ENDOCRINOLOGY WK 3 Flashcards
1
Q
what are the 3 corticosteroids made in the adrenal and what do they do?
A
Corticosteroids - Made in cortex of adrenal gland Mineralocorticoids - Salt and water retention (electrolyte and fluid balance) Glucocorticoids - Glucose synthesis - Protein and lipid metabolism - Inflammation, immune response - Cortisol supresses immune system Adrenal androgens - Fetal steroids and growth
2
Q
what are the 3 main sex steroids made in the gonad and what do they do? and what vitamin is also a steroid
A
1- Androgens
- Growth and function of the male reproductive system
2- Oestrogens
- Growth and function of the female reproductive system
3- Progesterone
- Female menstraul cycle and maintenance of pregnancy
vitamin D
3
Q
how do steroid hormones work - classical genomic mechanism
A
- Travel in blood taken up when bind to cell receptors on outside of cell
- Make active transcription factor than goe sinto cell and binds to DNA in nucleus – mRNA made = protein synthesis in cytoplasm
- Slow action (>30 mins – 48hrs)
- Eg aldosterone-regulated synthesis of kidney epithelial sodium channel subunit – absorption of sodium takes a while
4
Q
how do steroid hormones work - non-genomic mechanism
A
- Non-classical receptors, activated by steroid bindingd eg ion channels in the plasma membrane
- Intra-cellular signalling pathways, eg calcium/inositol
- Rapid signalling (<1 min)
- Eg aldosterone vasoconstriction of vascular smooth muscle and endothelial cells
5
Q
how are steroid hormones made
A
Get rid of fatty 6-carbon cholesterol sidechain
- Makes steroid hromone slightly more soluble than cholesterol
Varied addition of substituent at C-17
- Enzyme nomenclature indicated the site of action
- Eg 17-a-hydroxylase introduces a hydroxyl group at C-17
Extra specifity from side chain modification eg C-11
- Enzyme nomenclature indicates site of action
- 11B-hydroxylase introduces hydroxyl group
6
Q
what are the 2 main enzymes involved in steroid synthesis
A
1. CYTOCHROME P450s (CYPs) Highly expressed in… - Liver (drug detoxification) - Organs that synthesise steroids o Adrenal cortex o Testis, ovary, placenta - Cleave or modify the c holesterol side groups – cut off fatty tail - Converts cholesterol to pregnelonone - 27 carbons -> 21 carbons
- Steroid dehydrogenases
Steroid deydrogenases/reductases (usually paired)
- Interconvert active and inactive forms of steroids
- Examples 11B-HSD1 – in liver and peripheral tissues
- Cortisol -> cortisone in kidney
7
Q
cortisol metabolism and transport
A
Bound and inactive hormones transported in the plasma
- Synthesis of cortisol in adrenal gland
- Released into circulation
- A lot binds to transport proteins (90+%)
- Levels of free cortisol increase in diseases – appears in urine(measured)
2 routes
- Bound cortisol tranported to target peripheral tissue where they have local effects
- Or recycles through the liver
o Cortisol converted to inactive cortisone in liver
o Cortisone circulates through blood to peripheral target where it’s then reactivated by 11B-HSD1
8
Q
what is the inactive form of cortisol called and what hormone can activate it
A
cortisone
11B-HSD1
9
Q
where are the adrenal glands found
A
- Around the 12th thoracic vertebrae
- Above the kidneys
- Triangular shaoe ~4g
- Anatomist call them suprarenal gland
10
Q
what 2 systems are the adrenal glands involved in
A
- Hypothalamic-pituitary-adrenal (HPA) axis (adrenal cortex)
- Neuroendocrine sympathetic nervous system (adrenal medulla)
11
Q
what are the 2 main divisions of the adrenal and whats made in each place
A
Cortex > 80-90% of normal gland make steroid hormones
- mineralocorticoids
- glucocorticoids
- adrenal andorgens
Medulla > 10-20% of normal gland make catecholamines
- adrenaline
- nonadrenaline
12
Q
whats the blood supply to the cortex and medulla of the adrenal
A
Adrenal cortex
- receives vlood from 30-50 short arteries penetrating the capsule
- arteries supply subcapsular plexus of arterioles
- sinisuidal fenestrated capillary network – have holes in them for rapid transmission fo stimuli to cells and products to targets
- no cell instructure is more than one cell away from capillary gland
Adrenal medulla
- receives long cortical arteries and capillaries from cortex
- medulla and cortex drain via the central medullary vein
o medulla recieves output of cortex
o in fight or fligth repsonse - adrenaline release, cortisol sustains this repsonse
13
Q
what are the subdivisions of the adrenal cortex
A
- zone glomerulosa (ZG)
- zone fasciculata (ZF)
- zone reticularis (ZR_
14
Q
what area are mineralocorticoids made - what’s the main product and it’s actions
A
Aldosterone – principle mineralocorticoid SALT
- made in zona glomerulosa
- under control of RAS
o regulated by AII and plasma K
- regulates salt and water retention in kidney distal tubule
15
Q
what area are glucocorticoids made - what’s the main product and it’s actions
A
Cortisol – principle glucocorticoid SUGAR - made in zona fasciculata (ZF) - low levles in averag ehealthy human – but problem if oevrproduced pathologically - under control of HPA axis o regulated by ACTH from pituitary gland - regulates lucose homesostasis - stress response - inflammation, immune response
16
Q
what area are adrenal androgens made - what’s the main product and it’s actions
A
adrenal androgens - DHEA SEX
- made in zona reticularis
- also under control of HPA axis
o also regulated by ACTH from pituitary gland
- co-regulated with glucocorticoid
o if you have excess glucocorticoid you will have excess adrenal androgens
o causes alterations in hair patterns
- intracrine conversion to testosterone and oestradoil in peripheral tissues
- adrenal androgens provide all oestrogen in post-menopausal females
17
Q
DHEA production - pre and post natal
A
Dehydroepiandrosterone Prenatal DHEA production - role in maintaining oestrogenic environment - role in foetal development Postnatal DHEA production - role in intitiation of puberty - main source of andorgens and post-menopasual oestrogen in females? - Role in longevity, elixir of life?
18
Q
what P450s are expressed in each area of the cortex
A
Mineralocorticoid in zona glomerulus…
- Due to aldosterone synthase expression here
Glucocorticoid in zona fasciculata…
- Due to 17a-hydroxylase
- Then 11B-hydroxylase
Adrenal andorgens in zona rectularis…
- Due to 17a-hydorxlase
- Then 17,20 lysase
19
Q
circadian rhythm stress inputs
A
- Circadian rhytm and stress inputs stimulate CRH release from hypothalamus
- CRH stimulates ACTH production from pituitary gland (corticophs)
- ACTH stimulates cortisol production from adrenal zona fasciculata
- Cortisol feeds back on production of CRH from hypothalamus and ACTH from the anterior pituitary
20
Q
diurnal rhythm of plasma cortisol and its regulation
A
Diurnal CRH release regulates ACTH release
- High in early morning
- Lower later in day
ACTH regulates cortisol synthesis
- High on waking
- Lower later in the day (with ‘stress activity spikes)
- Lowest in the middle of the night
21
Q
cortisol and other molecules that combat low glucose and the dual action of cortisol
A
- Essential for survival and to resist physiological and environmental stress
- Part of the ‘counter-regulatory’ hormone defence against hypoglycaemia
- Levels of these rise as plasma glucose falls-
o Glucagon from alpha cells of the pancreas
o Adrenaline
o Noradrenaline
o Growth hormone
o Cortisol (in strarvation aka stress It can maintain plasma glucose) - Dual action of cortisol
o Anabolic in liver to promote gluconeogenesis
o Catabolic in peripheral muscle and fat to promote protein and lipid breakdown
22
Q
anabolic vs catabolic effects of cortisol
A
Anabolic
- Increased gluconeogenesis and liver glucose output
Catabolic
- Inhibittion of glucose uptake by peripheral muscle and fat tissue
- Immune system suppression
- Increased muscle protein breakdown
- Increased fat breakdown
- Increased bone resorption
- Increased appetite and central fat deposition
23
Q
excess cortisol - what are 2 main causes, whats the phenotype
A
Cushing’s disease (pituitary tumour)
Cushing’s syndrome (adrenal or ectopic tumours)
Phenotype – hypertension, low plasma K+, elevated plasma cortisol, low plasma aldosterone and renin activity
Hypertension due to multiple effects of elevated plamsa cortisol
24
Q
what are products of each adrenal cortex layer that contribute to BP contorl
A
zona glomerulus - aldosterone zona fasciculata - cortisol, corticosterone zona reticularis - cortisol, DHEA
25
what are the 3 adrenal hormones systems that regulate BP
- Sympathetic NS
- RAS
- HPA axis
26
how are the 3 main physiological factors that regulate BP affected by steroids from the adrenal
```
Cardiac output
- Increased by
o Catecholamines (SNS)
o Cortisol production (HPA)
Vadcular tone – vasoconstriction
- Increased by
o Ang II (AII, RAS)
o Aldosterone (RAS)
o Catecholamines (SNS)
o Cortisol potentiation (HPA)
Extracellular fluid volume
- Increased by
o Aldosterone (RAS)
o Cortisol (HPA)
```
27
what steroid hormones in the adrenal are general causes of endocrine hyper(hypo)tension
- Aldosterone from ZG
- cortisol or precursors from ZF
- catecholamines from medulla
28
what mechanisms cause renin release int he kidnyes
- JG cell baroreceptor
- Macula densa Na+ sending
- Carotid arch baroreceptors
29
what are the short term effects of RAS and aldosterone
Vasculature > rapid secs
- Inc. vasoconstriction
- Postural reg. of BP
Adrenal > rapid mins
- Inc. aldosterone synthesis
- Inc. catecholamine synthesis
Kidney > rapidish 6-48hr
- Inc. Na+ and water resorption
- In distal tubule epithelial cells of kidney…
o Aldosterone binds to mineralocorticoid receptor
o Complex migraite from cytoplasm into nucleus = changes in gene expression
o Transcribes new protein ENaC which goes to apical membrane
o Sodium brought into cell through apical membrane (from tubule into blood)
30
what are the longterm effects of RAS and aldosterone
```
Vasculature > long term
- Smooth muscle
o Inc. cell hyperplasia
o Inc. cell hypertrophy
o Long-lasting change in vascular tone (stiffer)
CNS > long term
- Inc. thirst
- Inc. salt appetite
- Inc. ADH release
Adrenal > longterm
- Inc. aldosterone synthase enzyme expression
- Inc. glomerulosa cell proliferation
```
31
Conn's syndrome - what does it cause, what is it, phenotype, treatment
```
PRIMARY HYPERALDOSTERONE
Conn’s syndrome
o Unilateral adrenal tumour
o Aldosterone-producing adenoma
- Phenotype –
o High aldosterone, MR acitvation
o High Na+, Low K+, ECF expansion
o Hypertension, low renin (RAS)
- Treatment – surgical
o Venous sampling and/or CT scan
o Unilateral adrenalectomy
```
32
Bilateral adrenal hyperplasia - what does it cause, what is it, phenotype, treatment
```
PRIMARY HYPERALDOSTERONE
Bilateral adrenal hyperplasia
- Most common form 60-70% of PA
Phenotype
- Hig aldosterone, MR activation
- High Na, low K, ECF expansion
- Hypertension, low renin
Treatment – pharmacological
- Anti-hypertensive
- MR antagonists
- Spironolactone, epierone
```
33
glucocorticoid-remediable aldosteronism (GRA)
- Autosomal dominant genetic disorder (human chromosome 8)
- ACTH-driven hyperaldosteronism
Genes for Aldo synthase and 11B-OHase are 95% identical in protein-coding regions
- BUT gene promoters different…
o Aldo synthase regulated by K+
o 11B-OHase regulated by ACTH-driven
GRA hydrid gene
o Unequal meiotic exchange leading to...
- 11B-OHase promoter
- Aldo synthase coding region
o So Aldo production regulated by ACTH which is bad because ACTH promoter Is much more active = hyperaldosteronism / hypertension
- Very bad hypertension in childhood - Normally die in young adulthood
phenotype
- high aldosterone, MR activation
- High Na, Low K, High ECF
- hypertension, low renin
Treatments
o Give synthetic glucocorticoids
o Feedback in hypothalamus supressing pituitary ACTH secretion
o Is ENTIRELY TREATABLE
34
renin-secreting JG cell tumour - what does it cause, phenotypes, treatment
```
endocrine hypertension - SECONDARY HYPERTENSION
Renin-secreting JG cell tumour
- Renin hyper-secretion, inc. RAAS
- Severe hypertension
Phenotype
- High plasma renin, high aldosterone
- MR activation, high Na, low K
- ECF expansion, hypetension
Treatment
- Surgical removal of tumour/ kidney
```
35
renal artery stenosis - what does it cause, phenotypes, treatment
```
endocrine hypertension - SECONDARY HYPERTENSION
- Low perfusion pressure, renin secretion
- Inc. RAAS – hypertension
Phenotype
- High plasma renin, high aldosterone
- MR activation, high Na, low K
- ECF expansion, hypetension
Treatment
- Anti-hypertensive
- Statins, anti-platelet agents
- Balloon angioplastsy +/- stent
```
36
cortisol overproduction as a cause of endocrine hypertension
Adrenal tumour (Cushings syndrome) or pituitary tumour (Cushings Disease)
Presentation
- Weight gain, stretch marks, easy brusing, proximal muscle weakness
- Diabetes mellitus (high plasma glucose), mestrual irregularities, depression
Phenotype
- Hypertension due to multiple effects of elevated plasma cortisol
- High cortisol, high Na+, low K+, (=MR activation), low renin and low aldosterone
Cushings syndrome
- Cortisol-secreting adrenal tumour
- ACTH-secreting pituitary tumour
37
how does plasma cortisol cause hypertension
1- glucocorticoids inhibit vascular nitric oxide production by eNOS
2- glucocorticoids potentiate catcholamine action in heart and vasculature
3- glucocorticoids can inappropriately activate the kidney MR
38
glucocorticoid hyperactivity as a cause of endocrine hypertension - Apparent mineralocorticoid excess
```
Apparent mineralocorticoid excess
- autosomal recessive loss of function mutation in 11B-HSD2
- decreased conversion of cortisol to cortisone
Phenotype
- high local kidney cortisol, low RAS
- MR activation, high Na+, low K+
- ECF expansion, hypertension
Treatment – pharmacological
- MR antagonists
o Sprinoolactone, eplerenone
- Low Na+ diet and K+ supplements
```
39
drugs and liquorice ingestion as a cause of endocrine hypertension
```
Drugs and liquorice ingestion
- Carbenoxolone, glycyrrhizinic acid inhibitors of kidney 11B-HSD2
- Dec. conversion of cortisol to cortisone
Phenotype
- high local kidney cortisol, low RAS
- MR activation, high Na+, low K+
- ECF expansion, hypertension
Treatment – environmental
- Altered drug treatment
```
40
pheochromocytoma as a cause of endocrine hypertension
Catecholamine-secreting tumour of the adrenal medulla
Adrenaline from the adrenal medulla-
- Freeze, flight and flight response
- Inc. HR, vasoconstriction, peripheral resistance
- Inc. glucagon secretin, dec. insulin secretion
- Inc. glycogen and lipid breakdown
Pheochromocytoma
- Chromaffin cell tumour
- Secrete catecholamine
- Noradrenaline and/or adrenaline
Distinctive but variable symptoms
Palpitations, Headache, Episodic sweating
- Racing heart, anxiety (~50%)
- Hypertension – sustained/paroxysmal (~50%)
- Diabetes mellitus (~40%)
Diagnosis and treament
- 24 hr urinary metanephrines and catecholamines
- A-blockers, B-blockers, surgical resection
41
what hormones are made/ activated in reproductive/peripheral tissue
Sex steroids (NOT corticosteroids) are made in reproductive tissues
- Sex steroids are made through exact route in the adrenal gland in other tissues
- Cortisol not made in reproductive tissues but inactive cortisone can be activated by reproductive tissues
o This is why you get cortisone injections in sport injuries as it is activated locally to produce antiinflammatory repsonse
42
what are the 2 types of enzymes involved in sex hormone synthesis
1- Cytochrome P450s (CYPs)
a. 17a- OHase and17, 20 lyase (CYP17A1)
i. In adrenal cortex ZR
ii. And testis and ovary
b. Aromatase (CYP19A1)
i. Ovary
ii. AND periphral ostrogen targets eg breast, bone etc
iii. (aromatase inhibitors used to treat cancer)
2- Steroid dehydrogenase
a. Interconvert steroids
i. 3B-HSDs – adrenal, testis, ovary
ii. 17B-HSDs – testis, ovary
iii. 5a-reductass – testis and peripheral tissues
43
testosterone and estradiol production
- DHEA and androstenedione made in BOTH male and female gonads
- Same pathway as adrenal glands
- BUT ovaries and testis Leydig cells contain an additional enzyme
- 17B-hydroxysteroid dehydrogenase-3 (17B-HSD-3)
- Converts androstenedione (‘pro’) to weak C19 androgen testosterone
In testis sertoli cells 5a-reductase converts testosterone to strong androgen 5a-dihydrotestosterone
In ovary and peripheral tissues, aromatase converts testosterons to strong oestrogen oestradiol (C18)
44
how are sex steroids regulated by the HPG axis
- Gonadotrophin-releasing hormone (GnRH) from HP preoptic nucleus
- Acts on anterior pituitary gonadotrophs
o FSH
o LH
- FSH and LH stimulate sex steroid hormone production in gonads
o Andorgens (male)
o Oestrogens (female)
o ALSO inhibins (male and female)
- Hormonal feedback on pituitary and hypothalamus regulate synthesis
45
male sex steroid synthesis in the testis - what cells are involved in synthesis of what hormones, how do the hormones travel through this system
Steroidogenic leydig cells – make testosterone
- The triangle area between cells
Sertoli cells – ‘nursery’ cells for sperm production make inhibin and ABP
- The cells themselves
- LH stimulates testosterone production by leydig cells
- FSH promotes inhibin and androgen binding protein (ABG) in sertoli cells
- T moves from leydig to sertoli cells
- T converted to DHT and binds to ABP in luminal of the semineferous tubules
- Need high levels of testosterone and DHT in seminiferous tubules to drive spermogenesis (sperm maturation and production)
Inhibin is a key marker of sertoli cell function
46
how is testosterone transported to peripheral targets and how is this disturbed by drug therapy
- Testosterone transported in plasma to peripheral targets bound (98%) to sex hormone-binding globulin (SHBG)
- Conc. Of this hormone can be disturbed by drug therapy
o This effects amount of free testosterone in the body
o Can make people infertile
47
how does testosterone and inhibin feedback on the HPG axis
- T from leydig cells and inhibin from sertoli cells feedback on GnRH, LH and FSH
48
what are the actions of male sex hormones
```
Androgens (testosterone, 5a-DHT) regulate
- Primary male reproductive functions eg
o Spermatogenesis, prostate secretions
- Secondary male sex characteristics
o Anabolic build muscle
o Deep voice, facial and body hair
o Brain – libido and aggression
- Essential during foetal life
o Male sex determination
o Genital development
Testosterone from mother
Sex-determination gene SRY in males which causes sertoli cell differentiation – allow testis to form and leydig cells to develop leading to testosterone surge at 7-8 weeks, without this foetus wont develop into male phenotypically
```
49
what is androgen insensitivity syndrome
• Functional mutation
• Due to mutated testosterone receptor
• Arrested testis development, lack of testosterone and anti-mullerian hormone
- phenotypically female, genome is XY
50
what does lack of oestrogen in males lead to
```
o Lack of oestrogen in males … failure to convert testorsterone to oestradiol
Tall and long arms
Bone epiphyses did not close
Loss of bone mass
Osteoporosis
```
51
synthesis of female sex steroid hormones in the ovary - what cells are involved, and what is the order of synthesis, what is involved in negative feedback, how are the hormones transported to peripheral targets
- LH stimulates production of androstenedione and testosterone in thecal cells of the primary follicle
- Androgens move from thecal to granulosa cells
- FSH stimulates androgen conversion to oestrogens by aromatase
- Action – estradiol regulates the proliferative phase of the female menstrual cycle
- Estradiol and inhibin from granulosa cells feed back on GnRH + LH and FSH release from HP and pituitary
- Estradiol also transported in plasam to peripheral targets bound to gonadal sex hormone-binding globulin (SHBG)
52
oestrogen role
- Female genital development and differentiation
- Secondary female sex characteristics eg body fat distribution, cardiovascular system, skin, bone, epiphyseal closure
- Estrogen from the primary ovarian follicle promotes endometrial growth during the follicular or ‘proliferative’ phase
53
progesterone role
- Made in the corpus luteum promotes endometrial secretion and vascularisation during the luteal or ‘secretory’ phase
- Prepares uterus for implantation of fertilised egg
- If no egg progesterone falls away = menstuation
54
normal ovarian cycle
Follicular (proliferative) phase
- Day 0-14
- FSH and LH stimulate estradiol production by the primary follicle
- Promotes endometrial growth
LH surge triggering ovulation
- Day 14
- Rising estradiol stimulate LH production = the LH surge
- LH surge stimulates ovulation aka follicle ruptue and egg releases
- It’s the egg that makes oestrogen so when lost follicle begin to make progesterone
Luteal (secretory) phase
- Day 14-28
- Corpus luteum makes progesterone
- Receptive secretory environment for implantation of a fertilised egg
55
sex steroid regulation without implantation of egg (day 14-28)
- Corpeus luteum regrasses and stops producing progesterone
- Declining feedback of
o Progesterone, oestrogen, inhibin
- Allows a new cycle of LH and FSH release
56
sex steroid regulation with implantation of egg (day 14-28)
- Developing embryo produces hCG (human chorionic gonadotrophin) an alternative form of LH
- Does the same as LH – binds to LH receptor and prompts prgesterone to be made
- hCG binds to LH receptors on corpus luteum and endometrium
o maintains progesterone secretion
o inhibits maternal immune rejection of placenta
- progesterone promotes uterine blood vessels to sustain the growing fetus
57
luteal-placenta shift 7-9 weeks of pregnancy
Hormone decline
- hCG from embryo
- prgesterone from corpus luteum
to maintain pregnancy, placenta begins to produce;
- progesterone from cholesterol
- oestrogen from DHEA (fetal adrenal)
58
primary adrenal insufficiency - addisons disease - causes, presentation, phenotype, treatment
Causes
- destruction of adrenal gland
- by TB, cancer metastases, autoimmune disease
Presentation
- disease of all 3 adrenocortical zones
- aldosterone, cortisol and adrenal androgens all affected
Phenotype
- low plasma aldosterone = lack of MR activation
- low Na+, high K+, reduced ECF, hypotension
- low plasma cortisol, low glucose, high ACTH (lack of cortisol feedback)
- skin pigmentation (due to high ACTH)
Treatment
- fluid and hormone replacement
- synthetic glucocorticoid (hydrocortisone, prednisone)
- synthetic mineralocorticoid (flucrocortisone)
59
secondary adrenal insufficiency - hypopituitarism - causes, presentation, phenotype, treatment
Causes
- partial or complete loss of anterior lobe pituitary function
- tumour, pituitary apoplexy, suppression by long-term corticosteroids
- lack of pituitary ACTH secretion and adrenocortical trophic stimulation
presentation
- malfunction of ZF and ZR, reduced cortisol and androgen secretion
- RAS and aldosterone secretion (ZG) largely unaffected
Phenotype
- Low plasma ACTH and cortisol due to pituitary and adrenal failure
- Inc. vasopressin release from posterior pituitary
- ECV expansion low Na+, low K+ (dilutional hyponatraemia)
Treatment
- Hormone replacement, transsphenoidal decompression/tumour removal
- Synthetic glucocorticoid (hydrocortisone, prednisone), thyroxine, etc.
60
congenital adrenal hyperplasia - presentation, genetics and phenotype
Presentation
- Inherited condition present at birth (congenital) in which adrenal gland is larger than usual
- A form of primary adrenal insufficiency
- Usually caused by a inherited defect in gene for any steroidogenic enzyme
- Inactivating mutations partial or complete
Genetics
- Autosomal recessive - both parents carriers
- Heterozygote ‘carriers’ usually asymptomatic (may affect immune system)
- Affected individuals usually compound heterozygotes
o Both alleles altered, but different mutations inherited from mother and father
- BUT also see genuine hmozygotes
o Eg consaginous marriages
```
Phenotype in all CAH syndromes
o Block cortisol syntheis pathway…
Reduced cortisol
Impaired stress response
Reduced plasma glucose
Reduced feedback on CRG-ACTH (pituitary and hypothalamus)
o Due to reduced feedback you get large secretion of CRH and ACTH
ACTH promotes growth in the adrenal gland
Adrenal gland grows
o Also changes in other steroids
Excess intermediaes before block
Reduced hormones after block
```
61
different type of CAH and their frequencies
Frequency?
Common (90-95%) cases
o Steroid 21-hydroxylase/ 21-OHase
o Population frequency 1:14,500
o Heterozygous frequency 1:61
o This is due to pseudo gene – 2 21-OHase genes, so corssing over of these is more likely
o Suggestion that mutation is beneficial as lower cortisol is immunologically beneficial
Less common (5% of cases)
o 11b-OHase
o Affects glucocorticoid synthesis but not mineralocorticoid synthesis
Rare (0.1-1% of cases)
o 17a-OHase
o 3B-HSD
o StAR (Lipoid CAH)
62
partial steroid 21-hydroxylase deficiency in ZG and ZF?ZR (CAH) - presentation, treatment and monitoring
dec. cortisol, dec. feedback, inc. ACTH
- Symptoms reflect mainly lack of cortisol (enough aldo still made)
o Remember – cortisol is made at 100x higher levels than aldosterone
- Increased androgens
o Virilisation in boys, masculinisation in girls
- Most common cause of ambiguous genitilia due to prenatal masculinisation of genetically female (XX) infants
Treatment
- Replace cortisol function
- Feed-back inhibit ACTH ‘drive’
- Reduce ACTH-driven androgens
Monitoring
- Glucocorticoid replacement
- Monitor 17-OH progesterone
- Androgen levels (most important)
63
complete steroid 21-hydroxylase deficiency in ZG and ZF?ZR (CAH) - presentation, treatment and monitoring
dec. cortisol + aldosterone, dec. feedback, inc. ACTH
- Severe classical ‘salt wasting’ form… aldo synthesis also blocked
- Symptoms reflect a lack of cortisol AND aldosterone
o Low plasma aldosterone = lack of MR activation
o Low plasma Na+, high plasma K+, H+ = hyperkalaemic acidosis
o ECF deficit, hypotension and vascular collapse
o Life-threatening vomiting and dehydration in new-borns – treatment essential
- Increased androgens
o Virilisation in boys, masculinisation in girls
Treatment
- Replace cortisol and mineralocorticoid
- Reduce ACTH-driven androgens
- Normalise plasma Na+, ECF and bp
monitoring
- Glucocorticoid replacement
- Monitor 17-OH progesterone
- Androgen levels (most important)
64
general info on 21-hydroxlase deficiency - screening, problems associated with excess androgens if left untreated
Screening for common gene mutations in some countries
- In UK with family history
- ? introduction in UK – under debate but cost
- Early intervention in utero improves outcomes
```
Excess androgen production in females, left untreated
- Gender mis-assignment
- Psychological problems
- May need corrective surgery
Untreated 21-OH CAH
- Ambiguous genitalia
- Single urethral/ vaginal orifice
- Fused labia and enlarged clitoris
```
65
late onset 21-OHase deficiency - presentation, treatment, monitoring
Late onset 21-OH CAH
- Mild inactivating mutation – less severe than in affected neonates
- Usually presents after puberty in women
- Following upsurge in ACTH and adrenal steroid secretion (adrenarche)
Excess adrenal androgen result in
- Menstrual cycle disturbances
- Polycystic ovarain syndrome and hirsutism
- Possible infertility (key differential diagnosis for PCOS)
Treatment – hydrocortisone replacement
- Replace cortisol function
- Feed-back inhibit ACTH ‘drive’
- Reduce ACTH-driven androgens
Monitoring
- Titrate glucocorticoid replacement
- Monitor 17-OH progesterone and androgen levels
66
11B-hydroxylase deficiency in ZF - hormonal pattern, presentation, treatment, monitoring
Affects just glucocorticoid production
Hormonal pattern…
- Dec. cortisol (partial block), dec. feedback, inc. ACTH
- Inc. 11b-OH substrates -> deoxycortisol and deoxycorticosterone (DOC) in ZF
- Excess adrenal androgens
- Hypertension due to weak mineralocorticoid activity of DOC at the MR (mineralocorticoid receptor) in the kidney
Increased 11B-hydroxylase enzyme substrates
- 11-deoxycortisol
- 11-deoxycorticosterone (DOC) – weak mineralocorticoid (active at the kidney MR, NOT inactivated by 11B-HSD-2)
- Inappropriate MR activation causes Na+ retention, ECF expansion, hypertension, low renin (RAS) and inhibition of aldo production in the ZG
- Hypertension the clinical clue that a pateint has 11OH-CAH (rather than 21-OH CAH)
- Increased andorgens
o Virilisation in boys, masculinisation in girls
Treatment – life-long glucocorticoid replacement
- Replace cortisol function
- Feed-back inhibit ACTH ‘drive’
- Reduce ACTH-driven androgen and mineralocorticoid production
Monitoring
- Monitor 17-OH progesterone and androgen levels as for 21-OH CAH
- Also measure plasma Na+ concentration
67
what is the main clinical clue that a patient has 11OH > 21-OH CAH
- Hypertension the clinical clue that a patient has 11OH-CAH (rather than 21-OH CAH
68
what 2 specific stains are used to biopsy neuroendocrine tumours
o Chromogranin A and synaptophysin
69
what are carcinoid symptoms associated with NET and what can be measured to assess these
- Flushing and diarhhoea
- Measure…
o Urine 5-HIAA
o Chromogrannin A
70
what is a common hormone produced by NETs - what does it cause and how is it measured
- Can’t measure serotonin in blood
- Measure downstream metabolite of this 5-Hydroxyindole Acetic Acid
- Serotonin leads to… flushing, diarrhoea, bronchospasm, right heart failure
- Often have patients with severe diarrhoea that go undiagnosed for ages
- Presnet as RHF as serotonin sticks to receptors on right side of heart
- Flushing during alcohol / social interaction is a sign
71
why is right heart disease associated with NETs
- When you have NET in liver lots of serotonin travelling to the heart
- Serotonin sticks onto heart valves = valve dysfunction, tricuspid regurgitation
- Sytmpomts > leg swelling, elevated JVP, ascites
72
clinical characteristics of NETs
- Rare
- Significant majority arise in GI system (including pancreas)
- Usually slow growing
- Wide specturm of disease activity
- Often metastatic at presentation
- Prolonged survival is possible
- Neuroendocrine carcinomas
o Follow traditonal cancer pathway = poorer diagnosis
- Neuroencorine tumours ing neeral act differently
o Grade 1, 2, 3, 4 (carcinoma)
73
presentation of NETs in different body regions
```
- Liver
o pain due to enlargement of capsule
o abnormal LFTs
- stomach
o indigestion
o iron deficiency anaemia
o some blood loss
- appendix
o appendicitus
o small apendicial tumour on appendectomy
- bowels
o bowel obstruction – abdominal distetnion, vomitting, pain
- rectal
o bleeding from rectus
- pancreas
o picked up on CT when present with abdominal pain
o producing hormone – present with symptoms speciifc to hormone
- lung
o cough
o on chest x-ray
```
74
hormonal presentation of NETs - depending on specific hormone
```
if make hromones present earlier
- insulin
o Present with hypoglycaemia
- Glucagon
o Present with diabetes
o Classical rash
- Gastrin
o Heart burn
o Peptic ulcers despite PPIs
- Vasoactive intestinal polypeptide (VIP)
o Diarrhoea
o Hypokalaemia
```
75
firstline treatment of NETs
- Active surveillance as treatment can make QoL worse
- Surgery (bowel/ pancreatic/ hepatic)
- Somatostatin analogue therapy
o expensive
76
somatostatin analogue mode of action
- get hormonal levels down – dec. serotonin
- have anti-tumour effecst also
o reduced cell proliferation
o dec. rate of change of NET
77
what type of scan can be useful to find metastases in NETs
Do a nuclear medicine scan
- inject radio labelled octreotide
- taken up by NET
- is NET lights up you can do specialised treatment to make it better
78
radionuclide therapy for NETs
- because tumour took up ocreotide you can attach radiotherapy to this compund for treatment
- can target the relatively ischaemic central core of metastic deposits
- potentially toxic to bone marrow an dkidneys
In scotland use lutetium
- slow down rate of change of tumour
- for hromonally active tumour this can be effective to dec. hormone levels
79
transarterial chemoembolisation for NETs
- injection of small molecules that block blood vessels of tumours and kill the tumours
- can be given in most large centres
- only targets cancer deposits in the liver
- destructive therapy so potential for rapid release of hormones from the dying cells
- this can cause major mood swings in blood pressure
80
general info about multiple endocrine neoplasia MEN
Arises from problem in tumour suppressor genes
- lose ability to stop proliferation
- but resulting proliferation is relatively slow
- can be screened for in childhood if patient had condition
o to pick up tumours that develop
o manage psychological aspects
- autosomal dominant inheritance
- 1:30,000
81
MEN type 1 - what genes affected and what the clinical presentation
- Defect in the MEN1 gene
- Gene product is menin (TSG)
- Chromosome 11
Clinical presentation (Ps)
- Primary hyperparathyroidism
- Pituitary adenomas
- Pancreatic tumours
- Adrenal adenomas
- Bronchial / thymic carcinoids
- (lipomas/ angiofibromas)
82
screening for MEN
- Annual calcium and PTH
- Annual fasting gut hormones
o Chromogrannin A, insulin-glucose, gastrin glucagon, pancreatic polypeptide
- 3 yearly MRI of pituitary and now pancreas
- Consideration for CT/MRI of chest and thymus
83
MEN type 2 - what gene affected and presentation of both MEN 2A and MEN 2B
- Defect in MEN2 gene
- Gene product is ret
- Proto-oncogne
- Chromosome 10
Many codon mutations that happen in MEN2 gene
- The codon determines when thyroidectomy is performed to prevent medullary thyroid cancer
```
2A (85%)
- Hyperparathyroidism
- Medullary thyroid cancer
- Phaeochromocytoma
o Important because anaesthesia can kill them due to release of too much adrenaline
```
2B (5%)
- Hyperparathyroidism
- Medullary thyroid cancer
- Phaechromocytoma
- Neuromas, fibromas, musculoskeletal abnormalities
- Marfanoid habitus
84
at what time in foetal development is the 'jolt of testosterone' that makes the baby develop into a male, what causes this and what happens without this
7-8 wks
- sertoli cell differentiation from genes on the SRY gene in foetus
- if this doesn't happen may develop down a female pathway
