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Year 2 - Semester 2 > Endocrinology - Week 3 > Flashcards

Endocrinology - Week 3 Flashcards

1
Q

describe cholesterol

A

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

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2
Q

what are the three types of corticosteroids

A

(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

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3
Q

what are the three types of sex steroids

A

(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

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4
Q

what steroid is often forgotten?

A

vitamin D

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5
Q

how do steroid hormones work

A

• 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

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6
Q

how are steroids made

A

• 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

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7
Q

what types of enzyme are involved in steroid synthesis

A

• 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

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8
Q

describe cortisol metabolism and transport

A
  • 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
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9
Q

describe adrenal gland blood supply

A
  • 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
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10
Q

describe adrenal glands

A
  • 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)
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11
Q

describe the adrenal cortex

A

• 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??

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12
Q

what determines which steroid is synthesised in each zone

A

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
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13
Q

what determines Corticotrophin-Releasing Hormone (CRH) secretion from PVN of the hypothalamus

A

• 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

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14
Q

why do cortisol levels have a diurnal rhythm

A

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

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15
Q

how does CRH stimulate ACTH release

A

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

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16
Q

how does ACTH stimulate cortisol synthesis

A

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

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17
Q

describe cortisol

A

• 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

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18
Q

what are the normal physiological actions of cortisol

A

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

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19
Q

what are the pathophysiological actions of cortisol

A

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

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20
Q

describe cortisol excess phenotype

A
  • Phenotype: Hypertension; low plasma K+, elevated plasma cortisol, low plasma aldosterone & renin activity
  • Hypertension due to multiple effects of elevated plasma cortisol
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21
Q

what would you see with a ACTH-secreting pituitary tumour

A

HIGH Plasma ACTH

HIGH Plasma Cortisol

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22
Q

what would you see with a Cortisol-secreting adrenal tumour

A

LOW Plasma ACTH

HIGH Plasma Cortisol

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23
Q

what is important if a patient presents with excess adrenal androgens (DHEA)

A

also need to think about excess cortisol as they are intimately linked (both produced in zona reticularis)

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24
Q

what are the 3 main physiological factors that regulate blood pressure

A

• 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

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25
Q

how do the three adrenal hormone systems regulate blood pressure

A

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)

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26
Q

what causes endocrine hyper(hypo)tension:

A

caused by excess (lack):
aldosterone from ZG
cortisol or precursors from ZF
catecholamines from medulla

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27
Q

what is the role of the kidney in blood pressure

A

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

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28
Q

what are the rapid and long term effects of RAS and aldosterone

A

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
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29
Q

what is the link between aldosterone and heart failure

A

• 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

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30
Q

describe hypertension epidemiology and classification

A

• 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

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31
Q

describe conns syndrome

A

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
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32
Q

describe bilateral adrenal hyperplasia

A

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
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33
Q

what is Glucocorticoid-Remediable Aldosteronism (GRA):

A
  • 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)
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34
Q

describe Renin-secreting JG cell tumour

A 
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
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35
Q

describe Renal arterial stenosis

A

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
36
Q

describe Adrenal tumour (Cushing’s Syndrome) or Pituitary tumour (Cushing’s Disease

A

• 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

37
Q

How does elevated plasma cortisol cause hypertension?

A
  • 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!

38
Q

So why isn’t the MR receptor fully occupied by cortisol??

A

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

39
Q

describe apparent mineralocorticoid excess

A
  • 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
40
Q

describe liquorice ingestion and drugs

A 
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!
41
Q

describe pheochromocytoma

A

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

42
Q

describe monogenic endocrine hypertension

A

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

43
Q

why sub-classify patients on low plasma renin status

A

• < 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!

44
Q

why sub-classify patients on Aldosterone-Renin Ratio (ARR):

A

• <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!

45
Q

two types of aldosterone-producing microadenomas:

A 
1. Aldo-producing cell clusters (APCCs): somatic mutations in genes controlling:
membrane depolarisation & intracellular Ca2+
increased AS (aldosterone synthase) expression
uncontrolled aldosterone production
  1. 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?

46
Q

describe addisons disease

A

• 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)

47
Q

describe Secondary Adrenal Insufficiency (hypopituitarism)

A

• 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.

48
Q

describe congenital adrenal hyperplasia (CAH)

A

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
49
Q

describe partial block in 21-OHase activity

A

↓ 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)

50
Q

describe complete block in 21-OHase activity

A

↓ 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)

51
Q

what happens in pubertal girls with 21-hydroxylase CAH

A
  • 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
52
Q

describe late onset 21-hydroxylase deficiency

A

– 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)

53
Q

describe 11β-hydroxylase deficiency in the ZF

A

↓ 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

54
Q

What does aldosterone look like

A

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

55
Q

What does cortisol look like

A

glucocorticoid

CH3 at carbon 10

OH at carbon 11

CH3 at carbon 13

large structure on carbon 17

56
Q

What do adrenal androgens look like

A

CH3 at carbon 10
CH3 at carbon 13
a double bonded O on carbon 17

57
Q

What does progesterone look like

A

CH3 at carbon 10
CH3 at carbon 13
Carbon bonded to a CH3 and double bonded to an O on carbon 17

58
Q

What does testosterone look like

A

CH3 at carbon 10
CH3 at carbon 13
just an OH on carbon 17

59
Q

What does oestradiol look like

A

nothing at carbon 10
CH3 at carbon 13
an OH on each end of the steroid

60
Q

What does cholesterol look like

A

CH3 at carbon 10
CH3 at carbon 13
very large structure on carbon 17

61
Q

What does DHT look like

A

the same as testosterone but has a single H opposite the C10 CH3

62
Q

what steroids are made in the gonads

A

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.

63
Q

what are the two types of enzyme involved in

human sex steroid hormone synthesis

A 
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
64
Q

what are the similarities and differences between sex steroid synthesis in male and female gonads

A

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)
65
Q

describe the HPG axis

A

• 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

66
Q

describe the actions of testes cells

A

Steroidogenic Leydig cells = make testosterone

Sertoli cells = ‘nursery’ cells for sperm production/ make inhibin & ABP (androgen binding protein)

67
Q

describe the actions of hormones on the testes

A

• 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)
68
Q

what are the actions of male sex hormones

A 
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
69
Q

what happens in androgen insensitivity syndrome

A

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

70
Q

what happens if males dont get oestrogen

A

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

71
Q

describe female sex hormone synthesis

A
  • 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)
72
Q

what is the action of oestrogen in females

A
  • 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
73
Q

what is the action of progesterone in females

A
  • 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
74
Q

describe sex steroid regulation of the normal ovarian cycle: proliferative & secretory phases

A 
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

75
Q

what happens if there is NO implantation

A 
corpus luteum regresses & stops producing progesterone
declining feedback of :
     -  progesterone
     -  oestrogen
     -  inhibin
allows a new cycle of LH & FSH release
76
Q

what happens if there is implantation

A

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)

77
Q

what are the stains for NETs

A
  • Chromogranin-A

* Synaptophysin

78
Q

how do we measure serotonin

A

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.

79
Q

describe the actions of serotonin

A
  • 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

80
Q

what are the clinical characteristics of NETs

A
  • 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
81
Q

what is the presentation of NETs

A
  • 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
82
Q

what are the common sites

A 
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%
83
Q

what is the prognosis for NETs

A

Prognosis is very high for 5 years with no metastasis. Around 40% for metastasis

84
Q

what are the treatment options for NETs

A 
•	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

85
Q

describe MEN inheritance

A

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

86
Q

describe MEN type 1

A
  • 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

87
Q

describe MEN type 2

A
  • 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!

Year 2 - Semester 2 (8 decks)

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