
175
Thyroid hormones T3+T4
T4: Major form released to blood, less active (prohormone)
T3: active form, converted in target cells
176
Circulating Thyroid hormones
Over 99% bound to plasma protein, mainly thyroid-binding globulin (approx. 70%), also transthyretin (approx. 10-20%), albumin (approx. 10-20%)
177
TH Synthesis
1. Active uptake of I- across basolateral membrane, against concentration and electrical gradient, by Na/I symporter (NIS). Stimulated by TSH.
2. Iodide efflux (diffusion) across apical membrane via exchanger known as pendrin (PDS).
3. At extracellular apical membrane iodide is oxidized to iodine and covalently bound to tyrosine residues within the thyroglobulin (TG) macromolecule. Requires thyroid peroxidase (TPO) and H2O2.
4. Tyrosine residues may be iodinated in one (mono-iodotyrosine, MIT) or two (DIT) positions. Coupling of iodotyrosine residues (catalysed by TPO) produces T4 (DIT-DIT) and a smaller amount of T3 (MIT-DIT
178
TH Release
1. Under the influence of TSH, colloid droplets consisting of thyroid hormones within the thyroglobulin molecules are taken back up into the follicular cells by pinocytosis.
2. Fusion of colloid droplets with lysosomes causes hydrolysis of thyroglobulin and release of T3 and T4.
3. About 10% of T4 undergoes mono- deiodination to T3 before it is secreted. The released iodide is reutilized. Several-fold more iodide is reused than is taken from the blood each day but in states of iodide excess there is loss from the thyroid.
4. Approximately 100 μg TH secreted per day (90% T4 and about 10% T3). Secretion probably relies on membrane transporter
179
TH Receptors
Belong to the nuclear receptor superfamily.
Ligand-activated transcription factors.
High affinity for T3: activation requires dimerization with another TR or Retinoid X receptor (RXR)
TR's encoded by 2 genes: TR alpha and TR beta
180
Metabolic regulation of THs
Controlled in target tissues
3 iodothyronine selenodeiodinases, D1-3 is essential in diet
Tissue-specific expression
Regulate the amount of T3 actually available to bind with receptor
T2, rT3: inactive metabolites of T3/T4
181
TH transporters
TH previously thought free to diffuse across cell membrane, but transporters are required, some recently identified, e.g., MCT8, OATP1C1
MCT8: mutations in gene discovered to underlie an X-linked condition, Allan--Herndon--Dudley syndrome, which is associated with psychomotor retardation
182
Functions of TH
Increase metabolic rate: Number and size of mitochondria, enzymes in metabolic chain, Na/K ATPase activity, positive inotropic and chronotropic effects on heart, synergizes with sympathetic nervous system
Energy metabolism:
Partially antagonizes insulin signalling, gluconeogenesis, lipolysis
Growth and development
183
Hypothalamic-pituitary-thyroid axis
Negative feedback control of thyroid hormone synthesis and secretion, via the hypothalamo-pituitary axis
Hypothalamic neurosecretory cells release thyrotrophin-releasing hormone (TRH) into the portal capillaries
TRH stimulates thyrotrophs of anterior pituitary to secrete thyroid stimulating hormone (TSH)
184
Actions of TSH
Increases iodine uptake
Stimulates other reactions involved in TH synthesis (e.g., TPO)
Stimulates uptake of colloid
Induces growth of thyroid gland (which can lead to goitre)
185
Euthyroid
Normal thyroid function
186
Hyperthyroidism
XS TH
Primary: problem is thyroid gland itself
Secondary: problem is pituitary regulation
187
Hypothyroidism
TH deficiency
188
Grave's disease
```
primary hyperthyroidism
Autoimmune
High circulating TH, low TSH
Weight loss, tachycardia, fatigue
Diffuse goitre (TSH receptor stimulation)
Opthalmopathy
```
189
Hashimoto’s
```
primary hypothyroidism
Autoimmune
Low circulating TH, high TSH
Lethargy, intolerance to cold
Lack of growth and development
Diffuse goitre
```
190
Steroids of Adrenal cortex
Glucocorticoids: principally cortisol in mammals
Mineralocorticoids: aldosterone
Androgens
191
Adrenal blood flow and functional Zonation
Blood flows from outer cortex to inner medulla
Layer-specific enzymes; steroid synthesis in one layer can inhibit different enzymes in subsequent layers
Results in functional zonation of cortex with different hormones made in each layer
192
Actions of adrenal steroids
Mineralocorticoids: salt and water balance
Glucocorticoids: metabolism and immune function. Stress increases release, but minimal levels essential for normal function
Androgens: so called ‘weak androgens’
193
Mineralocorticoid function
Sodium retention (whole body sodium): active reabsorption of sodium (with associated passive reabsorption of water), active secretion of potassium
Volume regulation (part of RAAS)
194
Circulating concentrations of cortisol much higher than aldosterone so why doesn't cortisol stimulate salt and water retention?
Cortisol is rapidly metabolized to inactive cortisone in the kidney
Requires enzyme, 11beta-hydroxysteroid dehydrogenase type 2
195
Apparent Mineralocorticoid Excess (AME)
Rare inactivating mutation of 11B-HSD2 leads to syndrome of apparent mineralocorticoid excess (AME). Liquorice contains a compound that blocks this enzyme
196
Glucocorticoid receptor
Member of the nuclear receptor super-family
Characteristic 3-domain structure
197
Transactivation:
glucocorticoid receptor (GR) enhances transcription of target gene
198
Transrepression:
GR represses transcription of target gene
Many anti-inflammatory effects of GCs thought to be due to transrepression – major therapeutic research target
199
ACTH in detail
ACTH is synthesized from the pro-opiomelanocortin prohormone.
ACTH receptor is member of the melanocortin group of receptors
Different forms of melanocyte-stimulating hormones bind to melanocortin receptors
Can also bind to other melanocortin receptors
XAs circulating ACTH may cause skin pigmentation
200
Adrenal insufficiency
Addison’s disease: primary adrenal insufficiency
Secondary (hypopituitarism; secondary to failure in RAAS)
Enzyme defect in steroid synthesis pathways
201
Clinical features of Addison’s
```
Primary adrenal insufficiency
Low circulating adrenal steroids
Plasma [Na+]: normal to low
High ACTH
Plasma [K+]: normal to high
Elevated plasma renin
May be unmasked by significant stress or illness – shock, hypotension, volume depletion (adrenal crisis)
```
202
Hypercortisolism
Cushing’s syndrome: excess glucocorticoid
ACTH-DEpendent:
Cushing's disease: due to increased ACTH secretion (typically due to pituitary adenoma: secondary)
Ectopic ACTH-secreting tumour
ACTH-INdependent:
Adrenal adenoma or carcinoma (primary)
Latrogenic; effect of GC therapy
203
Hypercortisolism: clinical features
Hypertension (salt + water retention)
Hyperglycaemia
Truncal obesity (changes in protein and fat metabolism)
Fatigue, muscle weakness
Virilization (hirsutism in females) (changes in sex hormones)
Depression, mood or psychiatric disturbances
204
Diagnosis of Cushing's
First step: confirm hypersecretion of cortisol
24-hour urinary cortisol
Cortisol at nadir of increased secretion (around midnight)
Next, determine the cause
Plasma ACTH
Dexamethosone suppression test
205
Most common cause of Cushing’s syndrome...
...Is iatrogenic.
Exogenous glucocorticoids activate cortisol receptor
@ high doses will shut down HPA
Adrenal cortex atrophies with lack of ACTH stimulation
Several days may be required for adrenal to become responsive to ACTH again
206
Dexamethasone suppresion test
Dexamethasone: exogenous steroid
Low doses will normally supress ACTH secretion via negative feedback
Low dose fails to supress ACTH secretion with pituitary disease (Cushing's)
Higher dose will supress ACTH secretion in Cushing's
No suppression with low or high dose: suggests ectopic source of ACTH (e.g., tumour elsewhere
207
Pituitary gland location and info
2 lobes
Under the brain, in the Sella Turcica
The anterior lobe(adenohypophysis) is derived from and invagination of the roof of the embryonic oropharynx= Rathke's pouch
Notochordal prjection forms the pituitary stalk, which connects the gland to the brain and also the posterior lobe of the pituitary (neurohypophysis)
208
Pituitary Gland blood supply
dual blood supply: 1st is via the long + short pituitary arteries, 2nd is from the hypophyseal portal circulation. Begins as a capillary plexus around the Arc.
209
Pituitary cells
Originally classified by their staining characteristics w/ acidic (orange-G) and basic (aldehyde fuscin) dyes
210
Anterior pituitary hormones
ACTH, TSH, GH, LH/FSH, PRL
211
Posterior pituitary hormones
ADH, Oxytocin,
212
Pituitary gland layers
Primary = end organ
Secondary = pituitary
Tertiary = hypothalamus
This allows endocrine control.
213
Clinical features of pituitary features
Hormone hypersecretion, space occupying lesion (Headaches, visual loss(field defect), cavernous sinus invasion) , hormone deficiency states (interference with surrounding normal pituitary)
214
XS pituitary hormone diseases
```
GH: Acromegaly
ACTH: Cushing's disease
TSH: Secondary Thyrotoxicosis
LH/FSH: Non-functioning pituitary tumour
PRL: Prolactinoma
```
215
Systemic effects of XS GH/IGF-I
```
Acral enlargement
Increased skin thickness
Increased sweating
Skin tags and acanthosis nigricans
Change appearance
Visceral enlargement
Metabolic Changes
Impaired fasting glucose
Impaired glucose tolerance
Diabetes mellitus
Insulin resistance
Reduced total cholesterol
Increased triglycerides
Increased nitrogen retention
```
```
Cardiomyopathy
Hypertension
Bowel Polyps
Colonic Cancer
Multinodular goiter
Hypogonadism
Arthropathy
OSA
```
216
Actions of Cortisol
```
Increases plasma glucose levels
Increases lipolysis
Proteins are catabolised
Na+ and H2O Retention
Anti inflammatory
Increased gastric acid production
```
217
Prolactinomas
Common
PRL different control to all other anterior pituitary hormones - tonic release of DA inhibits PRL release
Positive feedback
218
Prolactinomas drugs
Many drugs interfere with DA and PRL secretion:
Antiemetics
Antipsychotics
OCP/HRT
219
Features of XS PRL (hypogonadism)
```
Infertility
Oligoamenorrhoea
Amenorrhoea
Galactorrhoea
Reduced libido
Impotence
```
220
Prolactinomas treatment - dopamine agonists
Bromocriptine
Cabergoline
not surgery
221
Non-functioning pituitary tumours
30% of all pituitary tumours
No syndrome of hormone excess produced
Cause symptoms due to space occupation( headache, visual field defects, nerve palsies, interfere with rest of pituitary function - deficiencies of hormones)
222
Non-functioning pituitary tumours treatment
surgery (transsphenoidal approach) ± radiotherapy
| no effective medical therapy
223
Loss of pituitary w/ an expanding tumour
```
LH/FSH - sex
GH - growth
TSH - metabolism
ACTH - survival
Prolactin - stalk compression
ALL DECREASE (based on biological importance)
```
224
Treatment of pituitary Adenomas
Surgery:
- Transsphenoidal
- (Adrenalectomy - Nelson’s syndrome)
Radiotherapy:
-Slow
Drugs:
- Block hormone production
- Stop Hormone Release
225
Causes of Pituitary failure
```
Tumour(benign, malignant)
Trauma
Infection
Inflammation(sarcoidosis, histiocytosis)
Iatrogenic
```
226
Hypopituitarism
Thyroid (bradycardia, weight gain, cold intolerance, hypothermia, constipation)
sex steroids (oligomenorrhoea, reduced libido. hot flushes, reduced body hair)
reduced cortisol( tiredness, weakness, anorexia, postural hypotension, myalgia)
reduced GH( tired, central weight gain)
227
Hypopituitarism treatment
Thyroid- thyroxine
sex steroids- testosterone, oestrogen
reduced cortisol- hydrocortisone
reduced GH- growth hormone
228
Syndrome of Inappropriate ADH (SIADH)
Too much ADH
Brain injury/infection
Lung cancer/infection asthma IPPV
Metabolic (Hypothyroidism, Addison’s)
229
SIADH Diagnosis
Plasma Na+
Plasma osmolality
Urine osmolality
Urine Sodium
230
SIADH Treatment
```
Fluid restriction
Demeclocyline
ADH Antagonist (Tolvaptan)
```
231
Diabetes Insipidus
Underproduction ADH
Cranial (Lack of Production)
Nephrogenic(Receptor resistance)
232
Diabetes Insipidus Diagnosis
```
Polyuria (>3l)
Polydipsia:
- Plasma Na+
- Plasma osmolality (> 295 mosmol/kg)
- Urine osmolality (< 700 mosmol/kg)
- Urine Na+
```
233
Water Deprivation test
```
Discard urine
Collect Plasma 1
Collecting urine 1 ml
Discard urine
Collect plasma 2
Collect U2 ml
Discard urine
Collect P3
Collect P4
Collect U4
give DDAVP
Collect U5
Collect U6
Collect U7
Collect U8
```
234
Water Deprivation test
before DDAVP:
| after DDAVP:
235
Pseudocushing's Syndrome
Depression, alcoholism, anorexia nervosa, obesity
