Endocrinology - Week 3 Flashcards
describe cholesterol
sterol
• Polar head group
• Steroid body
• Hydrophobic side chain
Component of cell membrane as its attracted to polar heads and hydrophobic tails in the membrane
what are the three types of corticosteroids
(made in the cortex)
• Mineralocorticoids
o Salt and water retention
• Glucocorticoids
o Glucose synthesis
o Protein and lipid metabolism
o Inflammation and immune response
• Adrenal androgens
o Fetal steroids and growth
what are the three types of sex steroids
(made in the gonads)
• Androgens
o Growth and function of the male reproductive system
• Oestrogens
o Growth and function of the female reproductive system
• Progesterones
o Female menstrual cycle and maintenance of pregnancy
what steroid is often forgotten?
vitamin D
how do steroid hormones work
• Classical’ receptors in the cytoplasm activated by steroid binding - translocate to nucleus
o Gene transcription & protein synthesis
o Slow action (>30 mins-48hr)
o e.g. aldosterone-regulated synthesis of kidney epithelial sodium channel (ENaC) subunits
• Non-classical’ receptors, activated by steroid binding, e.g. ion channels in the plasma membrane
o Intra-cellular signalling pathways, e.g. calcium/inositol
o Rapid signalling (< 1 min)
o e.g. aldosterone-mediated vasoconstriction of vascular smooth muscle & endothelial cells
how are steroids made
• first step : hydrophobic 6 carbon side chain removed
o steroid hormones more water soluble than cholesterol
• most steroids have a varied substituent at C-17
o Enzyme nomenclature indicates the site of action …
o e.g. ‘17α-hydroxylase’ introduces a hydroxyl group at C- 17
• extra specificity from side chain modification e.g. C-11
o Enzyme nomenclature indicates the site of action …
o e.g. ‘11β-hydroxylase’ introduces a hydroxyl group at C- 11
what types of enzyme are involved in steroid synthesis
• cytochrome P450s (over 1000 of these)
o Highly expressed in
Liver (drug detoxification)
Organs that synthesise steroids
• adrenal cortex,
• testis, ovary, placenta
o Cleave or modify cholesterol side groups
o Example: (clue in the name)
cholesterol side chain cleavage enzyme (SSC; CYP 11A1)
Converts cholesterol to pregnenolone
C27 → C21 = First step in steroid synthesis
• steroid dehydrogenases
o Steroid dehydrogenases/reductases: (usually paired)
o Key concept:
Interconvert active & inactive forms of steroid
o Example: 11β-HSD1 and 11β-HSD2 - liver & peripheral tissues
Turn cortisone into cortisol (active form) and vice versa
describe cortisol metabolism and transport
- Made and released from the adrenal gland
- Much binds to transport proteins
- Cortisol converted to cortisone by the liver
- Then reactivated at the site of action
describe adrenal gland blood supply
- From renal arteries or aorta
- Short arteries penetrate capsule and form a subcapsular plexus of arterioles
- These then give off sinusoidal capillaries which separate chords of cells
- The medulla gets its blood from long arteries and capillaries from cortex
- Medulla and cortex drain via the central medullary vein
describe adrenal glands
- Around the 12th thoracic vertebra
- Positioned anteriorly on superior poles of kidneys
Cortex • 80-90% of normal gland • Makes steroid hormones Medulla • 10-20% • Makes catecholamines (adrenaline and noradrenaline)
describe the adrenal cortex
• Zona glomerulosa
o Synthesizes aldosterone (SALT)
• Zona fasciculata
o Synthesizes cortisol (SUGAR)
• Zona reticularis
o Synthesizes “C19” adrenal androgens (SEX)
Under the control of the HPA axis
Also regulated by ACTH from pituitary
o Prenatal DHEA production
Role in maintaining oestrogenic environment
role in foetal development??
o Postnatal DHEA production:
role in initiation of puberty (adrenarche)??
main source of androgens & post-menopausal oestrogen in females
role in longevity; elixir of life??
what determines which steroid is synthesised in each zone
determined by zone-specific P450 gene expression
- zona glomerulosa produces mineralocorticoid (aldosterone) due to expressing a gene for aldosterone synthase but not 17α-Hydroxylase and 11β-Hydroxylase
- zona fasciculata produces glucocorticoid (cortisol) due to having 17α-Hydroxylase and 11β-Hydroxylase but not aldosterone synthase
- zona reticularis produces adrenal androgen (“C19”) due to having 17α-Hydroxylase but not aldosterone synthase and only a little 11β-Hydroxylase
what determines Corticotrophin-Releasing Hormone (CRH) secretion from PVN of the hypothalamus
• diurnal circadian rhythm from the suprachiasmic nucleus stimulates the hypothalamus to release CRH at the median eminence
• there are a number of things which inhibit or promote this release
o ADH/AVP (potentiates CRH)
o cortisol negative feedback
why do cortisol levels have a diurnal rhythm
Diurnal CRH release regulates ACTH release:
• high in the early morning (04.00-08.00)
• lower later in the day
ACTH regulates cortisol synthesis:
• High on waking (06.00-10.00)
• lower later in the day (with ‘stress’ activity spikes)
• lowest in the middle of the night
how does CRH stimulate ACTH release
Hypothalamic CRH stimulates AdrenoCorticoTrophic Hormone (ACTH) secretion
from anterior pituitary corticotrophs
• CRH stimulates production of pro-opiomelanocortin (POMC) …
• POMC cleaved to ACTH and other peptides
how does ACTH stimulate cortisol synthesis
ACTH stimulates cortisol synthesis & secretion from adrenal zona fasciculata (&ZR) cells
• cortisol & adrenal androgen synthesis and release (1-2 mins)
• cholesterol ester hydrolase increased which increases free cholesterol
• activates StAR protein (steroid acute regulatory protein) which increases cholesterol transport to mitochondria
o this is the rate limiting step which is shown by mutations to this protein
Cortisol feeds back on production of CRH from hypothalamus & ACTH from the anterior pituitary
describe cortisol
• Essential for survival and to resist physiological and environmental stress
• Part of the ‘counter-regulatory’ hormone defence against hypoglycaemia
• Levels rise as plasma glucose falls:
o glucagon (from α cells of the pancreas)
o adrenaline (epinephrine)
o noradrenaline (norepinephrine)
o growth hormone
o cortisol
• Dual action of cortisol:
o Anabolic in the liver to promote gluconeogenesis
o Catabolic in peripheral muscle & fat to promote protein and lipid breakdown
what are the normal physiological actions of cortisol
maintains plasma glucose levels for the brain
Anabolic:
• Increased gluconeogenesis & liver glucose output
Catabolic:
• Inhibition of glucose uptake by peripheral muscle & fat tissue
• Immune system suppression
• Increased muscle protein breakdown
• Increased fat breakdown
• Increased bone resorption
• Increased appetite & central fat deposition
what are the pathophysiological actions of cortisol
elevated plasma glucose & peripheral tissue wasting
Anabolic:
• Elevated plasma glucose = secondary diabetes mellitus
Catabolic:
• Muscle and connective tissue wasting and weakness
• Poor wound healing & skin ulcers
• Uncontrolled muscle protein breakdown
• Increased fat redistribution
• Osteoporosis
• Uncontrolled appetite & central fat deposition
• Excess mineralocorticoid action = Na+ & fluid retention & hypertension
describe cortisol excess phenotype
- Phenotype: Hypertension; low plasma K+, elevated plasma cortisol, low plasma aldosterone & renin activity
- Hypertension due to multiple effects of elevated plasma cortisol
what would you see with a ACTH-secreting pituitary tumour
HIGH Plasma ACTH
HIGH Plasma Cortisol
what would you see with a Cortisol-secreting adrenal tumour
LOW Plasma ACTH
HIGH Plasma Cortisol
what is important if a patient presents with excess adrenal androgens (DHEA)
also need to think about excess cortisol as they are intimately linked (both produced in zona reticularis)
what are the 3 main physiological factors that regulate blood pressure
• Cardiac output
– volume of blood pumped out by the heart
– stroke volume x heart rate (beats/min)
• Vascular tone
– ‘stiffness’ or resistance of blood vessels
– balance between vasoconstrictor & vasodilator influences
• Extracellular fluid (ECF) volume
– Interstitial fluid in tissues
– intravascular fluid in the plasma
– increased by kidney water resorption
• these are all regulated by hormones
how do the three adrenal hormone systems regulate blood pressure
Cardiac output:
increased by:
catecholamines (SNS)
cortisol potentiation (HPA)
Vascular tone (vasoconstriction):
increased by:
angiotensin II (AII; RAS)
aldosterone (RAS)
catecholamines (SNS)
cortisol potentiation (HPA)
Extracellular fluid (ECF) volume:
increased by:
aldosterone (RAS)
cortisol (HPA)
what causes endocrine hyper(hypo)tension:
caused by excess (lack):
aldosterone from ZG
cortisol or precursors from ZF
catecholamines from medulla
what is the role of the kidney in blood pressure
mechanisms regulating renin release from kidney juxtaglomerular (JG) cells
Renin release in response to:
JG cell baroreceptors
• reduced ECF & renal perfusion pressure
• directly activates renin release
Macula densa cell Na+ sensing
• decreased Na+ load to distal tubule (↓ECF/plasma Na+)
• activates sympathetic innervation of JG apparatus
Carotid arch baroreceptors
• Low systemic arterial pressure (reduced ECF, cardiac output, vascular tone)
• activates sympathetic innervation of JG apparatus
what are the rapid and long term effects of RAS and aldosterone
VASCULATURE
Rapid (secs)
vasoconstriction
Postural regulation of BP
ADRENAL
Rapid (mins)
aldosterone synthesis
Catecholamine synthesis
KIDNEY
6-48 hr
Na+ & water reabsorption via RAAS
VASCULATURE Long term smooth muscle cell hyperplasia cell hypertrophy Long-lasting change in vascular tone
ADRENAL Long term aldosterone synthase enzyme expression glomerulosa cell proliferation
CNS Long term thirst salt appetite ADH release
what is the link between aldosterone and heart failure
• Plasma aldosterone elevated in patients with heart failure
• Standard HF therapy: ACE inhibitor + loop diuretic + digoxin
• Clinical & experimental studies show benefits of
mineralocorticoid receptor antagonists e.g. spironolactone
• Spironolactone (MR antagonist) blocks aldosterone action in kidney AND other tissues (e.g. heart)
• Which otherwise leads to:
- myocardial remodelling,
- Na+ retention & vascular dysfunction
• Decreases all-cause mortality in heart failure patients
describe hypertension epidemiology and classification
• risk factor - high blood pressure … 1.2 billion people worldwide!
- ~30% lifestyle/environmental (poor diet, lack of exercise) - ~70% major familial/genetic mono- or polygenic component
• 85-90% classified as ‘Primary’ or ‘Essential’ hypertension
- all cases without any identifiable cause
• 10-15% classified as ‘secondary’ hypertension
- neoplasia, vascular damage & endocrine causes
describe conns syndrome
primary hyperaldosteronism
- unilateral adrenal tumour
- aldosterone-producing adenoma
- Phenotype:
• high aldosterone, MR activation,
• high Na+, low K+, ECF expansion,
• hypertension, low renin (RAS) - Treatment – surgical:
• venous sampling and/or CT scan
• unilateral adrenalectomy
describe bilateral adrenal hyperplasia
primary hyperaldosteronism
- most common form (60-70%) of PA
- Phenotype:
- high aldosterone, MR activation,
- high Na+, low K+, ECF expansion,
- hypertension, low renin (RAS)
- Treatment – pharmacological:
- anti-hypertensives
- e.g. MR antagonists
- spironolactone, eplerenone
what is Glucocorticoid-Remediable Aldosteronism (GRA):
- Autosomal dominant genetic disorder (human chromosome 8)
- ACTH-driven hyperaldosteronism
• Genes for Aldo synthase & 11β-OHase - 95% identity in protein-coding regions
BUT gene promoters different: - Aldo synthase regulated by Angiotensin II & K+
- 11β-OHase regulated by ACTH
• GRA hybrid gene : - Unequal meiotic exchange
- 11β-OHase promoter (ACTH-driven)
- aldo synthase coding region
• Phenotype: - high aldosterone, MR activation,
- high Na+, low K+, ECF expansion,
- hypertension, low renin (RAS)
• Treatment: - suppress pituitary ACTH secretion
- synthetic glucocorticoid (Dex)
describe Renin-secreting JG cell tumour
secondary hyperaldosteronism - renin hyper-secretion, ↑RAAS - severe hypertension • Phenotype: - high plasma renin, high aldosterone - MR activation, high Na+, low K+ - ECF expansion, hypertension • Treatment: - surgical removal of tumour
describe Renal arterial stenosis
secondary hyperaldosteronism
- low perfusion pressure, renin
- secretion, ↑RAAS, hypertension
• Phenotype: - high plasma renin, high aldosterone
- MR activation, high Na+, low K+,
- ECF expansion, hypertension
• Treatment: - anti-hypertensive, e.g. MR blockers
- statins, anti-platelet agents;
- balloon angioplasty +/- stent
describe Adrenal tumour (Cushing’s Syndrome) or Pituitary tumour (Cushing’s Disease
• Presentation:
– weight gain, stretch marks, easy bruising, proximal muscle weakness
– diabetes mellitus (high plasma glucose), menstrual irregularities, depression
• Phenotype:
– hypertension due to multiple effects of elevated plasma cortisol - …
– high cortisol, high Na+, low K+ (=MR activation?), low renin & low aldosterone
How does elevated plasma cortisol cause hypertension?
- Glucocorticoids inhibit vascular nitric oxide production by eNOS
- Glucocorticoids potentiate catecholamine action in heart & vasculature
- Glucocorticoids can inappropriately activate the kidney MR
Cortisol has a moderate affinity for the kidney MR receptor:
Aldo 1.0 : Cortisol 0.4
Cortisol plasma concentrations
100-1000x higher than aldosterone!
So why isn’t the MR receptor fully occupied by cortisol??
11β-HSD-2 protects kidney MR from inappropriate activation by cortisol by converting it to inactive cortisone
Increased plasma cortisol exceeds capacity of 11β-HSD2 to convert cortisol to cortisone
Active cortisol inappropriately activates the kidney MR receptor
Increases Na+ & water retention causing ECF expansion
describe apparent mineralocorticoid excess
- Autosomal recessive ‘loss of function’ mutation in 11β-HSD2
- ↓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
(spironolactone, eplerenone) - low-Na+ diet & K+ supplements
- MR antagonists
describe liquorice ingestion and drugs
carbenoxolone, glycyrrhizinic acid
inhibitors of kidney 11β-HSD2
- ↓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
- stop eating liquorice!describe pheochromocytoma
catecholamine-secreting tumour of the adrenal medulla
• Adrenaline from the adrenal medulla:
– freeze, fight & flight response
– ↑ heart rate, vasoconstriction, peripheral resistance
– ↑ glucagon secretion, ↓ insulin secretion
– ↑ glycogen & lipid breakdown
• Pheochromocytoma:
– chromaffin cell tumour
– secrete catecholamines
– noradrenaline and/or adrenaline
• Distinctive but variable symptoms
• Palpitations, Headache, Episodic sweating
– racing heart, anxiety (~50%),
– hypertension – sustained/paroxysmal (~50%)
– diabetes mellitus (~40%)
• Diagnosis & Treatment:
– 24 hour urinary metanephrines & catecholamines
– α-blockers, β-blockers, surgical resection
describe monogenic endocrine hypertension
accounts for 10-15% of hypertension
• Majority (85-90%) of hypertensive patients have ‘Essential’ hypertension,
- all cases lacking a single identifiable cause
• BUT: RAAS inhibitors can treat some ‘Essential’ Hypertension patients
why sub-classify patients on low plasma renin status
• < 20% of hypertensive patients display:
low plasma renin (= expected feedback),
but inappropriately ‘normal’ or high aldo levels
– are low plasma renin due to high blood pressure?
OR ‘excess’ mineralocorticoid feedback?
– suggests altered aldosterone levels may be
involved in essential hypertension after all!
why sub-classify patients on Aldosterone-Renin Ratio (ARR):
• <15% of hypertensive patients display:
inappropriately normal or high plasma aldo & raised ARR
– both renin and aldosterone should be low in hypertension (= expected feedback)
– ARR = mass concentration of aldosterone divided by plasma renin activity (recommended screening tool for primary hyperaldosteronism)
– high ARR = evidence of undiagnosed aldosterone-secreting adenomas … ?
Patients with hypertension should always be suspected of 1° hyperaldosteronism!
two types of aldosterone-producing microadenomas:
1. Aldo-producing cell clusters (APCCs): somatic mutations in genes controlling: membrane depolarisation & intracellular Ca2+ increased AS (aldosterone synthase) expression uncontrolled aldosterone production
- Aldo-producing adenomas (APAs): somatic mutations in genes controlling:
membrane depolarisation & intracellular Ca2+
increased AS expression
uncontrolled aldosterone production
+ cell proliferation & nodule formation
APCCs may explain a greater proportion of essential hypertension?
Opportunity for rational treatment?
describe addisons disease
• Causes:
- destruction of adrenal gland
- by tuberculosis, cancer metastases, autoimmune disease
• Presentation:
- disease of all three adrenocortical zones
- aldosterone, cortisol & 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)
• Treatment:
- Fluid & hormone replacement
synthetic glucocorticoid (hydrocortisone, prednisone)
synthetic mineralocorticoid (fludrocortisone)
describe Secondary Adrenal Insufficiency (hypopituitarism)
• Causes:
- partial or complete loss of anterior lobe pituitary function
- tumour, pituitary apoplexy, suppression by long-term corticosteroids
- lack of pituitary ACTH secretion & adrenocortical trophic stimulation
• Presentation:
- malfunction of ZF & ZR, reduced cortisol & androgen secretion
- RAS and aldosterone secretion (ZG) largely unaffected
• Phenotype:
- low plasma ACTH & cortisol due to pituitary & adrenal failure
- Increased 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.
describe congenital adrenal hyperplasia (CAH)
Presentation:
• Inherited condition present at birth (congenital) in which the adrenal gland is larger than usual (hyperplasia)
• A form of primary adrenal insufficiency
• Usually caused by an 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:
• both alleles altered, but different mutations inherited from mother & father
• BUT also see genuine homozygotes e.g. from consanguineous marriages
Frequency: how common?
Common (90-95% of cases):
• Steroid 21-hydroxylase (21-OHase)
• population frequency 1 : 14,500 = heterozygote frequency of 1 : 61
- (NB: 21-OHase pseudogene)
Less common (5% of cases):
• 11β-OHase
Rare (0.1-1% of cases):
• 17α-OHase
• 3β-HSD
• StAR (lipoid CAH)
Presentation in all CAH syndromes: Block in cortisol synthetic pathway: • reduced cortisol • impaired stress response • reduced plasma glucose • reduced feedback on CRH-ACTH Elevated ACTH: • increased pituitary ACTH secretion • adrenal stimulation & hyperplasia (pathophysiological growth) Also changes in other steroids: • excess intermediates before block • reduced hormones after block Diagnosis: • Usually soon after birth • Less severe CAH not apparent until puberty • Prenatal diagnosis possible now affected genes identified
describe partial block in 21-OHase activity
↓ Cortisol, ↓ feedback, ↑ACTH;
Symptoms reflect mainly a lack of cortisol (enough aldo still made)
remember: cortisol is made at 100x higher levels than aldosterone
Increased androgens
virilisation in boys; masculinisation in girls
Most common cause of ambiguous genitalia 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)
describe complete block in 21-OHase activity
↓ Cortisol + Aldo, ↓ feedback, ↑ACTH;
↑Progesterone, ↑17α-OH progesterone, ↑DHEA & androstenedione
↑adrenal androgen feedback on pituitary → ↓FSH, ↓LH
Severe classical ‘salt wasting’ form … aldo synthesis also blocked
Symptoms reflect a lack of cortisol AND aldosterone
low plasma aldosterone = lack of MR activation
low plasma Na+ , high plasma K+, H+ = hyperkalaemic acidosis
ECF deficit, hypotension & vascular collapse
Life-threatening vomiting & dehydration in new-borns – treatment essential
Increased androgens
virilisation in boys; masculinisation in girls
Treatment:
replace cortisol & mineralocorticoid
reduce ACTH-driven androgens
normalise plasma Na+, ECF & bp
Monitoring:
glucocorticoid & mineralocorticoid
monitor 17-OH progesterone
androgen levels (most important)
what happens in pubertal girls with 21-hydroxylase CAH
- feedback-inhibits ACTH-driven androgen over-production
- delayed treatment leads to progressive masculinisation of body shape:
Excess androgen production in females, left untreated: gender mis-assignment psychological problems may need corrective surgery Untreated 21-OH CAH (Left): • ambiguous genitalia • single urethral/vaginal orifice • fused labia & enlarged clitoris Prenatal Dex* treatment (Right): (*dexamethasone crosses placenta) • reduces clitoral size • allows urethral/vaginal separation
describe late onset 21-hydroxylase deficiency
– mild inactivating mutation – less severe than in affected neonates
– usually presents after puberty in women
– following upsurge in ACTH & adrenal steroid secretion (adrenarche)
Excess adrenal androgen results in:
– menstrual cycle disturbances
– polycystic ovarian syndrome & 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 &
– androgen levels (most important)
describe 11β-hydroxylase deficiency in the ZF
↓ Cortisol (partial block), ↓ feedback, ↑ACTH;
↑ 11β-OH substrates: deoxycortisol & deoxycorticosterone (DOC) in ZF
excess adrenal androgens
hypertension due weak mineralocorticoid activity of DOC at the MR
Increased 11β-hydroxylase enzyme substrates:
11-deoxycortisol, 11-deoxycorticosterone (DOC); weak mineralocorticoid
(active at the kidney MR; NOT inactivated by 11β-HSD-2)
Inappropriate MR activation causes Na+ retention, ECF expansion, hypertension, low renin (RAS) & inhibition of aldo production in the ZG
hypertension the clinical clue that a patient has 11OH-CAH (rather than 21-OH CAH)
Increased androgens
virilisation in boys; masculinisation in girls
Treatment: Life-long glucocorticoid replacement
replace cortisol function
feed-back inhibit ACTH ‘drive’
reduce ACTH-driven androgen & mineralocorticoid production
Monitoring:
monitor 17-OH progesterone & androgen
levels, as for 21-OH CAH
also measure plasma Na+ concentration
What does aldosterone look like
mineralocorticoid
CH3 at carbon 10
CH at carbon 13 which links to an OH and and O which links back onto the steroid backbone
large structure on carbon 17
What does cortisol look like
glucocorticoid
CH3 at carbon 10
OH at carbon 11
CH3 at carbon 13
large structure on carbon 17
What do adrenal androgens look like
CH3 at carbon 10
CH3 at carbon 13
a double bonded O on carbon 17
What does progesterone look like
CH3 at carbon 10
CH3 at carbon 13
Carbon bonded to a CH3 and double bonded to an O on carbon 17
What does testosterone look like
CH3 at carbon 10
CH3 at carbon 13
just an OH on carbon 17
What does oestradiol look like
nothing at carbon 10
CH3 at carbon 13
an OH on each end of the steroid
What does cholesterol look like
CH3 at carbon 10
CH3 at carbon 13
very large structure on carbon 17
What does DHT look like
the same as testosterone but has a single H opposite the C10 CH3
what steroids are made in the gonads
Sex steroids are made in the same way in the gonads as in the adrenal cortex and corticosteroids can be activated there but not made.
what are the two types of enzyme involved in
human sex steroid hormone synthesis
1. Cytochrome P450s (CYPs):
cleave cholesterol side chains
• 17-OHase/17, 20 lyase (CYP17A1)
adrenal cortex ZR
testis, ovary
• Aromatase (CYP19A1)
ovary
AND peripheral oestrogen targets
e.g. breast, bone, etc.
converts testosterone to estradiol – mutations can lead to problems with sexual maturation
(aromatase inhibitors used to treat cancer)
2. Steroid dehydrogenases: interconvert steroids • 3β-HSDs: adrenal, testis, ovary • 17β-HSDs: testis, ovary • 5-reductases: testis & peripheral tissues
what are the similarities and differences between sex steroid synthesis in male and female gonads
DHEA & androstenedione made in BOTH male & female gonads
Same pathway as adrenal gland
BUT ovaries & testis Leydig cells contain an additional enzyme:
17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3)
Converts androstenedione (‘pro’) to weak C19 androgen testosterone:
- 3β-HSD converts pregnenalone into progesterone in corpus luteum
- In testis Sertoli cells 5α-reductase converts testosterone to strong androgen 5α-dihydrotestosterone
- In ovary & peripheral tissues, aromatase converts testosterone to strong oestrogen oestradiol (C18)
describe the HPG axis
• Gonadotrophin-releasing hormone (GnRH) from HP preoptic nucleus
• Acts on anterior pituitary gonadotrophs:
o follicle-stimulating hormone (FSH)
o luteinizing hormone (LH)
• FSH and LH stimulate sex steroid hormone production in gonads
o androgens (male),
o oestrogens (female)
o ALSO inhibins (male & female)
• Hormonal feedback on pituitary & hypothalamus regulates synthesis
describe the actions of testes cells
Steroidogenic Leydig cells = make testosterone
Sertoli cells = ‘nursery’ cells for sperm production/ make inhibin & ABP (androgen binding protein)
describe the actions of hormones on the testes
• LH stimulates testosterone (T) production by Leydig cells
• FSH promotes inhibin & androgen-binding protein (ABP) in Sertoli cells
• T moves from Leydig to Sertoli cells
• T converted to DHT & binds to ABP in luminal fluid of the seminiferous tubules
Action:
High T & DHT in seminiferous tubules promote sperm production & maturation
Inhibin is a key marker of Sertoli cell function
- T from Leydig cells & inhibin from Sertoli cells feedback on GnRH, LH & FSH
- Testosterone transported in plasma to peripheral targets bound (98%) to sex hormone-binding globulin (SHBG)
what are the actions of male sex hormones
Primary male reproductive function, e.g. • Spermatogenesis, prostate secretions Secondary male sex characteristics, e.g.: • anabolic (build muscle) • deep voice, facial & body hair • brain – libido & aggression Also essential during foetal life for: • male sex determination • genital development what
what happens in androgen insensitivity syndrome
due to mutated testosterone receptor:
• Arrested testis development; lack of testosterone & anti-mullerian hormone
- mullerian duct fails to regress
• Partial insensitivity:
male external genitalia & body shape,
& mild spermatogenic defect after puberty
• Complete insensitivity:
Female external genitalia & body shape,
female internal organs undeveloped or absent
what happens if males dont get oestrogen
Natural mutation in the aromatase gene
• fail to convert testosterone to oestradiol
• oestrogen deficiency affects bone maturation:
– tall and long arms
– bone epiphyses did not close
– Loss of bone mass
– Osteoporosis
describe female sex hormone synthesis
- LH stimulates production of androstenedione & testosterone in thecal cells of the primary follicle
- Androgens move from thecal to granulosa cells
- FSH stimulates androgen conversion to estrogens by aromatase
- Action: Estradiol regulates the proliferative phase of the female menstrual cycle
- Estradiol & inhibin from granulosa cells feed back on GnRH + LH & FSH release from HP & pituitary
- Estradiol also transported in plasma, to peripheral targets bound to gonadal sex hormone-binding globulin (SHBG)
what is the action of oestrogen in females
- Female genital development & differentiation
- Secondary female sex characteristics, e.g. body fat distribution, cardiovascular system, skin, bone, epiphyseal closure
- Estrogen from the primary ovarian follicle promotes endometrial growth during the follicular or ‘proliferative’ phase
what is the action of progesterone in females
- Made in the corpus luteum promotes endometrial secretion & vascularisation during the luteal or ‘secretory’ phase
- Prepares uterus for implantation of a fertilised egg
- Without implantation falling progesterone initiates menstruation
describe sex steroid regulation of the normal ovarian cycle: proliferative & secretory phases
Follicular (proliferative) phase: Day 0-14 FSH & LH stimulate estradiol production by the primary follicle promotes endometrial growth LH Surge triggering ovulation Day 14 Rising estradiol stimulates LH production = the ‘LH surge’ ‘LH surge’ stimulates ovulation
Luteal (secretory) phase:
Day 14-28
corpus luteum makes progesterone
receptive ‘secretory’ environment for implantation of a fertilised egg
what happens if there is NO implantation
corpus luteum regresses & stops producing progesterone
declining feedback of :
- progesterone
- oestrogen
- inhibin
allows a new cycle of LH & FSH releasewhat happens if there is implantation
Developing embryo produces hCG (human chorionic gonadotrophin) an alternative form of LH
hCG binds to LH receptors on corpus luteum & endometrium:
maintains progesterone secretion
suppresses maternal immune rejection of placenta
progesterone promotes uterine blood vessels to sustain the growing fetus
Luteal-placental shift (7-9 weeks)
• Hormones decline:
• hCG from embryo
• progesterone from corpus luteum
• To maintain pregnancy, placenta begins to produce:
(i) progesterone from cholesterol
(i) oestrogen from DHEA (fetal adrenal)
what are the stains for NETs
- Chromogranin-A
* Synaptophysin
how do we measure serotonin
Many hormonal features of NETs are due to serotonin which cannot be measured in the blood. Instead we measure 5HIAA through 24 hour urine collection.
describe the actions of serotonin
- Flushing
- Diarrhoea
- Bronchospasm
- Right heart failure
o Serotonin is usually cleared by enterohepatic circulation but, when there is disease in the liver, it becomes too much and a bunch of serotonin in dumped into the IVC which heads straight to the heart and can cause
Valve fibrosis – usually tricuspid regurgitation
Right heart failure
Elevated jugular venous pressure
Peripheral oedema
Hepatic congestion
what are the clinical characteristics of NETs
- Rare – diagnosis has increased due to greater understanding
- Significant majority arise in GI system including pancreas
- 25% we only find the metastasis and not the primary tumour
- Usually slow growing
- Wide spectrum of disease activity
- There are also neuro endocrine carcinomas which are more like classic cancers
- Often metastatic at presentation
- Prolonged survival is possible
what is the presentation of NETs
- People with hormone production will present earlier
- Insulin production could lead to hypoglycaemia
- Glucagon could lead to a rare form of diabetes
- Gastrin would lead to acid heartburn and peptic ulcers
- Vasoactive intestinal polypeptide would lead to very frequent and watery diarrhoea
what are the common sites
Mid-Gut • Appendix – 17% • Ileum – 16% • Ileo-caecal junction – 11% • Caecum – 3% Hind-gut • Colorectal – 7% Fore-gut • Pancreas – 11% • Stomach 7% • Duodenum – 4% • Oesophagus – 2% Unknown – 22%
what is the prognosis for NETs
Prognosis is very high for 5 years with no metastasis. Around 40% for metastasis
what are the treatment options for NETs
• Active surveillance • Surgery (bowel / pancreatic / hepatic) • Somatostatin analogue therapy Somatostatin analogues • Used to get hormone levels down • Now understood to have an anti-tumour effect as well
Radionuclide Therapy
• MIBG or radiolabeled somatostatin analogues
• Must have positive uptake of relevant agent
• Can target the relatively ischaemic central core of metastatic deposits
• Good for symptom control when SA no longer fully effective
• Potential toxicity to bone marrow and kidneys
• You get a radiation “crossfire” so the cells in the middle get a lot of radiation
Transarterial chemoemolisation
• Can be given in most large centres
• Only targets cancer deposits in the liver by blocking the blood supply and causing infarction
• Destructive therapy so potential for rapid release of hormones from the dying cells
• This can cause major swings in blood pressure – in both the patient AND the interventional radiologist
describe MEN inheritance
Begins with the mutation of a tumour suppressor gene.
The growth of the neoplasia is quite slow so if you know your parents have it then you could have decades of screening - immense psychological aspect
• 1:30,000
• Autosomal dominant inheritance
describe MEN type 1
- Defect in the MEN1 gene
- Gene product is menin
- Tumour suppressor gene
- Chromosome 11
Clinical features • Primary hyperparathyroidism • Pituitary adenomas • Pancreatic tumours (pituitary, pancreas, parathyroid) • Adrenal adenomas • Bronchial / Thymic carcinoids • (lipomas / angiofibromas)
Screening
• Annual calcium and PTH
• Annual fasting gut hormones
– Chromogrannin A, insulin-glucose, gastrin glucagon, pancreatic polypeptide
• 3 yearly MRI of pituitary and now pancreas
• Consideration for CT / MRI of chest and thymus
describe MEN type 2
- Defect in the MEN2 gene
- Gene product is ret
- Proto-oncogene gene
- Chromosome 10
Clinical features • 2A (85%) – Hyperparathyroidism – Medullary thyroid cancer – Phaeochromocytoma • 2B (5%) – Hyperparathyroidism – Medullary thyroid cancer – Phaeochromocytoma – neuromas, fibromas, musculoskeletal abnormalities – Marfanoid habitus • Familial medullary thyroid cancer (15%)
MEN 2A has a whole array of mutations which can lead to different things and there are tables recommending when to remove a thyroid for example
- Rare
- Lifelong follow-up
- Genetic counselling
- It just takes identification of one case!
