SUGER 🍦🍧🍨🍩🍪🎂🍭🍬🍫 Flashcards
What proteins contribute to polycystic kidney disease?
Polycystin-1 causes PKD1
Polycystin-2 causes PKD2
How much of the cardiac output does the kidney receive?
Each kidney receives 10% of the cardiac output
Not just to meet their metabolic requirements, but to filter and excrete the metabolic waste products of the whole body
Key volumes of the kidney
Cardiac output - 5 L/min
Renal blood flow- 1 L/min
Urine flow- 1 ml/min
What do afferent and efferent mean?
afferent away
efferent towards
Factors determining filtration
Pressure
Size of the molecule
Charge
Rate of blood flow
Protein binding
How does pressure affect glomerular filtration?
Favours filtration:
Glomerular capillary blood pressure (PG)
Opposes filtration:
Fluid pressure in Bowman’s space (PBS)
Osmotic forces due to protein (πG)
How does size affect glomerular filtration?
Small molecules and ions up to 10kDa can pass freely
e.g. glucose, uric acid, potassium, creatinine
Larger molecules increasingly restricted
e.g. plasma proteins
How does charge affect glomerular filtration?
Fixed negative charge in GBM (glycoproteins and proteoglycans) repels negatively charged anions
e.g. albumin, phosphate, sulfate, organic anions
How does protein binding affect glomerular filtration?
Albumin has a molecular weight of around 66kDa but is negatively charged ∴ cannot easily pass into the tubule
Filtered fluid is essentially protein-free
Tamm Horsfall protein in urine produced by tubule
Affects substances that bind to proteins e.g. drugs, calcium, thyroxine etc
Glomerular filtration rate equation
Glomerular filtration rate = filtration volume per unit time (minutes)
GFR = KF (PG - PBS) - (πG)
KF is the filtration coefficient
Net filtration is normally always positive
Units are ml/min/1.73m2
What is GFR determined by?
-Net filtration pressure
-Permeability of the filtration barrier
-Surface area available for filtration (approx. 1.2-1.5m2 total)
GFR is not measured directly- how is it measured?
Calculated by measuring excretion of marker (M)
CM = UMV/PM
V = urine flow rate (ml/min)
UM = urine concentration of marker
PM = plasma concentration of marker
Properties of a good marker to measure GFR
Properties of a good marker:
freely filtered
not secreted or absorbed
not metabolised
∴ All the M that is filtered will end up in the urine, no more (as it is not secreted) and no less (as it is not reabsorbed)
Normal GFR
Has to be above 90
normal is 125ml/min
Why is creatinine used?
- Muscle metabolite
- Constant production
- Freely filtered
- Not metabolised
Although tubular secretion which is not the best as should not be secreted or absorbed
Things affecting creatinine
Gender
Height
Age
muscle damage
muscle mass
Supplements/ medications
Weight
Renal tubular handling
Outline cystatin c as a marker for measuring GFR
Cystatin C
Non-glycosylated protein produced by all cells
Properties of a good marker:
freely filtered ✓
not secreted or absorbed ✗ (reabsorbed)
not metabolised ✗ (metabolised)
Influenced by thyroid disease, corticosteroids, age, sex and adipose tissue
Inulin as a marker for measuring GFR
Inulin (gold standard)
Properties of a good marker:
freely filtered ✓
not secreted or absorbed ✓
not metabolised ✓
51Cr EDTA
99mTc-DTPA
Radioisotopes
Iohexol
Pressure regulation in the kidneys
Aim to maintain renal blood flow and GFR over defined range 80-180 mmHg
Protects against extremes of pressure
Independent of renal perfusion
Outline renal autoregulation of pressure
Myogenic mechanism
Tuboglomerular feedback
Outline myogenic mechanism
- Intrinsic ability of renal arterioles
- Able to constrict or dilate
- only pre glomerular vessles
- opposite for low bp
How does the myogenic mechanism work?
↑BP → stretches blood vessel wall → opens stretch-activated cation channels → membrane depolarisation → opens voltage-dependent calcium channels → ↑ intracellular calcium → smooth muscle contraction → ↑ vascular resistance → minimises changes in GFR
↓BP causes the opposite
ONLY PRE-GLOMERULAR RESISTANCE VESSELS
Outlinw tuboglomerular feedback
Juxtaglomerular apparatus
Stimulus NaCl concentration
Influences AFFERENT arteriolar resistance
Outline neural regulation of glomerular regulation
Sympathetic nervous system:
-Vasoconstriction of AFFERENT arterioles
-Important in response to stress, bleeding or low BP
Outline hormonal regulation of glomerular filtration
Renin-Angiotensin-Aldosterone System (RAAS)
Atrial Natriuretic Peptide (ANP)
Outline the Renin-Angiotensin-Aldosterone System (RAAS):
Renin released from JGA
Initiates cascade
Aldosterone influences Na reabsorption at distal tubule which influences blood volume and pressure
Outline the role of Atrial Natriuretic Peptide (ANP) in glomerular filtration
Released by atria
Stimulus of blood volume
Vasodilation of AFFERENT arterioles
What does the RAAS system do?
Negative feedback mechanism
Stabilises RBF and GFR
Minimises impact of changes in BP on Na excretion
Without renal autoreg - increase in BP leads to increase GFR and losses
How do intrarenal baroreceptors affect glomerular filtration?
- Respond to changes in pressure in glomerulus
- Influence diameter of AFFERENT arterioles
Outline the affect of extracellular fluid volume on glomerular filtration
Changes in blood volume
Resultant hydrostatic pressure
Effect of Blood colloid osmotic pressure
on glomerular filtration
Oncotic pressure exerted by proteins
Effect of inflammatory mediators in glomerular filtration
Local release of prostaglandins, nitric oxide, bradykinin, leukotrienes, histamine, cytokines, thromboxanes
What causes vasodilation of afferent arteriole?
Prostaglandins
Nitric slide 50
slide 51
slide 52
slide 53
Outline glomerular nephritis
Umbrella term
Causes: infection (bacterial/viral), autoimmune disorders, systemic diseases
Presentation: haematuria, proteinuria, hypertension, impaired kidney function
Outline nephrotic syndrome
Umbrella term
Increased permeability of glomerular filtration barrier
Presentation: triad of oedema + proteinuria + low albumin
Outline IgA neuropathy
Deposition of IgA antibody in the glomerulus
Resultant inflammation and damage
Cause: immune-mediated
Presentation: haematuria, potentially following resp/GI infection
Outline membranous neuropathy
Thickening of GBM
Most common cause of nephrotic syndrome in adults
Cause: primary or secondary
Presentation: proteinuria (often leading to nephrotic syndrome)
Outline diabetic neuropathy
Prolonged exposure to high blood glucose
Presentation: initially asymptomatic then progresses to proteinuria, hypertension and reduced kidney function
Outline minimal change disease
Type of nephrotic syndrome, only in children
Only visible under electron microscope
Outline Alport syndrome
Genetic disorder affecting GBM (X linked or autosomal recessive)
Progressive kidney damage
Potentially includes hearing loss and eye abnormalities
Define acidosis
Disorder tending to make blood more acid than normal
Define alkalosis
Disorder tending to make blood more alkaline than normal
Define acidemia
Low blood pH
Define alkalemia
High blood pH
Factors affecting pH
Metabolic component
intrinsic acid
extrinsic acid
1more
resp CO2 component
CO2 bicarbonate
What is Stewart’s strong ion difference?
Principle: pH and HCO3- are dependent variables governed by:
pCO2
Concentration of weak acids (ATOT)
ATOT = Pi + Pr + Alb
Strong ion difference (SID)
SID = Na+ + K+ + Mg2+ + Ca2+ – Cl- – other strong anions (eg lactate, ketoacids)
Strengths and problems with Stewart’s strong ion difference
Strengths:
Identifies the factors controlling pH
Problems:
Calculation can be very problematic
Probably adds little in practice
How do you diagnose an acid base disorder?
Disorders can be divided into acidoses – disorders that tend to make the blood acid and alkaloses
Disorders can be respiratory (ie driven by changes in CO2 excretion) or metabolic (ie driven by changes in acid load, acid excretion or bicarbonate recycling)
Different disorders can co-exist (mixed patterns)
What is measured in arterial blood gas?
pH
pO2
pCO2
Std HCO3-
Std Base excess
May include other measures (eg lactate, Na+, K+)
What is standard bicarbonate for?
What it would be if CO2 was normal- allows you to ignore the resp component of acid base in the blood
Outline standard bicarbonate
Measures of metabolic component of any acid-base disturbance
Absolute bicarbonate is affected by both respiratory and metabolic components
Standard bicarbonate is the bicarbonate concentration standardised to pCO2 5.3kPa and temp 37
Bicarbonate and std bicarbonate are calculated not actually measured
What is base excess?
Quantity of acid required to return pH to normal under standard conditions
Standard base excess corrected to Hb 50g/L
Can be used to calculate bicarbonate dose to correct acidosis 0.3xWtxBE (but not generally used in practice)
Base excess is negative in acidosis, can be referred to as base deficit
How do we interpret acid-base status?
2 major approaches:
Henderson
Stewart’s theory (strong ion difference)
What are the clinical features of acidosis
long term- stunted growth and muscle wasting
Clinical features: Sighing respirations (Kussmaul’s resps), tachypnoea
Compensatory mechanism: Hyperventilation to increase CO2 excretion
Outline investigation using the anion gap
Difference between measured anions and cations
Anion gap = [Na+] + [K+] – [Cl-] – [HCO3-]
Normal 10-16
What causes a wide anion gap?
Lactic acidosis, ketoacidosis, ingestion of acid, renal failure
What causes a narrow anion gap?
GI HCO3- loss: diahorrea, fissure, renal tubular acidosis,
Outline causes of metabolic alkalosis
Alkali ingestion
Gastrointestinal acid loss: Vomiting
Renal acid loss: Hyperaldosteronism, hypokalaemia
Compensatory mechanism of metabolic alkalosis
Hypoventilation (but limited by hypoxic drive), renal bicarbonate excretion
Outline respiratory acidosis
CO2 retention, leading to increased carbonic acid dissociation
Causes: Any cause of respiratory failure
Compensatory mechanism: Increased renal H+ excretion and bicarbonate retention (but only if chronic)
Outline respiratory alkalosis
CO2 depletion due to hyperventilation
Causes: Type 1 respiratory failure, anxiety/panic
Compensation: Increased renal bicarbonate loss (if chronic)
Questions to ask in ABG interpretation
What is the pH?
What is the respiratory component (ie pCO2)?
What is the metabolic component (std HCO3-, base excess)?
Which component is congruent with the pH?
Renal function numbers
Renal blood flow- 1250ml/min
Renal plasma flow- 700ml/min
Glomerular filtration rate- 120ml/min
Urine flow rate- 1ml/min
Outline the proximal tubule
Active reabsorption of multiple solutes
Metabolically active cells – lots of mitochondria
Sodium gradient generated by Na/K ATPases
Vulnerable to hypoxia and toxicity
Proximal tubular disorders
Reabsorbed solute Disorder
Glucose Renal glycosuria
AAs Aminoacidurias (eg
cystinuria)
Phosphate Hypophosphataemic rickets
(eg XLH)
Bicarbonate Proximal renal tubular
acidosis
Multiple Fanconi syndrome
Outline renal glycosuria
Defect: Sodium glucose transporter 2 (SGLT2)
Mechanism: Failure of glucose reabsorption
Clinical features: Incidental finding on testing, benign
SGLT2 inhibitors (eg empagliflozin) now established as treatments for type 2 diabetes
Wider use in heart failure and CKD
Outline Aminoaciduria: Cystinuria
Defect: Sodium glucose transporter 2 (SGLT2)
Mechanism: Failure of glucose reabsorption
Clinical features: Incidental finding on testing, benign
SGLT2 inhibitors (eg empagliflozin) now established as treatments for type 2 diabetes
Wider use in heart failure and CKD
Treatment of aminoaciduria: cystinuria
High fluid intake: High urine flow, lower concentration
Alkalinise urine: Increases solubility of cystine
Chelation: Penicillamine, captopril
Management of individual stones (percutaneous treatment, surgery etc)
Outline Hypophosphataemic rickets
Commonest form is X-linked hypophosphataemic rickets (XLH)
Defect: PHEX – zinc dependent metalloprotease
PHEX mutation results in increased FGF-23 levels, leading to decreased expression and activity of NaPi-II in proximal tubule
Clinical features and treatment of Hypophosphataemic rickets
Clinical features: Bow legged deformity, impaired growth
Treatment: Phosphate replacement
Outline proximal (type 2) renal tubular acidosis
Defect: Na/H antiporter
Mechanism: Failure of bicarbonate reabsorption
Clinical features: Acidosis, impaired growth
Treatment: Bicarbonate supplementation
Outline the disorder affecting carbonic anhydrase
Genetic defects in carbonic anhydrase produce a mixed proximal/distal renal tubular acidosis
Inhibited by acetazolamide – mild diuretic effect and induces a metabolic acidosis
Used to treat altitude sickness – allows more rapid compensation of respiratory alkalosis
Outline Fanconi syndrome
- Mechanism: Generalised proximal tubular dysfunction, possibly due to failure to generate sodium gradient by Na/K ATPase
- Clinical features: Glycosuria, aminoaciduria, phosphaturic rickets, renal tubular acidosis
- Causes: Genetic (eg cystinosis, Wilson’s disease), myeloma, lead poisoning, cisplatin
- Not to be confused with Fanconi anaemia
What does the loop of henle do?
Generates medullary concentration gradient
Active Na reabsorption in thick ascending limb
Loop of Henle disorders: Barrter’s syndrome
Defect: NKCC2, ROMK, ClCKa/b, Barrtin
Mechanism: Failure of sodium, potassium and chloride cotransport in thick ascending limb. Salt wasting, hypokalaemic alkalosis due to volume contraction, failure of voltage dependent calcium & magnesium absorption
Clinical features of Barrter’s syndrome and what it is similar to
Clinical features:
Antenatal: Polyhydramnios, prematurity, delayed growth, nephrocalcinosis
Classical: Delayed growth, polyuria, polydipsia
Similar to effects of loop diuretics (eg furosemide, bumetanide)
What does the distal tubule and collecting duct do?
Distal tubule and cortical collecting duct allow “fine tuning” of sodium reabsorption, potassium and acid-base balance
Collecting duct mediates water reabsorption and urine concentration
Distal tubular & collecting duct disorders
Gitelman’s syndrome
Distal (type 1) renal tubular acidosis
Disorders resembling hyperaldosteronism
Type 4 renal tubular acidosis
Nephrogenic diabetes insipidus
Outline Gitelman’s syndrome
Gitelman’s syndrome
Distal (type 1) renal tubular acidosis
Disorders resembling hyperaldosteronism
Type 4 renal tubular acidosis
Nephrogenic diabetes insipidus
Outline the actions of aldosterone
Steroid hormone – predominantly acts on transcription
Increase expression of ENaC, Na/K ATP-ase
Mineralocorticoid receptor also activated by cortisol
Cortisol entry to renal tubular cells prevented by 11-beta hydroxysteroid dehydrogenase
Outline distal (type 1) renal tubular acidosis
Defect: ? Luminal H+ ATPase or H+/K+ ATPase
Mechanism: Failure of H+ excretion and urinary acidification
Can be genetic or acquired (eg Sjogren’s syndrome, chronic pyelonephritis, drugs – amphotericin)
Outline the disorders that cause aldosterone levels to be out of control
Excessive aldosterone activity produces sodium retention, hypertension and hypokalaemic alkalosis
Excessive aldosterone production may be primary (eg Conn’s syndrome) or secondary (eg renal artery stenosis)
Several disorders can produce a “hyperaldosteronism” phenotype with high blood pressure, hypokalaemia and alkalosis
Outline Glucocorticoid remediable aldosteronism
Defect: Chimeric gene – 11beta hydroxylase and aldosterone synthetase
Mechanism: Aldosterone is produced in the adrenal in response to ACTH, so levels inappropriately high
Treatment: Suppress ACTH using glucocorticoids
Outline Liddle’s syndrome
Defect: Activating mutation of ENaC
Mechanism: Sodium channel always open so constant aldosterone like effect
Treatment: Amiloride (blocks ENaC)
Outline Syndrome of Apparent Mineralocorticoid Excess (AME)
Defect: 11-beta hydroxysteroid dehydrogenase
Mechanism: Cortisol not broken down in the renal tubules, therefore activates mineralocorticoid receptor.
Treatment: Spironolactone (mineralocorticoid receptor antagonist)
Outline Hyperkalaemic distal (type 4 ) renal tubular acidosis
Defect: Low aldosterone levels
Mechanism: Reduced generation of electrochemical gradient, resulting in failure of H+ and K+ excretion
Common in elderly patients with diabetes
Treatment: Diuretics or fludrocortisone
Outline Nephrogenic diabetes insipidus
Defect: Vasopressin V2 receptor or aquaporin 2 water channel
Mechanism: Failure of water reabsorption in the collecting duct, resulting in inability to concentrate urine
Clinical features: Polyuria, polydipsia, hypernatraemia
Describe the make up of the pancreas
- Formed of small clusters of glandular epithelial cells
- 98-99% of cells are clusters called acini
Outline the exocrine activity of the pancreas
Exocrine activity performed by acinar cells
Manufacture and secrete fluid and digestive enzymes, called pancreatic juice, which is released into the gut
Outline the endocrine activity of the pancreas
- Endocrine activity performed by islet cells
- Manufacture and release several peptide hormones into portal vein
60-70% beta cells- insulin
rest alpha cells which secrete glucagon
and delta cells which secrete somatostatin
Outline the communication between the alpha and beta cells of the islets of langerhans
Paracrine ‘crosstalk’ between alpha and betacells is physiological, i.e., local insulinrelease inhibits glucagon
What are the peptides secreted by the islets of langerhans?
Insulin
Glucagon
Somatostatin
Pancreatic polypeptide
Ghrelin
Outline insulin
polypeptide, 51 amino acids
Reduces glucose output by liver, increases storage of glucose, fatty acids, amino acids
Outline glucagon
29 amino acid peptide
Mobilises glucose, fatty acids and amino acids from stores
Outline somatostatin
Somatostatin secreted from d cells – inhibitor
Outline pancreatic polypeptide
Pancreatic Polypeptide – inhibit gastric emptying
Outline ghrelin
Ghrelin – stimulates release of glucagon
What does insulin do?
Suppresses hepatic glucose output
- Decreases Glycogenolysis
- Decreases Gluconeogenesis
Increases glucose uptake into insulin sensitive tissues
- Muscle – glycogen, and protein synthesis
- Fat – fatty acid synthesis
Suppresses
- Lipolysis
- Breakdown of muscle (decreased ketogenesis)
What is the function of glucagon?
Counterregulatory
Increases hepatic glucose output
- Increases Glycogenolysis
- Increases Gluconeogenesis
Reduces peripheral glucose uptake
Stimulates peripheral release of gluconeogenic precursors (glycerol, AAs)
- Lipolysis
-Muscle glycogenolysis and breakdown
Other counterregulatory hormones (adrenaline, cortisol, growth hormone have similareffects to glucagon and become relevant in certain disease states, including diabetes
Outline insulin secretion by the beta cells
Glucose entry via GLUT2 glucosetransporter
Glucokinase does glucose metabolism which produces ATP which stimulates the
—-> look at it again- slide 12
Outline the role of proinsulin in insulin release
- Proinsulin contains the A and B chains of insulin (21 and 30 amino acid residues respectively), joined by the C peptide.
- Disulfide bridges link a and B chains
- Presence of C peptide implies endogenous insulin production
Outline the biphasic insulin release
- B-cells sense rising glucose and aim to metabolise it
- First phase response is rapid release of stored product
- Second phase response is slower and as it is the release of newly synthesised hormone
Insulin receptors on plasma membrane-n high affinity
Signalling cascade
stimulates GLUT4 vesicles which mobo
15
Outline glucose homeostasis
Glucose levels should remain constant
Liver glycogen is a short-term glucose buffer
What happens if blood glucose is too high?
> 6 is too high
SHort term response- Make glycogen (glucose to glycogen= glycogenesis)
Long term response- Make triglyceride lipogenesis slide 16
Outline glucose sensing
- Primary glucose sensors are in the pancreatic islets
- Also in medulla, hypothalamus and carotid bodies
- Inputs from eyes, nose, taste buds, gut all involved in regulating food
- Sensory cells in gut wall also stimulate insulin release from pancreas - incretins
Does it matter where you get the glucose from?
- Primary glucose sensors are in the pancreatic islets
Also in medulla, hypothalamus and carotid bodies - Inputs from eyes, nose, taste buds, gut all involved in regulating food
Sensory cells in gut wall also stimulate insulin release from pancreas - incretins
Outline incretins
K and L cells in gut
secrete glp 1 and gip
How are post prandial glucose levels regulated?
Increase of insulin-> rising plasma glucose stimulates beta cells to secrete incuijn
GLP1- glucose dependent and short half life
dipeptidyl peptidase IV cleaves GLP-1
Half life is 1-2 mins
DPPIV prevents hypoglycaemia
Outline regulation of CHO metabolism
- In the fasting state, all glucose comes from liver
- Breakdown of glycogen
- Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol) - Glucose is delivered to insulin independent tissues, brain and red blood cells
- Insulin levels are low
- Muscle uses FFA for fuel
- Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
Outline the regulation of CHO metabolism post prandial
- After feeding (post prandial) - physiological need to dispose of a nutrient load
- Rising glucose (5-10 min after eating) stimulates 5-10 fold increase in insulin secretion and suppresses glucagon
- 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
- Ingested glucose helps to replenish glycogen stores both in liver and muscle
- Excess glucose is converted into fats
- High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
What is diabetes mellitus?
A disorder of carbohydrate metabolism characterised by hyperglycaemia
What causes diabetes
Mutations to Kir 6.2
Sulphonylureas
Describe pathogenesis of diabetic ketoacidosis
Outline gametogenesis
-The process by which gametes are produced in the reproductive organs (gonads)
of an organism.
-Gametes are fundamental for sexual reproduction and genetic diversity.
follicule 1 oocyte
Steps of folliculogenesis
Primordial follicle-> Primary follicle -> Developing follicles -> Mature (graafian) follicle + secondary ovum -> ruptured follicle + liberated ovum -> early corpus luteum -> corpus luteum -> corpus albicans
What is oogenesis?
Oogenesis Begins in fetal life, with significant milestones at puberty and ceasing at menopause
Describe the stage of oogenesis that happens during foetal life
Oogonium (diploid) divides by mitosis to form 2 daughter oogonium
These then grow and form primary oocytes
Describe the stage of oogenesis that happens after puberty
Primary oocyte (diploid) undergoes meiosis I to form the first polar body and a secondary oocyte (haploid)
What covers the oocyte?
Oocyte initially covered in cumulus cells
then when that is gone it is covered in a layer of proteins called the zona pellucida
What are the two female reproductive hormones that are produced by the pituitary gland
FSH- stimulates maturation of the oocyte
LH- stimulates the release of an oocyte
What is the duration of the menstrual cycle?
Around 28 days
What does FSH do?
FSH goes to ovary and stimulates production of follicles and stimulates oestrogen production
What does oestrogen do?
Oestrogen stimulates proliferates endometrium cells so the endometrium gets thicker
What are the first 14 days categorised as?
Proliferating phase
What happens at around day 14 of the menstrual cycle?
Surge of LH
stimulates ovulation release of oocyte
What happens on day 20?
Empty follicle converts to corpus luteum and corpus albicans
What phase is it between days 14 and 28?
cyclical phase
progesterone is high
Describe the relationship between GnRH, FSH and Oestrogen
GnRH- starts
Stimulates pituitary to produce FSH
FSH affects oestrogen
Oestrogen increases eggs and uterus
Describe the relationship between LH and Progesterone
LH surge
stimulates ovulation
corpus luteum
progesterone produced
Days 1-7 of menstrual cycle
menstruation
Days 8-11 of menstrual cycle
Lining of womb thickens in preparation for the egg
Day 14 of menstrual cycle
ovulation
Days 18-25 of menstrual cycle
If fertilisation has not taken place the corpus luteum fades away
Days 26-28 of menstrual cycle
The uterine lining detaches leading to menstruation
What is spermatogenesis?
Spermatozoa being produced in the testis
What is ejaculate made of?
-Ejaculate is a mixture of spermatozoa and seminal
plasm
Outline the testes
Oval organ, 4 cm long x 2.5 cm in
diameter
* Covered anteriorly by a saclike extension
of the peritoneum (tunica vaginalis) that
descended into the scrotum with the testes
* Tunica albuginea = white fibrous capsule
Outline the compartments of the testes
septa divide the organ into compartments containing
seminiferous tubules where sperm are produced
Outline leydig cells
clusters of cells between the seminiferous
tubules and source of testosterone
AKA interstitial cells
produce sperm
Outline sertoli cells
s promote sperm cell development
* blood-testis barrier is formed by tight junctions between
sertoli cells; separating sperm from immune system
Where do seminiferous tubules drain into?
eminiferous tubules drain into network called rete testi
Outline male inguinal and scrotal region
*Pendulous pouch holding the testes divided into 2 compartments
by median septum
*Testicular thermoregulation is necessary since sperm are not
produced at core body temperature - need to be 35 not 37
Outline mitosis
Mitosis produces 2 genetically identical daughter
cells (occurs in tissue repair & embryonic growth)
Outline meiosis
Meiosis produces gametes haploid cells required
for sexual reproduction
– 2 cell divisions (after only one replication of DNA)
– meiosis keeps chromosome number constant from
generation to generation after fertilization
– meiosis occurs in seminiferous tubules of males
What are the 2 cell divisions of meiosis?
Meiosis produces gametes haploid cells required
for sexual reproduction
– 2 cell divisions (after only one replication of DNA)
* meiosis I separates homologous chromosome pairs2
haploid cells
* meiosis II separates duplicated sister chromatids4 haploid
cells
– meiosis keeps chromosome number constant from
generation to generation after fertilization
– meiosis occurs in seminiferous tubules of males
What are the 2 types of spermatogonia daughter cells?
Type A
Type B
Describe type A spermatogonia
Type A remain outside blood-testis
barrier & produce more
daughter cells until death
Outline type B spermatogonia
type B differentiate into
primary spermatocytes
* cells must pass through
BTB to move inward
toward lumen - new tight
junctions form behind
these cells
* meiosis I 2 secondary
spermatocytes
* meiosis II 4 spermatids
What is spermiogenesis?
Spermiogenesis is transformation of spermatids into
spermatozoa
– sprouts tail and discards cytoplasm to become lighter
Number of sperm produced
-300 to 600 sperm are made
per gram of testis per second.
-50g x 50 min x 60 sec x 500
sperm =
75,000,000 spermatozoa
Describe the hormonal regulation of sperm production
GnRH-
ptuitary produces FSH and LH
FSH induces surge if spermatogenesis
LH acts on leydig cells
leydig cells produces testosterone inhibits gnrh
Outline the head of the sperm
Head is pear-shaped front end
– 4 to 5 microns long structure
containing the nucleus, acrosome
and basal body of the tail flagellum
* nucleus contains haploid set
of chromosomes
* acrosome contains enzymes
that penetrate the egg
* basal body
Outline the tail of the sperm
Tail is divided into 3 regions
– midpiece contains mitochondria
around axoneme of the flagellum
(produce ATP for flagellar
movement)
– principal piece is axoneme
surrounded by fibers
– endpiece is axoneme only and is
very narrow tip of flagellum
Outline the efferent ductules
– 12 small ciliated ducts collecting sperm
from the rete testes and transporting it
to the epididymis
Outline the epididymis
– 6 m long coiled duct adhering to the
posterior of testis
– site of sperm maturation & storage
(fertile for 40 to 60 days)
Outline the ductus (vas) deferens
– muscular tube 45 cm long passing up
from scrotum through inguinal canal to
posterior surface of bladder
– widens into a terminal ampulla
Outline ejaculatory duct
– 2 cm duct formed from ductus deferens
& seminal vesicle & passing through
prostate to empty into urethra
What are the accessory glands?
Seminal vesicles
Prostate gland
Bulbourethral gland
Outline main components of semen
-2-5 mL of fluid expelled during orgasm
– 60% seminal vesicle fluid, 30% prostatic & 10% sperm and
trace of bulbourethral fluid
* normal sperm count is 50-120 million/mL (< 25 million/mL is
associated with infertility)
* sperm serve to digest path through cervical mucus and to
fertilize egg
Outline other components of semen
– fructose provide energy for sperm motility
– fibrinogen
– clotting enzymes convert fibrinogen to fibrin causing semen to
clot
– fibrinolysin liquefies semen within 30 minutes
– prostaglandins stimulate female peristaltic contractions
– spermine is a base stabilizing sperm pH at 7.2 to 7.6
Outline the role of sex chromosomes
- Our cells contain 23 pairs of chromosomes
– 22 pairs of autosomes
– 1 pair of sex chromosomes (XY males: XX females) - males produce 50% Y carrying sperm and 50% X carrying
- all eggs carry the X chromosome
- Sex of the child is
determined by the type
of sperm that fertilizes
the mother’s egg
Sperm transport in female reproductive tract
*A small number of
spermatozoa reach to the
upper part of female
reproductive tract
*Both Sperm motility and
female reproductive tract
movement are responsible
for sperm transport
*Cervical mucus
Penetration test
Outline capacitation
*Capacitation was first discovered by Chang and
Austin independently (1950).
*The final maturational stage of spermatozoa that
takes place in the female genital tract, before
spermatozoa gain the ability to fertilize oocyte.
*It is one of the most investigated areas of
andrology and one of the least understood areas
of andrology.
Decsribe acrosome reaction
Happens when sperm is in contact with the zona pellucida
zp3 starts
then zp2
What is an embryo morula?
The morula is a globular solid mass of 16-32 blastomeres formed by cleavage of the zygote that precedes the blastocyst
Different types of lab processes to do with stem cells and gametes
*Artificial Insemination (AI)
*Embryo Transfer (ET)
*In Vitro Fertilization (IVF)
*Intra-Cytoplasmic Sperm Injection (ICSI)
*Somatic Nuclear Transfer (Cloning)
*Stem Cell Therapy (Regenerative Medicine)
*IPS Cells (Induced pluripotent Stem Cells)
Outline day 1 of fertilisation
Oocyte activation is key and is triggered by a sperm protein called Phospholipase C zeta (PLCz).
This ‘activates’ the egg to release calcium from internal stores and this rise in calcium facilitates fertilisation.
Oocyte activation is essential for the transformation of the decondensed sperm nucleus in to pronucleus.
4-7 hours after gamete fusion the two sets of haploid chromosomes form the female and male pronucleus (23 chromosomes each)
Pronuclei are equal size and contain nucleoli
In IVF multinucleate oocytes can be identified - polyspermic
What happens in syngamy?
- Male and Female pronucleus migrate to centre (cytoskeletal system plays important role)
- Haploid chromosomes pair and replicate DNA in preparation for the first mitotic division
- The pronuclear membranes breakdown
- The mitotic metaphase spindle forms
- 46 Chromosomes organise at the spindle equator
Describe day 2 cleavage
Approx 24 hours after fertilisation the ooplasm divides in to two equal halves
If one or more of the PN fail to decondense and move in to one of the blastomeres, diploid or triploid mosaics may occur
What is cleavage and what does it do?
Cleavages are timed from sperm entry by an oocyte program that also regulates ‘house keeping’ activities in embryos.
Successive cleavages result in an increase in cell number – essential to provide sufficient cells for differentiation.
Describe genetic control in the embryo
Prior to 4-8 cell stage the developmental control depends on maternally-derived stores of RNA laid down during oogenesis.
Activation of the embryonic genome and start of embryonic transcription occurs in a 4-8 cell embryo.
Developmental arrest can occur.
Describe day 3 cleavage
Early cleavage stage embryos are ‘totipotent’ – the nuclei of individual blastomeres are each capable of forming an entire foetus.
Describe day 4 compaction
- Cells flatten
- Maximise intracellular contacts
- Tight junctions form
- Polarisation of outer cells
- Morula – 16 cells
Descriebe day 5 cavitation and differentiation
- Tight junctions occur between outer cells – forms the trophectoderm
- Fluid filled cavity expands
- Sodium pumped in which pulls water in by osmosis
Now >80 cells
50-66% comprise trophectoderm, rest is ICM
Pluripotent
What do trophectoderm cells do?
Trophectoderm cells pump fluid in to the embryo to form the blastocoel cavity
Describe day 5/6 expansion
- Cavity expands
- Diameter increases
- ZP thins
Outline day 6+ hatching
- Blastocyst expansion and enzymatic factors cause the embryo to hatch from the ZP.
Essential for implantation - TE – extraembyronic
- ICM - embryonic
When is the embryo transplanted into the uterus?
Day 5
Describe the energy metabolism and requirements of the early pre-implantation embryo
ATP turnover low
ATP / ADP ratio is high
Energy metabolism characterised by consumption of pyruvate
Glucose uptake and utilisation is low
Describe the Energy metabolism and requirements in the Blastocyst stage
Metabolic activity rises sharply
ATP / ADP ratio falls, reflecting an increase demand for energy e.g for protein biosyntheses and ion pumping associated with blastocoel cavity.
Glucose is the predominant exogenous energy substrate
Genetic control of the embryo at different stages
early cleavage- maternal
blastocyst- embryonic
What is exogenous nutrients in vivo supplied by?
Cumulus cells
Fallopian Tube secretions e.g. calcium,
sodium, chloride, glucose, proteins.
Uterine secretions e.g. iron, fat soluble vitamins, glucose
How is the fallopian tube adapted to provide the right nutrients to the embryo?
Concentrations of nutrients vary along the tract to provide the embryo requirements at the right time
Growth factors and cytokines
important in embryonic growth and differentiation
Insulin-like growth factor - IGF–I and IGF–II increase cell numbers in blastocyst
Leukaemia inhibitory factor (LIF) enhances embryo-endo interaction
Cellular differentiation – 10 days
After implantation embryogenesis continues with the next stage of gastrulation when the three germ layers of the embryo form in a process called histogenesis
The 3 germ layers form: ectoderm, mesoderm and endoderm (three overlapping flat discs)
It is from these three layers that all the structures and organs of the body will be derived
Changes to the uterus for implantation
- Endometrial cell changes to help absorption of uterine fluid – bring the blastocyst nearer to the endometrium and immobilises it.
- Changes in thickness of endometrium and its blood supply development
- Formation of the decidua
Implantation window = 4 days (6-10 days postovulation)
Outline the implantation process
Well defined starting point
Gradual process over several weeks
No universal agreement when process is completed
Relationship between size of implantation site and thickness of endometrium
small size of implantation site compared to thickness of endometrium
Outline the regulation of implantation
After embryo hatched the embryonic and maternal cells enter into a complex dialogue
High degree of preparation and coordination required
Controlled cascade of trophoblast proliferation, differentiation, migration
and invasion
Mechanisms of embryo implantation
The cross talk between endometrium and the developing embryo is mediated by substances including:
Hormones (sex steroids)
Cell adhesion molecules
Proteases
Cytokines, Growth Factors
Also genetics
5 genes up regulated during implantation window (Haouzi et al 2009)
3 phases of embryo implantation
Apposition
Attachment
Invasion
Describe apposition
Unstable adhesion of the
blastocyst to the uterine lining
Synchronisation of embryo
and endometrium (decidua)
Hatched blastocyst orientates via embryonic pole (always attaches at the area above the ICM)
Receptive endometrium (implantation window day 19 – 22)
Describe Attachment (adhesion)
Stable/stronger adhesion
penetrate with protrusions of the trophoblast cells (microvilli)
Massive communication between the blastocyst and endometrium conveyed by receptor-ligand interactions
Apical surfaces of the endometrial epithelial cells express variety of adhesion molecules (integrin subunits)
Trophoblastic cells also express integrins
Attachment occurs through the mediation of bridging ligands that connect with integrins on their surfaces
Describe invasion (penetration)
Trophoblast protrusions continue to proliferate and penetrate the endometrium
cells differentiate to become syncytiotrophoblast
The trophoblast surrounding the ICM = cytotrophoblasts.
Highly invasive - trophoblast quickly expands and erodes into endometrial stroma.
Invasion is enzymatically mediated
Syncytiotrophoblast erodes endometrial blood vessels
Eventually syncytiotrophoblast comes into contact with maternal blood and form chorionic villi – in initiation of the formation of the placenta
Blood filled lacunae form (spaces filled with maternal blood). Exchange nutrients and waste products.
What happens to the invasiveness of the trophoblast?
After first few days of implantation, the trophoblast changes character to become less invasive
killer cells don’t attack it
Outline decidual reaction
Promotes placental formation
stromal cells adjacent to the blastocyst differentiate into metabolically active, secretory cells or Decidual Cells (under influence of progesterone)
Secretions include growth factors/proteins to support growth of implanting blastocyst in the initial stages before the placenta is fully developed.
Endometrial glands enlarge and local uterine wall becomes highly vascularised.
The decidual reaction is not required for implantation e.g. ectopic implantation can occur anywhere in the abdominal cavity.
What changes happen in the decidual reaction
These changes include swelling of stromal cells due to accumulation of glycogen and other nutrients. These nutrients help the embryo survive the initial days before the placenta is fully developed, which then establishes a channel for fetus nutrient exchange.
When does the decidual reaction happen and where?
The decidual reaction is seen in very early pregnancy in the generalized area where the blastocyst contacts the endometrial decidua. It consists of an increase in secretory functions of the endometrium at the area of implantation, as well as a surrounding stroma that becomes edematous.[1]
Role of progesterone in implantation
- Modifies the distribution of oestrogen receptors
- Stimulates secretory activity
- Stimulates stromal oedema
- Increases volume of blood vessels
- Primes decidual cells
- Stabilises lysosomes
- Might be an immunosuppresent
- May stimulate growth factors and binding proteins
- May regulate the formation of reactive oxygen species (reducing oxidative stress)
Describe maternal recognition of the embryo
Embryo is antigenically different from the mother
At the same time as the decidual reaction, leukocytes in the endometrial stroma secrete interleukin-2 which prevents maternal recognition of the embryo as a foreign body during the early stages of implantation
uterine natural killer cells
What is Human Chorionic Gonadotropin?
produced in the human placenta by the syncytiotrophoblast
hCG-a Synthesised in cytotrophoblast cells
hCG-b synthesised in syncytiotrophoblast cells of placenta
Rising hCG-b levels from day 7-8 signify onset of implantation
What is the role of hCG?
Essential to sustain early pregnancy
ensures the corpus luteum continues to produce progesterone throughout the first trimester of pregnancy (prevents menstruation).
Interacts with the endometrium via specific receptors
Immunosuppressive – has highly negative charge, may repel the immune cells of the mother & protect the foetus.
Outline hCG Measurement in early pregnancy
hCG to double every 1.3 days in the first 10-12 days of a normal singleton pregnancy
A short doubling time signifies a healthy pregnancy
What might slow rate of increase of HCG show?
Early abortion
Ectopic pregnancy
Delayed implantation
Inadequate trophoblast
Embryos are highly sensitive to the environment – essential to optimise conditions to enable successful program
Use a sequential culture medium – different composition at different stages
What does an embryo need in days 1-3
Day 1-3
Water, salts &ions
Pyruvate, lactate, protein
and
No/low Glucose
Non essential amino acids
What do embryos need in day 3+
Day 3+
Water, salts &ions
Pyruvate, lactate, protein
and
Glucose
Essential and non essential amino acids
Vitamins
Describe 1 step culture system
Culture day 1-6 in same media one media
Let the embryo choose principal
useful in uninterrupted systems like time lapse
Why? Reduce stress, less disturbance, Increase embryo viability
Factors affecting embryo growth
maternal factors
embryonic factors
lab conditions
Maternal factors
Follicle environment
Oocyte maturity (hCG trigger 36hours before egg collection)
Embryonic factors
Cleavage rate, size of blastomeres, degree of fragmentation
Gross chromosome imbalance
Variations in embryo metabolism
Failure or abnormal formation of the blastocoel cavity
Lab conditions
Exposure to light
Exposure to high oxygen concentrations
Changes in pH or osmolarity
Culture medium
Volatile organic compounds
outline embryo transfer
Select morphologically (and developmentally) best
embryo(s) to transfer on day 5.
If any remaining embryos - cryopreserve.
Need to be of good quality and correct stage of development to be frozen.
Describe the blastocyst transfer evidence
Enable better selection (embryonic genome activated)
Promotes synchronization with the endometrium.
Higher pregnancy and live birth rates for selected patient populations.
Recent systematic review and meta-analysis demonstrated a much improved live birth rate compared to the early cleavage stage when equal numbers of embryos were replaced
Outline failed implantation
Implantation failure is mainly related to either maternal factors or embryonic causes.
Problem with the embryo - high proportion of embryos fail to implant
Aneuploidy (40% IVF fertilised eggs abnormal)
Interaction between embryo and uterus - insufficient trophoblast invasion
miscarriage
Insufficient invasion of maternal blood vessels
Pre-eclampsia, poor foetal growth, hypertension
Sperm problem – DNA fragmentation (abnormal genetic material). Increase miscarriage. Nutrition & lifestyle.
Describe Recurrent Implantation failure (RIF)
Failure to achieve a clinical pregnancy after transfer of at least 4 good quality embryos in at least 3 cycles
Under the age of 40
Underlying causes of RIF
Poor ovarian function
Increased sperm DNA fragmentation
Uterine pathologies
Polyps/fibroids
Congenital anomalies
Intrauterine adhesions
Hydrosalpinges shown to significantly reduce implantation and preg rates - fluid toxic to embryos and affects endometrial receptivity.
Immunological factor (NK cells)
Outline management of RIF
Lifestyle changes (smoking, BMI)
Sperm DNA fragmentation test
Improve embryo selection e.g. PGT-A
Hysteroscopy – remove anomalies
Fibroid / Polyps /Hydrosalpinges removal
Immunotherapy (intravenous immunoglobulin) – maybe only subgroup of women benefit.
Describe the intermediate mesoderm
- Forms a ridge of issue on the posterior abdominal wall
- Both the renal and genital systems develop from it
What are the 3 systems of kidney development?
Three overlapping kidney systems develop from intermediate mesoderm
- Pronephros
- Mesonephros
- Metanephros
Outline pronephros
Develops in week - 4/40 (disappears by 5/40)
Function/ role- Non-functional, rudimentary
Outline the mesonephros
Develops in week- 4/40
Function/role- Part of it persists
in males.
Excretory tubules develop with a group of capillaries
Capillaries > glomerulus
Tubules > Bowman’s capsule
Collecting duct called the mesonephric duct forms
Gonad starts to develop
Outline the metanephros
Develops in week- 5/40; starts to function at 12/40
Function/ role- Definitive kidney
Definitive kidney
Develops in the pelvic region
Collecting system and excretory system develop differently
Starts to function in week 12 of gestation
Fate of the mesonephros in males and females
Females:
Tubules and mesonephric duct degenerate
Males:
A few tubules and the mesonephric ducts remain:
mesonephric duct = vas deferens
tubules = ducts of testis
Outline the development of the collecting system step 1
Develops from the ureteric bud
The ureteric bud grows out from the mesonephric duct
Covered over by a ‘cap’ of metanephric tissue
Bud grows into the cap = renal pelvis
Outline the development of the collecting system stage 2
Bud splits into two parts = major calyces
Continued subdivision and formation of tubules = ureter, renal pelvis, major and minor calyces, collecting tubules
Outline the development of the excretory system
Develops from metanephric cap
Development promoted by the developing collecting tubules
Development of each is dependent on the other
Metanephric tissue forms renal vesicles
Vesicles become tubular and capillaries develop = glomerulus
Form nephrons
What does the ureteric bud form?
Ureter
Renal pelvis
Major and minor calyces
Collecting tubules
Outline acid base homeostasis
Our systemic pH is maintained within a narrow range (7.35 – 7.45)
Normal diet generates non-volatile acid such as sulphuric and phosphoric acid from Protein metabolism, lactate from anaerobic metabolism of Glucose and volatile acid co2 primarily from carbohydrate metabolism.
Kidneys excrete the acid load and also reclaim filtered bicarbonate.
Lungs mediate excretion of co2.
Role of kidneys in acid-base metabolism
Role of kidneys in Acid-Base metabolism
Reclaim the filtered HCO3-
Regenerate HCO3-
Excretion of H ions buffered by phosphate or ammonia
What is measured in arterial blood gas?
pH
pO2
pCO2
Std HCO3-
Std Base excess
May include other measures (eg lactate, Na+, K+)
Metabolic acidosis
It is defined as low arterial pH with in conjunction with a reduced serum HCO3- concentration
What are the causes?
Ketoacidosis, shock, severe diarrhoea, impaired kidney function, ingested toxins
H + HCO3 = H2CO3 = H2O + CO2
Metabolic alkalosis
pH and bicarbonate is high
Causes:
- Alkali ingestion
- Gastrointestinal acid loss: Vomiting
- Renal acid loss: Hyperaldosteronism, hypokalaemia (use of diuretics)
Compensatory mechanism: Hypoventilation (but limited by hypoxic drive), renal bicarbonate excretion
Respiratory acidosis
CO2 retention, leading to increased carbonic acid dissociation
Causes: Any cause of respiratory failure
e.g hypo- over sedation, brain trauma, immobility, resp muscle paralysis
hyper- pneumonia, pulmonary oedema, emphysema, bronchitis
Compensatory mechanism: Increased renal H+ excretion and bicarbonate retention (but only if chronic)
Respiratory alkalosis
CO2 depletion due to hyperventilation
Causes: Type 1 respiratory failure, anxiety/panic
Compensation: Increased renal bicarbonate loss (if chronic)
Hormones
A hormone is a substance secreted directly into the blood by specialised cells
Hormones are present in only minute concentrations in the blood and bind specific receptors in target cells to influence cellular reactions
System of control using hormones
5
Examples of hormones
Insulin
Cortisol
Testosterone
Oestrogen
Thyroxine
Adrenaline
Aldosterone
Progesterone
Glucagon
VIP
Endocrine glands
Hypothalamus
Pituitary
Thyroid
Parathyroids
Adrenals
Pancreas
Ovary
Testes
What are the different hormone structures?
-Steroids- e.g cortisol
-Peptides- e.g insulin
-Thyroid hormones- e.g thyroxine
Steroid hormones
All steroid hormones are synthesised from cholesterol
What are catecholamines
Catecholamines synthesised from tyrosine
Peptides and proteins
Storage
Secretion
Binding protein
1/2 life
Time to action
Steroids and pseudo steroids
Storage
Secretion
Binding protein
1/2 life
Time to action
Thyroid hormones
Storage
Secretion
Binding protein
1/2 life
Time to action
Catecholamines
Storage
Secretion
Binding protein
1/2 life
Time to action
Extracellular receptors
Cascade function in the cell
hormone binds to cell surface and can’t go thru the membrane
G-protein coupl
Insulin receptors
Intracellular
Takes a while as it has to travel thru cell membrane and cell nucleus
Affects gene transcription in the cell
How do hormones affect us?
- Pre-menstrual tension
- Pregnancy – post natal depression
- Puberty
- High dose steroids – psychosis
- Hypogonadism – poor libido
- Insulinoma - behaviour
Thyroid hormone action
Basal metabolic rate, growth (esp. of the brain)
Low thyroid hormone means low bmr and lethargy
Parathyroid actions
Ca2+ regulation
Cortisol action
Glucose regulation, inflammation, cardiovascular system
Too little- addison’s disease (low BP and insufficiently raised heart rate)
Aldosterone action
BP, Na+ regulation
Catecholamines action
BP, stress
Oestradiol action
Menstruation and femininity
Testosterone action
Sexual function, masculinity
Insulin action
Glucose regulation
ANP action
Na+ regulation
Vitamin D action
Ca2+ regulation
How to measure hormone concentrations?
Bioassays
Immunoassays
Mass spectrometry
Importance of the pituitary in endocrinology
Controls the release of other hormones
Hormones of the anterior pituitary: ACTH, TSH, GH, LH/FSH, PRL
Hormones of the anterior pituitary: ADH, Oxytocin
Hormones of the anterior pituitary and functions
ACTH - Regulation of adrenal cortex
TSH- Thyroid hormone regulation
GH- Growth (+), metabolism
LH/FSH- Reproductive control
PRL- Breast milk production
Posterior pituitary hormones and functions
ADH- reduces urine output
Oxytocin- breast milk expression
Example of feedback principle
Hypothalamus releases TRH
TRH receptor in pituitary stimulates TSH release
This stimulates the TSH receptor in the thyroid which releases thyroxine
This thyroxine acts on cells but also stimulates the pituitary gland and hypothalamus to stop it
Excess production endocrine disease
Thyrotoxicosis
Cushing’s disease/syndrome- disease bc of pituitary tumour, syndrome bc of a collection of symptoms
Acromegaly
Treatment for thyrotoxicosis
- Destruction of thyroid tissue using radioiodine
- Antithyroid drugs to block hormone synthesis
- Partial surgical ablation of thyroid
Drugs to treat functioning pituitary tumours
Somatostatin analogues
Dopamine agonists
GH receptor antagonists
Too little endocrine production diseases
Severe hypothyroidism
Iodine deficiency- goitre
Addison’s disease
Treatments for underactive glands
Underactive thyroid – thyroxine
Underactive adrenals – hydrocortisone(cortisol) + fludrocortisone (synthetic aldosterone analogue)
(Premature) menopause – oestrogen replacement
Underactive testes - testosterone
Non-gland based endocrinology diseases
Carcinoid disease
Small cell lung cancer
Liver secondaries
- Flushing
- Wheezing
- Diarrhoea
- Valvular heart disease
Outline the pituitary gland
Pea-sized
Weighs ca. 0.5 g
Secretes hormones in response to signals from hypothalamus
Arterial supply of pituitrary
The anterior pituitary has no arterial blood supply but receives blood through a portal venous circulation from the hypothalamus
Slide 9
Pit. hormone
Hormone type
Action
Outline the hypothalamus
Collection of brain ‘nuclei’
Connections to almost all other areas of the brain
Important for homeostasis
primitive functions
appetite, thirst, sleep, temperature regulation
Control of autonomic function via brainstem autonomic centres
Control of endocrine function via pituitary gland
Hormone released Releasing hormone
TSH TRH
ACTH CRH
FSH GnRH or LHRH
LH
GH GHNRG
Prolactin Dopamine
Adrenocorticotropic hormone (ACTH) effects of excess and deficiency
Effect of deficiency is small adrenal gland
Effect of excess is large adrenal gland
How does ACTH regulate glucocorticoid synthesis?
- Acutely stimulates cortisol release
- Stimulates corticosteroid synthesis (and capacity)
- CRH stimulates ACTH release
- Negative feedback of cortisol on CRH and ACTH production
How do cortisol levels change thru the day?
Increase from 3-6 am getting you ready for the day then decreases thru the day with a small peal at 3-4pm
Growth hormone (GH) overview
Released throughout life
Pulsatile
Stimulated by low glucose, exercise, sleep
Suppressed by hyperglycaemia
Effects mediated by GH and IGF1
Actions of growth hormone
Linear growth in children
Acquisition of bone mass
Stimulates:
-protein synthesis
-lipolysis (fat breakdown)
-glucose metabolism
Regulation of body composition
Psychological well-being
Regulation of thyroid hormone levels
Negative feedback loop between TSH and thyroxine
In pituitary failure both TSH and thyroxine are low
(in a case of underactive thyroid, where thyroid and not pituitary is problem, thyroxine is low and TSH rises to stimulate thyroid)
LH/ FSH
Essential for reproductive cycle
LH stimulates sex hormone secretion
FSH stimulates development of follicles
Absence leads to infertility and hypogonadism
Mechanism to stimulate release of LH and FSH
E2 (and others) stimulate the hypothalamus to produce GnRH
This stimulates the pituitary to convert the FSH beta and LH beta to be converted to FSH and LH and then be released
Inhibitin
Control of prolactin secretion
- Synthesised in lactotrophs
Regulation of PRL different to other anterior pituitary hormones - Negative regulation by tonic release in inhibiting factor - dopamine
Prolactin overview
Essential for lactation
Levels increase dramatically in pregnancy and during breast-feeding – do not test at these times
Inhibits gonadal activity through central suppression of GnRH (and thus decreased LH/FSH)
Mainly causes disease when present in excess
Outline PHYSIOLOGICAL HYPERPROLACTAEMIA
- Physical or psychological stress
- Post seizure
- Greater in women
- Rarely exceeds 850 – 1000 mU/L
- PRL has circadian rhythm with peak during sleep
Clinical features of hyperprolactinemia
- Usually easy to recognise in pre-menopausal women
- Less apparent in men & post-menopausal women
- Pre-menopausal women
-Hypogonadism
-Oligo/amennorrhoea
-Oestrogen deficiency- Galactorrhoea – spontaneous/ expressible
- Post-menopausal women
- Due to hypogonadal status – none of the above
Outline PATHOLOGICAL HYPERPROLACTINAEMIA
-PRL-secreting pituitary tumours – prolactinomas
-Microadenoma (< 1 cm diameter)
-Macroadenoma (≥1 cm diameter)
-Loss of inhibitory effect hypothalamic DA
-Pituitary stalk compression/ pituitary disconection
-Drugs – DA antagonists
-Phenothiazines, metoclopramide, TCAs, verapamil
-Hypothyrodism
Diseases of the pituitary
- Benign pituitary adenoma
- Craniopharygioma
- Trauma
- Apoplexy / Sheehans
- Sarcoid / TB
Presentation of pituitary tumours
- Pressure on local structure e.g. optic nerves
Bitemporal hemianopia - Pressure on normal pituitary
hypopituitarism - Functioning tumour:
Prolactinoma
Acromegaly
Cushing’s disease
Why are post. and ant. pituitary separate?
Posterior pituitary comes from the neural ectoderm and anterior pituitary comes from oral ectoderm
Local effects of pituitary tumours
Chiasmatic compression
Cranial nerve damage
Hypothalamic damage
Bony invasion: pain, CSF leaks
What is bitemporal hemianopia?
Visual field loss due to damage to optic chiasm
Patient can adjust for this by moving head more from side to
side to compensate, may not be aware of deficit
Pituitary hormone excess- what it does
ACTH – Leads to increased cortisol levels (Cushing’s disease)
GH – Leads to increased GH and IGF-1 levels (Acromegaly)
LH or FSH – Very rare! Might stop periods (Gonadotrophinoma)
TSH – Leads to thyrotoxicosis. Very rare cause!
Prolactin – Leads to galactorrhoea and amenorrhoea
(Prolactinoma)
Prolactinomas
- More common in women
- Present with galactorrhoea / amenorrhoea / infertility
- Loss of libido
- Visual field defect
- Treatment dopamine agonist eg Cabergoline or bromocriptine.
Acromegaly
- GH excess
- Leads to increased Insulin-like Growth Factor-1 production in the liver
- Both GH and IGF1 increase growth of a range of soft and hard tissues
- > 98% due to a pituitary tumour, often large
Cushing disease/syndrome
Fat tissue: Central obesity, moon face, ‘buffalo hump”
Collagen/protein: Thin skin, striae, easy bruising, myopathy, osteoporosis
Androgen excess: Acne, hirsutism, amenorrhoea
Other: Hypertension, depression, diabetes, immunosuppression
What causes cushing’s disease and how is it diagnosed?
Diagnosed by:
high cortisol production
loss diurnal rhythm of cortisol
loss of negative feedback of glucocorticoids on the pituitary
With pituitary origin ACTH levels will be high or inappropriately normal for the high cortisol levels
ACTH levels will be high in the blood draining from the pituitary
Treatment is by transsphenoidal surgery
Hypopituitarism
- GH deficiency causes reduced linear growth in childhood. Symptoms less obvious in adulthood
- LH/FSH deficiency causes hypogonadism
- ACTH deficiency causes adrenal insufficiency
- TSH deficiency causes hypothyroidism
- Associated with increased morbidity & mortality
Causes of cushing’s syndrome
Pituitary tumour + Ectopic tumour both produce too much ACTH
Synthetic ACTH-> Biggest cause
Causes and clinical features of hypopituitarism
Common causes:
Pituitary tumours (often non-functioning)
Pituitary surgery / radiotherapy / infarction
Congenital
Moderate-severe Head injuries
Clinical Features:
Depend on hormones deficient
Usual sequence of failure:
GH, LH/FSH, ACTH, TSH +/- AVP
Which part of the nephron does bulk absorption and which part does fine tuning
Proximal = bulk absorption = leaky
Distal = fine tuning = impermeable
Segments of the nephron
Cortex- PCT, proximal straight tubule, part of thick ascending limb, DCT and part of collecting duct
Medulla- Thin descending limb, loop of Henle, thin ascending limb, part of thick ascending limb and collecting duct
What does the PCT do?
bulk reabsorption: Na, Cl, glucose, amino acids, HCO3; secretion of organic ions
What does the loop of henle do?
more Na reabsorption, urinary dilution and generation of medullary hypertonicity
Distal tubule
Fine regulation of Na, K, Ca, Pi, separation of Na from H2O
Collecting duct functions
similar to distal tubule, + acid secretion, regulated H2O reabsorption concentrating urine
Aminoaciduria: cystinuria
Tubular defect in uptake of amino acids
Defect; mutations in the SLC3A1 and SCL7A( genes
Genetic test available but not routinely used in clinical practice
Failure of cytokine reabsorption - urinary crystal
Proximal bicarbonate reabsorption
Acute tubular necrosis
Outline counter-current multiplication aim
to generate a hypertonic medullary interstitium so that H2O can be sucked out of the tubule in impermeable distal segments, thus concentrating the urine
Descending limb
simple squamous
flat cells sparse organelles
simple cuboidal/low collumnar
Countercurrent multiplication mechanism
- Solute reabsorption in the impermeable ascending limb lowers the lumenal osmolality and increases the medullary interstitial osmolarity
- Increased interstitial osmolarity draws H2O out of the permeable thin descending limb, increasing the lumenal osmolality.
- The continuous flow of fluid pushes the hyperosmotic fluid from end of the thin limb in to the ascending limb.
Action of aldosterone
- Increases transcription (steroid receptor) of ENaC (and NaKATPase)
- This increases apical Na influx
- This charge movement facilitates K efflux
- Thus aldosterone drives both Na reabsorption and K secretion
ADH (Vasopressin) Action
principal cells
adenylyl-cyclase coupled vasopressin receptor (V2R)
kinase actions culminate in insertion of vesicles containing aquaporin 2 into the apical membrane
increases water permeability
Bartter’s tubulopathies
Site- Loop of Henle
Molecules- NKCC2, ROMK or basolateral K/Cl efflux
Diuretic equivalent- Loop diuretic
Features-HypoK, alkalosis, secondary aldosteronism, lowish BP
Gitelman’s tubulopathy
Site- DCT
Molecule- NCC
Diuretic equivalent- Thiazide
Features- HypoK, HypoMg, lowish BP
Liddle’s tubulopathy
Site- Collecting duct
Molecule- ENaC- constitutively active
Diuretic equivalent- n/a
Features- Hypertension, hypokalaemia
Functions of skin
Waterproof barrier
Physical barrier
Vitamin D synthesis
Endocrine organ
UV barrier
Barrier to infection
Immune organ
Sensory organ
Thermoregulation
Energy store / Shock absorber
Key facts about the skin
Largest organ of the body
3.6 Kg
2 m2
3 layers
Epidermis
Dermis
Subcutis
Not just a wrapper for the interesting bits!
What does the epidermis do?
Waterproofing
Physical barrier
Immune function
Vitamin D synthesis (Endocrine)
UV protection
Thermoregulation
What does the dermis do?
Thermoregulation
Vitamin D synthesis (Endocrine)
Sensory organ
What does the subcutis do?
Thermoregulation
Energy reserve
Vitamin D storage
Endocrine organ
Shock absorber
Outline the waterproofing of the skin
Tight junctions between cells in stratum granulosum, epidermal lipids and keratin in stratum corneum form both an inside-out and outside-in barrier to water
Prevents transepidermal water loss
Why does the skin wrinkle when wet?
Skin on fingers and toes wrinkles if immersed for approx. 5 mins.
Mediated by sympathetic nervous system
Due to vasoconstriction in dermis
Improves grip
Outline the skin as a physical barrier
Structure of skin helps resist trauma
Stratified epithelium helps resist abrasive forces
Fat in subcutis acts as shock absorber
Outline an abrasion
Medical term for a graze
Stripping away of the epidermis
Secretions but not blood
Outline the skin’s role in vitamin D synthesis and storage
7-dehydrocholesterol in plasma membranes of epidermal keratinocytes and dermal fibroblasts converted to previtamin D3 by UVB
15-25 mins whole body exposure produces up to 10,000 IU Vitamin D
Serum concentrations peak 24-48 hours after exposure
Lipid soluble – can be stored in subcutis adipocytes
Outline the skin as an endocrine organ- site of hormone action
Site of hormone action
Androgens act on follicles and sebaceous glands
Thyroid hormones act on keratinocytes, follicles, dermal fibroblasts, sebaceous glands, eccrine glands
Outline skin changes in hypothyroidism
Epidermal changes
Coarsened thin scaly skin
Dermal changes
Myxoedema
Hair and Nail changes
Dry brittle coarse hair
Alopecia
Thin brittle nails
Sweat gland changes
Dry skin
Decreased sweating
Outline the skin as an endocrine organ- site of hormone synthesis
Vitamin D3 – unique site for cholecalciferol synthesis
17β-hydroxysteroid dehydrogenase in sebocytes and 5α-reductase in dermal adipocytes convert dehydroepiandrosterone (DHEA) and androstenedione to 5α-dihydrotestosterone
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) synthesised by dermal fibroblasts
Outline skin as a barrier to UV light
Both UV-A and UV-B damage skin
- Burns
- Suppress action of Langerhans cells
- Photo-aging
- DNA damage (skin cancers)
Skin colour depends on:
- Melanin
- Carotenoids
- Oxy/deoxyhaemoglobin
Melanin
Synthesised in melanosomes within melanocytes from tyrosine
Transported via dendrites to adjacent keratinocytes
Pheomelanin (red/yellow)
Eumelanin (brown/black)
Photoprotective – scatters/filters UV light
Outline density of melanocytes and presence of different types of melanin
Melanocyte density varies between body sites
Red hair contains more pheomelanin
All skin types contain more eumelanin than pheomelanin.
Bad bits of melanin
Prone to photodegradation – may generate reactive oxygen species!
Pheomelanin increases release of histamine
Lots of melanin = less able to utilize UV light to make vitamin D
Outline immediate pigment darkening of the skin
photooxidation of existing melanin
redistribution of melanosomes
occurs within minutes and lasts hours-days.
Outline Persistent pigment darkening (tanning)
UVA»_space; UVB
oxidation of melanin
occurs within hours, lasts 3-5 days
Outline delayed tanning
increased melanin synthesis
Occurs 2-3 days after UV exposure, maximal at 10-28 days
Outline the skin as a barrier to infection
- Skin presents a large surface area to environment
- The properties that render the skin a barrier to water also help prevent infection
- A range of peptides synthesised by granular layer keratinocytes have antimicrobial properties
- Cathelicidin-related antimicrobial peptide (Cramp – called LL37 in humans)
- β defensins
- S100A7 and S100A8
Outline the skin as an immune organ
- Innate and acquired immune functions
- Epidermis
-Langerhans cells - Dermis
- Regulatory T cells
- Natural killer cells
- Dendritic cells
- Macrophages
- Mast cells
Outline the immune function of the epidermis
Keratinocytes secrete cytokines and chemokines that maintain populations of leucocytes in skin
Langerhans cells are antigen-presenting cells and secrete cytokines
What happens in the skin when challenged with an infection?
- LC migrate to dermis and lymph nodes and activate a T-cell response
- Keratinocytes proliferate & secrete cytokines
- Leucocytes enter skin from blood
Outline the skin as a sensory organ
- Merkle cells - basal epidermis (Light touch)
- Encapsulated mechanoreceptors in dermis
- Pacinian corpuscles (Pressure/Vibration)
- Meissner corpuscles (Touch)
- Myelinated and unmyelinated sensory nerve endings in dermis (Pain, Itch, Temperature)
Outline skin as a heat keeper
Insulation
- Subcutaneous fat
Heat loss
- Cutaneous blood flow
- Deep vascular plexus (lower reticular dermis)
- Superficial vascular plexus (upper reticular dermis)
- Loops of blood vessels from superficial plexus extend to reticular dermis
- Eccrine sweating
- Hair [What might be other functions of human hair?]
Outline the skin as a mechanism of heat loss
Humans are endothermic homeotherms
Heat generated through metabolism
Evaporation depends on:
Surface area exposed to environment
Temp and relative humidity of ambient air
Convective air currents
Radiation, conduction and convection can add or remove heat
Outline heat storage equation
Heat storage = metabolism – work – evaporation +/- radiation +/- conduction +/- convection
Blood flow to the skin as a mechanism of thermoregulation
- Autonomic regulation of blood flow in dermal vascular plexuses
- Sympathetic alpha-noradrenergic: vasoconstriction
- Sympathetic cholinergic: vasodilation
- (Both in hairy skin. Hairless skin only has cholinergic innervation)
- Sympathetic cholinergic nerves that govern sweating may be the same as those controlling active vasodilation
- Nitric oxide may play a role in active vasodilation
Outline sweating
- 1.6-4 million eccrine sweat glands
- 1-3 L sweat per hour
- Availability of water is major limiting factor
Piloerection (goosebumps)
- Arrector pili muscles innervated by sympathetic α1-adrenergic fibres
- Contraction raises cutaneous hairs
- Likely little significant impact on heat conservation
Skin as an energy store
-Subcutaneous fat acts as an insulator, a shock absorber and as an energy store
- White adipose connective tissue
Maternal adaptation to pregnancy- endocrine/biochemical
Driven by hormonal changes- include
* Weight gain
* Maternal
* Fetoplacental
* Protein synthesis
* Lipid synthesis
* Insulin resistance
Key pregnancy hormones
- Human chorionic gonadotrophin
- Oestrogen
- Progesterone
- Prolactin
- Relaxin
- Oxytocin
- Prostaglandins
Outline human chorionic gonadotrophin (hCG)
- Stimulates oestrogen/progesterone production by ovary
- Pregnancy test hormone
- Diminishes once placenta mature enough to take over
oestrogen/progesterone production
Outline oestrogen in pregnancy
- Produced throughout pregnancy
- Regulates levels of progesterone
- Prepares uterus for baby, breasts for lactation
Outline progesterone in pregnancy
- Prevents miscarriage, builds up endometrium for
support of placenta - Prevents uterine contractions
Outline prolactin in pregnancy
- Produced by pituitary gland
- Increases cells that produce milk.
- After birth levels of P and oestrogen drop dramatically, allowing
prolactin to stimulate production of milk, also controlled by
suckling. - Prevents ovulation, unreliably
Outline relaxin in pregnancy
- High early in pregnancy
- Limits uterine activity, softens the cervix – cervical ripening in
preparation for delivery
Outline oxytocin in pregnancy
- Triggers “caring” reproductive behaviour.
- Responsible for uterine contractions during pregnancy
and labour. - Cause of contractions felt during breast feeding.
- Drug used to induce labour
Outline prostaglandins in pregnancy
- Tissue hormones, role in initiation of labour
- Synthetic prostaglandins used to induce labour
How do the hormone levels change during the pregnancy?
hCG highest in 1st few weeks then drops as the placenta develops
Progesterone increases a bit then plateaus before increasing exponentially from week 20 with the other hormones
The other hormones start to increase exponentially at the 10th week
Cardiovascular changes in pregnancy
- Increasing cardiac output (CO)
- Reduced systemic blood pressure
- Reduced total peripheral resistance
(TPR)
BP= CO x TPR - Increased uterine blood flow Increased blood volume
- Increased red cell mass
- Increased alveolar ventilation
Visible changes in pregnancy
Varicose veins- because of relaxation of smooth muscles
Striae gravidarum + Linea nigra - because of rapid increase in stomach size
Internal non-uterine changes in pregnancy
Compression of the organs so gastric acid reflux
Lumbar lordosis because of relaxation of ligaments
Common maternal problems affecting pregnancy
- Biological factors
- Poor weight gain/undernutrition
- Extremes of maternal age
- Medical conditions
- Drug misuse: cigarettes, heroin etc
- Haemorrhage
Common foetal problems
- Miscarriage
- Abnormal development
- Disordered fetal growth
- Too big
- Too small
- Premature birth and consequences
Changes to the uterus in pregnancy and birth
*Uterine growth - cell division and
hypertrophy of individual myometrial
cells
*Myometrium
*Smooth muscle cells in bundles,
contract and relax
Outline the uterine cervix
- Protects fetus during development
- Mainly collagen and ground substance with
glycosaminoglycans - Collagen has cross-links which increase tensile strength
Outline cervical ripening
- Growth and remodelling of the cervix prior to labour
- Occurs under influence of placental hormones and relaxin
throughout gestation - Process accelerates last 3 m due to oestrogens and
dehydroepiandrosterone. - Promoted by release of PGE from cervical mucosa,
relaxin and placental oestrogens. - Effacement and dilatation due to muscular action of
cervix and uterus
Prostaglandins in labour
- All uterine tissues able to synthesize PG
- PGE2 about 10 times as potent as PGF2a in human uterus.
- PGF2a - main prostaglandin released during labor
Different phases of labour
Phase 0 - myometrial repression
Phase 1 - Myometrial activation
Phase 2 - Biochemical activation
Phase 3 - Permanent changes
Summary of events prelabour
- Enhanced prostaglandin production
- The initiation of labor
- maternal signal oxytocin
- fetal signals oxytocin, vasopressin, & cytokines
- PGF2a enhance action of oxytocin.
- With pressure on cervix, release of PG from decidua
and chorioamnion.
Components of labour
3 Ps
* Passenger the baby
* Passages the pelvis
* Powers the uterus
Outline the passenger- foetus
Foetal skull bones not yet fused
Joined at sutures
Can overlap as they are squeezed thru the birth canal
Outline the powers- uterus
- Braxton-Hicks contraction
- Co-ordinate- fundal dominant -push baby down
- Inco-ordinate- not associated with good labour progress
Labour initiation and action
*Increased PGF2a enhancing action of oxytocin.
* Increased pressure on cervix, release of PGs from
decidua and chorioamnion.
* The contractile protein actomyosin, formed
from actin and myosin.
* Myosin can react with actin only when
phorphorylated by MLCK.
* MLCK functionally dependent on ca+ ions
and calmodulin, inactivated by its own
phosphorylation
Outline the passage- pelvis
Inlet- oval shapes - foetal head transverse
Main bit- circular- left occipital-anterior position
Outlet- Oval shaped but the other way- occipital anterior
Stages of labour
First stage- start of regular contraction and dilatation of the cervix
Second stage- cervix dilated baby travels through vaginal canal
Delivery- Baby comes out
Third stage- placenta is delivered
Problems with passages
- Too narrow
- Too wide
- Damaged
Problem with the passenger
- Too large or too small
- Abnormal lie or presentation eg breech
- Tumours
- Too poorly
Problems with powers
- Too strong
- Too weak
- Disorganised
- Cervix too rigid
- Cervix weak
- Postpartum bleeding
Problems with the stages of labour
- Prolonged latent phase
- Failure to progress in labour
- Delayed 2nd stage – instrumental delivery
- Delayed 3rd stage – manual removal of the placenta
Overview of the placenta
- Maternal-foetal organ
- Begins developing at blastocyst implantation.
- Delivered after the foetus at birth.
- Provides for the developing foetus:
- Nutrition
- gas exchange
- waste removal
- endocrine and immune support
Placental structure
Fetal surface
Maternal surface
Foetal surface of the placenta
- Umbilical cord attachment
- Covered with amnion attached
to chorionic plate - Umbilical vessels branch into
anastomosing chorionic vessels
Maternal surface of the placenta
- Cotyledons
- Cobblestone appearance
- Covered with maternal
decidua basalis
Implantation
1st stage in dev of
placenta
* Adhesion/attachment
of embryonic
trophoblast and
endometrial epithelial
cells
Placental functions
*Metabolism
*Transport
*Endocrine
Placental metabolism
*Synthesizes
*Glycogen
*Cholesterol
*Fatty acids
*Provides nutrient and energy
Placental transport
- Gases and nutrition
- Oxygen, carbon dioxide, CO
- Water, glucose, vitamins
- Hormones, mainly steroid not protein
- Electrolytes
- Maternal antibodies – IgG not IgM
- Waste products
- Urea, uric acid, bilirubin
- Drugs and their metabolites
- Fetal drug addiction
- Infectious agents
- Cytomegalovirus, rubella, measles,
microorganisms
Placental hormones
- Human chorionic gonadotrophin (hCG)
like leutenizing hormone, supports corpus luteum - Human chorionic somatommotropin (hCS)
or placental lactogen
stimulate mammary development - Human chorionic thyrotropin (hCT)
- Human chorionic corticotropin (hCACTH)
- Progesterone and Oestrogens
support maternal endometrium - Relaxin
Placental abnormalities
- placenta accreta
- abnormal adherence, with absence of
decidua basalis - placenta percreta
- villi penetrate myometrium
- placenta praevia
- placenta overlies internal os of uterus
- abnormal bleeding * usually require caesarean delivery
Haemolytic disease of the newborn
- Fetus Rh+ /maternal Rh-
- Fetus causes anti rh antibodies
*Dangerous for 2nd child
Placental problems
- Maternal hypertension: pre-eclampsia
- Foetal growth restriction
- Tumours
- Intra-uterine foetal death
Outline the posterior pituitary
Originates from Neuro tissue – large numbers of Glial-type cells
2 Hormones
vasopressin
Oxytocin
Vasopressin (ADH
Antidiuretic hormone – controls water secretion into urine)
Primarily from supraoptic nuclei
Oxytocin
expression of milk from the glands of the breasts to the nipples; promotes onset of labour.
Primarily from paraventricular nuclei
How is vasopressin produced?
Mechanism of action of ADH
- Binds to membrane receptor
- Receptor activates cAMP second messenger system
- Cell inserts AQP2 water pores into the apical membrane
- Water is absorbed by osmosis into the blood
2 types if receptor
Baroreceptors- changes in BP- signal to produce ADH
Osmoreceptors- changes in conc.- signal to produce ADH
What is osmolality?
- Concentration of particles per kilo of fluid
- size of particle not important, number is important - i.e one
molecule of larger protein albumin same effect as Na+ - sodium, potassium, chloride, bicarbonate, urea and glucose
present at high enough concentrations to affect osmolality - alcohol, methanol, polyethylene glycol or mannitol -
exogenous solutes that may affect osmolality
Serum osmolality
Sodium
Glucose
Urea
Osmolarity gap
0-10 mOsmo/kg gap between measured and calculated - higher
usually due to alcohol
Normal osmolality
282 - 295 mOsmol/kg
Outline the loss of relationship between plasma osmolality and vasopressin
- Drinking rapidly suppresses vasopressin release and thirst.
- In pregnancy osmotic threshold for VP release and thirst is decreased.
- Plasma VP concentrations increase with age (also thirst blunting, decreased renal concentrating ability, decreased fluid intake).
Disorders of vasopressin (ADH)
- Vasopressin Deficiency, Vasopressin Resistance
- Syndrome of inappropriate
antidiuretic hormone secretion -
SIADH
What is polyurea?
Large volumes of urine
What is polydypsia?
Large volumes of drinking
Clinical features or AVP-D or AVP-R
polyuria
polydypsia
no glycosuria or hypercalcaemia or hypokalaemia
How to diagnose AVP-D or AVP-R?
measure urine volume - DI unlikely if urine volume
<3L/day
biochemistry
inappropriately dilute urine (<300 mOsm/kg) for
plasma osmolality (>290 mOsm/kg)
normonatraemia or hypernatraemia
water deprivation test
Types of AVP diseases
Vasopressin Deficiency – Cranial
lack of vasopressin (ADH)
Vasopressin Resistance – Nephrogenic
resistance to vasopressin
Causes of AVP- Deficiency
Destruction of hypothalamus
Interruption of the connection
of hypothalamus to pituitary
Acquired
Idiopathic
Tumours - craniopharyngioma, germinoma, metastases
Trauma
Infections - TB
Vascular - neurosarcoidosis, Langerhans’s histiocytosis
Granuloma
Familial - very rare -
mutations in the neurophysin part of pro-AVP
Autosomal dominant
Rarely autosomal recessive
Causes of vasopressin resistance
Aquired-
Osmotic diuresis (diabetes mellitus)
Drugs (lithium, Demeclocycline tetracycline)
Chronic renal failure
Familial-
Investigation of VD/VR –
Hypertonic Saline Stimulation Test
measure random copeptin
then if iver 21.4 pmol/L
give
Management of AVP-D
treat any underlying condition
desmopressin
Management of AVP-R
try and avoid precipitating drugs
congenital DI - very difficult
free access to water
very high dose desmopressin
hydrochlorothiazide or indomethacin
SIADH-syndrome of antidiuretic hormone secretion
Common in clinical practice
Too much AVP, when it should not be being secreted
Causes low blood concentration - low osmolality
Urine is inappropriately concentrated
Plasma sodium is low
Euvolaemia
Criteria for diagnosis of SIADH
Hyponatraemia < 135 mmol/L
Plasma hypo-osmolality < 275 mOsm/Kg
Urine osmolality > 100 mOsm/Kg
Clinical euvolaemia
No clinical signs of hypovolaemia (orthostatic decreases in blood pressure, tachycardia, decreased skin turgor, dry mucous membranes)
No clinical signs of hypervolaemia (oedema, ascites)
Increased urinary sodium excretion > 30 mmol/L with normal salt and water intake
Exclude recent diuretic use, renal disease, hypothyroidism, and hypocortisolism
SIADH - management
treat underlying condition
fluid restriction <1L/24 hour
sometimes demeclocycline
‘Vaptans’ – V2 receptor antagonists
if Na+ low AND fitting hypertonic N/Saline on ITU
<12mmol/l increase in Na+ per 24 hour
Potential risk of central pontine myelinolysis
Oxytocin
release stimulated by milk suckling
Action
stimulates milk let down
stimulates contraction of myometrium (100X more potent that AVP)
200X less active at the V2 receptor compared to AVP
Cautions for change in sodium levels
Hypertonic saline should raise sodium by 1 to 2 mmol/l/hour; monitor sodium every 2 hours
Hypertonic saline should be stopped when asymptomatic or serum sodium >120mmol/l
One should increase sodium around 8 – 12 mmol/l in 24 hours or 16 – 24 mmol/l in 48 hours to avoid osmotic demyelination
Aim for a safe range as opposed to a normal range
Hypertonic saline should raise sodium by 1 to 2 mmol/l/hour; monitor sodium every 2 hours
Hypertonic saline should be stopped when asymptomatic or serum sodium >120mmol/l
One should increase sodium around 8 – 12 mmol/l in 24 hours or 16 – 24 mmol/l in 48 hours to avoid osmotic demyelination
Aim for a safe range as opposed to a normal range
What are the 3 layers of the cortex?
Zona glomerulosa
zona fasciculata
Zona reticularis
WHat does the zona glomerulosa secrete?
Mineralocorticoids- aldosterone
for salt
What does the zona fasciculata produce?
Glucorticoids – Cortisol
for sugar and stress
What does Zona reticularis produce?
Androgens – DHEA, androstenedione
For sex
How is the fetal adrenal gland different
Biiger than kidney
Fetal zone, transitional zone and definitive zone instead of layers of cortex (different thicknesses as well)
Corticosteroid structure
Cholesterol precursor for all adrenal steroidogenesis
cyclopentanoperhydrophenanthrene structure
three cyclohexane rings (A, B, and C)
single cyclopentane ring (D)
Overview of corticosteroids
- Lipid soluble - can pass through biological membranes
- Bind to specific intracellular receptors
- Alter gene transcription directly or indirectly
- Exact action depends on structure, ability to bind specific receptors (and recruit cofactors)
Classification of steroids
Type carbons hormone
pregnane
derivatives
Effect if ACTH on adrenal size
Deficiency-> small
Excess -> large
Outline glucocorticoids
- Synthesised in zona fasciculata and reticularis
- Essential to life
- Have actions on most tissues
- Many actions “permissive” (do not directly initiate but allow to occur in presence of other factors), e.g. the effects of catecholamines on vascular tone
- “Permissive” actions only apparent with deficiency
- Important in homeostasis e.g. conditioning body’s response to stress
Important actions of glucocorticoids
Increase glucose mobilisation
Augment gluconeogenesis
Amino acid generation
Increased lipolysis
Maintenance of circulation
Vascular tone
Salt and water balance
Immunomodulation
Dampen immune response
Important during stress
U shaped action of glucocorticoids
Too little -> depression and psychosis
Too much -> The same
Transport of glucocorticoids
In the circulation glucocorticoids are heavily bound to proteins
90% bound to Corticosteroid-Binding Globulin (CBG)
5% bound to albumin
5% “free”
Only “free” glucocorticoids bioavailable
In clinical practice “total” rather than “free” cortisol levels measured
CBG levels - with inflammation thus % free cortisol
Cortisol binding
Non stressed- most bind to CBG
STressed- break CBG most not bound
How does ACTH regulate glucocorticoid synthesis?
Acutely stimulates cortisol release
Stimulates corticosteroid synthesis (and capacity)
CRH stimulates ACTH release
Negative feedback of cortisol on CRH and ACTH production
MC2R and MRAP
Protein folding & translocation across ER
Escorting MC2R to cell surface
Stabilising of MC2R at cell surface
Ligand specificity
Regulation of glucocorticoid levels
Stress, cytokines and diurnal rhythm, stimulate hypothalamus to produce CRH which stimulates the pituitary to produce ACTH which stimulated the adrenal gland to produce Cortisol and CBG which then acts to reduce output of hypothalamus and pituitary
What is stress and what is it caused by?
“The sum of the bodies responses to adverse stimuli”
Infection
Trauma
Haemorrhage
Medical illness
Psychological
Exercise/exhaustion
Effects of surgery on cortisol levels
Huge spike
Loss of diurnal variation
Returns to normal after a few days
What is different for the cortisol feedback mechanism in stress?
Stress cytokines stimulate hypothalamus
Decreased synthesis and breakdown of CBG
Outline mineralocorticoids
Synthesised in zona glomerulosa
Aldosterone synthase present in this region
Main mineralocorticoids are aldosterone and DOC
-DOC has 3% mineralocorticoid activity of aldosterone
Essential to life
Critical to salt and water balance in
Kidney, Colon, Pancreas, Salivary glands
Sweat glands
Look up aldosterone action in kidney
Aldoesterone enters cell and stimulates mineralocorticoid receptors
Endocrine salt loss
Primary adrenal insufficiency (AI)
CAH
-Aldosterone synthase deficiency
-Inborn AI
Autoimmune AI
X-linked adrenoleukodystrophy
End organ resistance
Mineralocorticoid receptor defects
ENaC defects
Other deficiencies in the collecting tubule pathway
Not in secondary adrenal insufficiency
Sodium and potassium levels in plasma and urine when salt loss
Plasma: Sodium low, potassium high
Urine: Sodium high, potassium low
Other actions of mineralocorticoids
- Effects on pancreas
- Sweat glands
- Salivary glands
- Colon
All this causes sodium resorption and decrease sodium content
Non-classical effects:- Myocardial collagen production
- Role in cardiac fibrosis/remodelling
How to protect the mineralocorticoid receptors
Convert cortisol to cortisone
Overview of adrenal androgens
- Weak androgens generated in adrenal gland
- Dehydroepiandrosterone (DHEA) most abundant adrenal steroid but very weak androgen
- Androstenedione more androgenic but only 1/10th that of testosterone
- Major source of androgens in women
- Oestrogen precursors in postmenopausal women
- Production regulated by ACTH rather than gonadotrophins
Outline the adrenal medulla
- Part of autonomic nervous system
- Specialised ganglia supplied by sympathetic preganglionic neurones (ACh as transmitter)
- Synthesises catecholamines
- Main site for adrenaline synthesis
(Phenylethanolamine-N-methyl transferase present) - Not essential for life
Catecholamine synthesis
Tyrosine -> cortisol introduced and sympathetic stimulation-> DOPA -> Dopamine -> sympathetic stimulation -> Noradrenaline -> cortisol introduction -> adrenaline
Summary of adrenal medulla
Relative production of catecholamines
80% adrenaline, 20% noradrenaline
Dopamine in small amounts
Normal catecholamine synthesis dependent on high local cortisol levels (permissive effect)
Catecholamines released during “flight or fight”
gluconeogenesis in liver and muscle
lipolysis in adipose tissue
Tachycardia and cardiac contractility
Redistribution of circulating volume
When does sex determination happen?
- Migration of primordial germ cells from dorsal
endoderm to urogenital ridge by 6-8 wks
gestation - Development of indifferent gonad from
urogenital ridge - Presence of SRY gene (on Y chromosome)
® testes differentiated by week 9 - Absence of SRY gene ( on Y chromosome)
® ovaries present by 11-12 weeks
Organogenesis of adrenal and gonads
adrenal and gonads derive from same tissue
What do sertoli cells produce
AMH - anti mullarian hormone
Mullerian regression
What do leydig cells do?
Produce testosterone and DHT
Male sex differentiation
When does sex determination and differentiation happen?
Sex determination -> 4-6 weeks
Sex differentiation -> 7-9+ weeks
Sex steroid synthesis
Androstenedione produces both testosterone and oestrone
Oestrone produces oestradiol
Testosterone produces oestradiol and 5 alpha -dihydro-testosterone (DHT)
Development of the male internal genitalia
Testis present and Leydig cells
making testosterone:
Wolffian system develops into - epididymis, - vas deferens,
- seminal vesicles
- ejaculatory ducts
Sertoli cells secret AMH, which
leads to regression of Müllerian
system
Outline the development of female internal genitalia
No testis or Leydig cells
not making testosterone:
Müllerian system develops into - fallopian tubes
- uterus
- upper third vagina
Development of external genitalia
Common genital tubercle at
8 weeks, with lateral
urethral folds, labioscrotal
swellings
* Tubercle becomes glans
penis in male, clitoris in
female
* Urethral folds become
corpus spongiosum
enclosing urethra in male,
labia minora in female
* Labioscrotal folds fuse to
form scrotum and ventral
penis, or labia majora
What is hypospadias?
Opening on underside of penis
Androgen activation and action
Androgen insensitivity syndrome
Caused by mutations in
the androgen receptor (AR) Xq11-12
=> AR not responding to androgens
Clinical and biochemical phenotype
* Very high testosterone and dihydrotestosterone levels
* Internal genitalia male (due to AMH production)
* External genitalia and external appearance female
* Gender identity female
=> Diagnosis often because of primary amenorrhoea
Exome sequencing
- DSD with external genitalia classified
– typical female with or without clitoromegaly (21 cases)
– ambiguous (12 cases)
– typical male with or without micropenis (7 cases) - associated nongenital malformations (7 cases)
- Genetic diagnosis in a total of 35% (14 of 40)
– 22.5% with a pathogenic finding
– 12.5% with likely pathogenic findings
– 15% with variants of unknown clinical significance
Why measure children?
- Measurements of growth provide a sensitive
indication of health in childhood - Growth rates are narrowly defined in healthy
children with adequate nutrition and an
emotionally supportive environment - Changes in growth rates can provide an early and
sensitive pointer to health problems in children
Body proportions in newborns
- Newborns: larger head, smaller mandible, short neck,
chest rounded, abdomen prominent, limbs short - Adults: relative growth of limbs compared to trunk
Infancy component of growth
– Rapid, but rapidly decelerating growth in first 2-3 yrs
– determined by nutrition
– long term growth failure, if underfed in infancy
Childhood component of growth
– switch from nutritional to hormonal dependence
– height velocity slows 2-3 yrs to puberty
Puberty component of growth
- Puberty component:
– growth spurt, height velocity due to GH and
– sex hormones oestrogen and testosterone
– To age 14-15 girls, 16-17 boys - Growth ends with fusion of epiphyses due to
influence of oestrogens in boys and girls - Boys convert testosterone to oestrogens in
fatty tissues
Growth and height velocity
- Fastest growth rate in
utero and infancy - Gradually decreasing rate
to puberty - Pubertal growth spurt
- Growth ends with fusion of
epiphyses (Oestrogen
effect) - Huge inter-individual
variability
Important determinants of growth
- Parental phenotype and genotype
- Quality and duration of pregnancy
- Nutrition
- Specific system and organ integrity
- Psycho-social environment
- Growth promoting hormones and factors
Outline the growth plate
- Growth = Chondrogenesis
- All growth disorders originate from, or affect the growth plate
- Building material needed every day – direct effect of nutrition and
calcium/phosphate supply on growth rate and bone architecture
Regulators of growth
Endocrine signals
Nutrition
Inflammatory cytokines
Extracellular fluid
All apart from endocrine signals are affected by oxygen deficiency, acidosis and toxins
Hypothalamus impact on growth
- GHRH cell bodies in arcuate nucleus, project to
portal capillaries - Regulated by food, sleep, steroids
- Negative feedback: SST, GH, IGF-1
- Neurotransmitters: adrenergic, cholinergic, opioids
- Other hypothalamic hormones: TRH, CRH
Human growth hormone
- Synthesized in somatotroph cells, these account
for 40-50% of the anterior pituitary - most abundant hormone
- Pulsatile secretion max at night
- Growth Hormone Binding Protein GHBP
Action of growth hormone
- Stimulates Insulin like growth factor 1 (IGF-1)
- Direct effect on growth plate and cortical bone
- decrease glucose use; increase lipolysis; Increase muscle mass
What does GH stimulation influence?
Exercise
Stress
Hypoglycaemia
Fasting
High protein meals
Perinatal development
Puberty
What does GH suppression influence?
Hypothyroidism
Hyperglycaemia
High carbohydrate meals
Glucocorticoid excess
Aging
GH and IGF-1 signalling pathway
GH secretion
GH receptor
Post-receptor GH signalling
IGF-I gene expression
What causes overgrowth with impaired final height
- Precocious Puberty
- Congenital adrenal
hyperplasia - McAlbright syndrome
- Hyperthyroidism
What causes overgrowth with increased final height?
- Androgen/ or oestrogen
deficiency/ oestrogen
resistance - GH excess
- Klinefelter syndrome (XXY)
- Marfan syndrome
- (Homocystinuria)
What is puberty and what are the signs?
- Describes the physiological,
morphological, and behavioural changes
as the gonads switch from infantile to
adult forms. - Definitive signs:
–Girls - Menarche – first menstrual bleeding.
– Boys - first ejaculation, often nocturnal.
– These do not signify fertility
Secondary sexual characteristics in puberty
- Ovarian oestrogens regulate the growth of
breast and female genitalia - Ovarian and adrenal androgens control pubic
and axillary hair
Outline secondary sexual characteristics in boys at puberty
- Testicular androgens
–External genitalia and pubic hair growth
–enlargement of larynx and laryngeal muscles
-> voice deepening
Variability of secondary sexual characteristics
- Timing of changes are unique to the
individual - Sequence of events is related to specific
staging criteria, for example:
– Breast development
– Pubic hair development
– External genitalia development in boys
What is precocious puberty?
Precocious puberty: onset of secondary sexual
characteristics before 8 yrs (girl), 9 yrs (boy)
* Menarche before 9 yrs may lead to short stature
What is delayed puberty
Delayed puberty: absence of secondary sexual
characteristics by 14 yrs (girl), 16 yrs (boy)
* Delayed puberty leads to reduced peak bone mass
and osteoporosis
What is the female HPG axis?
Hypothalamus,
Pituitary- produces LH (binds to theca interna) and FSH (binds to granulosa cells)
Gonads (ovaries)
Male HPG Axis
Hypothalamus
Pituitary- LH (binds to leydig cells), FSH (binds to sertoli cells)
Gonads (testes)
Hormonal changes at puberty
- Physical changes controlled by gonadal and adrenal sex steroids regulated by the
gonadotrophins, LH and FSH - Marked by circadian rhythm of FSH and LH secretion:
– Sleep-augmented LH secretion – pulse-like
– Later puberty LH daytime pulses also
Hypothalamic maturation hypothesis
(GnRH pulse generator)
– Puberty only requires hypothalamic GnRH
– Emphasises the direct link CNS and pituitary
and hypothalamic GnRH neurons
– Supporting evidence from the rhesus macaque
Hypothalamic regulation at start of puberty
Increased stimulatory factors most prominently glutamate and kisspeptin
Decreased inhibitory tone mostly through GABAergic neurons secreting γ-aminobutyric
acid (GABA) and opioidergic neurons
Role of nutrition in puberty
- Critical body weight important for initiation of
reproductive cycle - In domestic species (i.e. cattle) body weight
rather than chronological age determines start
of puberty - Similar in humans
Factors influencing puberty
- Genetics: 50-80% of variation in pubertal timing
- Environmental factors e.g. nutritional status
- Leptin → regulates appetite and metabolism through
hypothalmus. Permissive role in regulation of timing
of puberty - Adrenarche: gradual “maturation” of the adrenal
gland, development of pubic and axillary hair, body
odour and acne
Incidence of precocious puberty
- Incidence 1 in 5,000 to 10,000
- 90% of patients female
- Idiopathic CPP
– Up to 80% female
– Only 30% male
Turner syndrome
- At birth oedema of dorsa of hands, feet and
loose skinfolds at the nape of the neck - Webbing of neck, low posterior hairline, small
mandible, prominent ears, epicanthal folds
high ached palate, broad cheast, cubitus
valgus, hyperconvex fingernails - Hypergonadotrophic hypogonadism,
streak gonads - Cardiovascular malformations
- Renal malformations (horseshoe kidney)
- Recurrent otitis media
- Short stature
Cells of thyroid
Follicular- around colloid
C-cells
What do thyroid hormones do?
- Control of metabolism:
energy generation and use - Regulation of growth
- Multiple roles in development
Thyroid hormone synthesis
- TSH binds to TSHR on the basolateral membrane of follicular cells
- I- uptake by NIS (Na/I symporter
- Iodination of Thyroglobulin tyrosyl residues by TPO (thyro- peroxidase)
- Coupling of iodotyrosyl residues by TPO on apical membrane
- Export of mature Tg (thyroglobulin) to colliid where it is stored
Outline thyroid hormones
- T3 is biologically active hormone
- Produced by mono-deiodination of T4 which most abundant
- Deiodinase (D1, D2, D3) enzymes in peripheral tissues
Key facts about thyroid hormone synthesis
Produced by follicular thyroid cells
Synthesised from the thyroglobulin precursor
Iodine is absorbed from bloodstream and concentrated in follicles
Thyroperoxidase binds iodine to tyrosine residues in thyroglobulin molecules to form MIT + DIT
- MIT + DIT = T3
- DIT + DIT = T4
What do each of the thyroid hormones bind to?
T4 and T3- TBG, transthyretin, albumin
How does thyroid hormone compare to other hormones?
Different to other types of hormones
Like steroid hormones as act on DNA but have to have a transporter protein
Outcome of thyroid function tests - hyperthyroidism
Decrease in Serum TSH
Increase in Serum free T4
Increase in Serum free T3
Outcome of thyroid function test results- hypothyroidism
Increase in Serum TSH
Decrease in Serum free T4
Decrease in Serum free T3
Outline the prevalence and aetiology of hyperthyroidism
Prevalence: ♀: 20/1000 ♂: 2/1000
Aetiology:
- Graves’ hyperthyroidism
- Toxic nodular goitre (single or multinodular)
- Thyroiditis (silent, subacute): inflammation
- Exogenous iodine
- Factitious (taking excess thyroid hormone)
- TSH secreting pituitary adenoma
- Neonatal hyperthyroidism
Outline the signs and symptoms of hyperthyroidism
Cardiovascular
- Tachycardia (rapid heart rate)
- AF (atrial fibrillation)
- Shortness of breath
- Ankle swelling
Neurological
- Tremor
- Myopathy (muscle weakness)
- Anxiety
Gastrointestinal
Weight loss
Diarrhoea
Increased appetite
Eyes/skin
Sore, gritty eyes
Double vision
Staring eyes
Pruritus (itching)
Outline prevalence and aetiology of hypothyroidism
Prevalence 40/1000 females
5% of over 60’s
Aetiology:
- Autoimmune – Hashimoto’s thyroiditis (TPO and Tg antibodies - genetic predisposition)
- After treatment for hyperthyroidism
- Subacute/silent thyroiditis
- Iodine deficiency
- Congenital (thyroid agenesis/enzyme defects)
Symptoms and signs of hypothyroidism
Cardiovascular
Bradycardia (slow heart rate)
Heart failure
Pericardial effusion
Gastrointestinal
Weight gain
Constipation
Skin Myxoedema Erythema ab igne Vitiligo Neurological Depression Psychosis Carpal tunnel syndrome
What do the parathyroid glands do?
Regulate calcium and phosphate levels
Secrete parathyroid hormone
(PTH) in response to: Low calcium or High phosphate
Actions of PTH:
Increases calcium reabsorption in renal distal tubule
Increases intestinal calcium absorption (via activation of vitamin D)
Increases calcium release from bone (stimulates osteoclast activity)
Decrease phosphate reabsorption
Outline calcium
For:
1. Excitable Tissue
2. Muscle/Nerves
3. Cell Adhesion
Stored and released by bone
Endocrine control of extracellular calcium homeostasis
Parathyroid hormone
Vitamin D
Calcitonin, FGF23
Bone control of bone homeostasis
Mineral phase (Calcium/phosphate)
Protein phase (Collagen and non-collagenous proteins)
Bone cells
Bone ‘turnover’ and remodelling units
Bone diseases
Hyperparathyroidism
Osteomalacia andosteoporosis
Calcium homeostasis
GI tract - releases via vitamin D
Kidney - releases via PTH, vitD and FG23
Bone - releases via PTH Vit D
50% of serum calcium ‘free’ (ionised)
50% bound to albumin (so cannot diffuse into cells)
Why can’t you reabsorb calcium and phosphate at the same time in the kidney?
It will lead to kidney stones
Outline parathyroid hormone PTH
84 amino acid peptide but biological activity in first 34 amino acids (PTH 1-34), half-life 8 mins
Cleaved to smaller peptides
Assayed by two site assay (to avoid detecting fragments)
Still detects some inactive fragments e.g. in renal failure
Normal adult reference range = 1.6 - 6.9 pmol/L
Binds to G protein coupled receptors mainly in kidney and osteoblasts
PTH action in the kidney
PTH increases distal tubular reabsorption of calcium
(+ inhibition of PO4 reabsorption)
PTH also stimulates production of the active form of vitamin D, 1,25(OH)2D
PTH enhances bone resorption by stimulating osteoclasts
Negative feedback of PTH
PTH transcription (mRNA production) is inhibited by 1,25D3
PTH translation (mRNA to protein synthesis) is inhibited by increased serum calcium
Primary (hyperparathyroidism) HPT
parathyroid tumour (usually benign adenoma)
Causes hypercalcaemia and low serum phosphate
Loss of negative feedback from hypercalcaemia
(Treatment is surgery)
Secondary HPT
renal disease (increased phosphate, decreased activation of vitamin D)
(Treatment with phosphate binders or vitamin D analogues)
Tertiary HPT
long-standing secondary HPT leads to irreversible parathyroid hyperplasia. Usually seen when renal disease corrected e.g. by transplantation
(Treatment is surgery)
Outline calcitonin
- Produced by thyroid c-cells (parafollicular)
- Calcitonin released in hypercalcaemia, inhibits bone resorption (by direct effect on osteoclasts)
- Not essential to life (post thyroidectomy no calcium problems)
- Two calcitonin genes products from a single gene and primary RNA transcript
Definition of menopause
Menopause: cessation of menstruation
Definition of climacteric (perimenopause)
the period around the menopause and at least the first year after it.
Post menopause
12 months of no period
Age of onset of menopause
Average age: 51 in the UK.
Range: 48-52.
Premature: before 40 (1%).
Cause of menopause
Age: Depletion of primordial follicles.
Premature menopause:
Idiopathic.
Iatrogenic.
Chromosomal (fragile X syndrome, FMR1)
Autoimmune.
Others.
Only the follicles that reach the right size at the right stage to respond to FSH
The other cells undergo atresia
Mechanism of menopause
Ovaries depleted of follicles.
Decline of oestrogen production.
Gradual decline with fluctuation over a few years.
Gradual rise of FSH and LH (lack of negative feedback mechanism).
Age of menopause decided by the size of the primordial pool.
Complications of premature menopause
Increased risk of mortality.
Risk of cognitive dysfunction.
Heart disease.
Mood and sexual disorders.
Bone mineral density.
Autoimmune and thyroid disease.
UK Guidelines on management.
How to diagnose menopause?
Above 45 years: symptoms are usually enough
40 y - 45 y : Symptoms +/- Tests (incl. antral follicle count, anti-mullerian hormone)
< 40 Years: careful !
Symptoms and risks of menopause
80% for 4 years, 10% up to 12 years!
Short term - Symptoms:
-Vasomotor.
-Psychological.
-Urogenital.
-Skin.
Long term - Risks:
-Osteoporosis.
-Cardiovascular disease.
Vasomotor symptoms of menopause
Hot flushes.
Sweats: mainly night.
Palpitations.
Headaches.
Psychological symptoms of menopayse
Irritability.
Lethargy.
Emotional lability.
Forgetfulness.
Loss of libido.
Loss of concentration
Urogenital and skin symptoms of menopause
Urogenital:
Vaginal dryness.
Dyspareunia: due to dryness.
Urethral syndrome: mainly later on in the absence of HRT.
Skin:
Dryness of skin and hair.
Brittle nails.
Osteoporosis as an outcome of menopause
Decreased amount of bony tissue per unit volume of bone.
Wrist, femoral neck and vertebrae.
Bone remodelling is uncoupled.
Exact aetiology not known.
5% loss of trabecular bone per year.
Risk factors for osteoporosis
Race: European and Asian women.
Nulliparity.
Low body weight.
Poor diet in childhood.
Alcohol abuse.
Heavy smoking.
Steroids,
thyrotoxicosis, hyperparatyhroidsm, Cushing disease etc.
Impact of menopause on cardiovascular disease
Protected before menopause but risk is equal to men by age 70
Cause unknown.
Family history is a determinant factor.
Other variables: obesity, diabetes etc
Treatment of menopause
HRT (ERT)
Women’s Health Initiative (2002) and
Million Women Study (2003)
Sedatives and tranquilisers.
Clonidine.
Beta blockers.
Maintaining pre-menopausal sexual activities.
Calcium, vitamin D, calcitonin.
Symptomatic treatment
Hormone replacement therapy
Oestrogen
Progestogen if uterus intact: to reduce risk of endometrial cancer.
Different formats.
Different doses.
Risks.
Contraindications.
Preparations- Oral, Skin patches, Vaginal cream, Skin cream, Nasal spray, Vaginal ring., Implants.
Long term risk of HRT
Cardiovascular (E):
- Slight increase in CVS (oral vs transdermal)
- IHD no increased risk but no benefit
Breast cancer (E + P vs E):
Increased by 2 per 1000 if taken for >5 years.
6/1000 for 10 years use.
12/1000 for 15 years use.
VTE: 1-3 in 10,000 women in the first year.
Cancer:
Slight increase in ovarian cancer (seq. HRT).
Endometrial Cancer: if unopposed E2.
Contraindications for HRT
Abnormal liver function.
Obstetric cholestasis.
Thromboemblic disease.
Congenital dist. of lipid metabolism.
Hormone dependent tumours.
Sickle cell anaemia
