Metabolism

Question 1

What are the histological zones of the adrenal?

Answer 1

Cortex: zona glomerulosa, fasciculata, reticularis

Medulla

Question 2

What does each layer of the cortex produce?

Answer 2

Glomerulosa - mineralocorticoids
Fasciculata - glucocorticoids
Reticularis - sex steroids

Question 3

What happens to the sex steroids produced by the adrenal?

Answer 3

Converted to more potent sex steroids by the gonads

Question 4

Describe sex steroid synthesis

Answer 4

DHEA to delta4 androstenedione to oestrone
testosterone, 17beta oestradiol
dihydrotestosterone to ADG

Question 5

What converts DHEA to delta 4 androstenedione?

Answer 5

3 beta hydroxysteroid dehydrogenase

Question 6

What converts androstenedione to testosterone or to oestrone?

Answer 6

17beta hydroxysteroid dehydrogenase

p450 aromatase

Question 7

What converts testosterone to DHT?

Answer 7

steroid 5alpha reductase

Question 8

What converts DHT to ADG?

Answer 8

steroid 3alpha reductase

Question 9

What converts oestrone to 17beta oestradiol?

Answer 9

17beta hydroxysteroid dehydrogenase

Question 10

Describe the isoforms of steroid 5alpha reductase

Answer 10

Type 1: pH optimum 6-8.5, higher Km, chromosome 5p15, hair follicles, sebum glands, liver

Type 2: pH optimum 5, lower Km, chromosome 2p23, prostate, genital skin and liver

Question 11

Describe girl to boy syndrome

Answer 11

Testosterone to DHT converted by SRD5A2
Phenotype: outwardly female and develop male characteristics at puberty
Genotype: 46 XY SRD5A2 mutant
SRD5A1 expression increases at puberty.
Neonatal virilisation requires SRD5A2.

Question 12

Describe P450 aromatase

Answer 12

Converts delta4 androstenedione to oestrone and testosterone to 17beta oestradiol.
Single gene, chromosome 15p21.1
Essential for generation of oestrogens.
Detrimental in cancer

Question 13

What converts DHEA to DHEAS?

Answer 13

Steroid sulphatase

Question 14

What converts DHEAS to DHEA?

Answer 14

SULT2A1

Question 15

What does sulphation of DHEA prevent?

Answer 15

Makes it hydrophilic, cannot cross membranes

Question 16

Which is more abundant, DHEA or DHEAS?

Answer 16

DHEAS

Question 17

What is OATP?

Answer 17

A transporter that allows DHEAS into cells

Question 18

Describe expression of SULTs

Answer 18

Different SULTs expressed in different places to control how much DHEA is available

Question 19

What comes before DHEA?

Answer 19

Cholesterol to pregnenolone to 17alpha OH pregnenolone

Question 20

What is the role of 3beta HSD?

Answer 20

Dual function with dehydrogenase and isomerase NAD-dependent isoforms
Type 1: placenta and skin
Type 2: adrenals and gonads
Mutations in type 2 cause congenital adrenal hyperplasia

Question 21

What catalyses pregnenolone to progesterone?

Answer 21

3beta HSD

Question 22

What is the role of 17beta HSD?

Answer 22

Converts delta4 androstenedione to testosterone and oestrone to 17beta oestradiol
Referred to as a sex steroid activating/inactivating switch
11 known isoforms. Not all understood.
Mutations in 17betaHSD3 feminises 46XY babies

Question 23

What is congenital adrenal hyperplasia?

Answer 23

21-hydroxylase deficiency
Large adrenal glands and shortage of cortisol
Hypothalamus stimulates pituitary, produces ACTH, signals to adrenals to produce cortisol
Deficiency in CYP21 prevents production of cortisol. No negative feedback to hypothalamus, constant production of ACTH.
Results in androgen excess
Virilisation of females.
Degree of virilisation = degree of enzyme function loss

Question 24

What enzymes can cause CAH?

Answer 24

21 hydroxylase
11 beta hydroxylase
3 beta HSD
17 alpha hydroxylase

Question 25

Where are glucocorticoids synthesised?

Answer 25

Zona fasciculata and zona reticularis

Question 26

Name some effects of glucocorticoids

Answer 26

``` Brain: depression, psychosis Eyes: glaucoma Carbohydrate and lipid metabolism Adipose tissue distribution Bone and calcium metabolism Growth and development Immune system ```

Question 27

What effects the release of CRH from the hypothalamus?

Answer 27

Stress Diurnal rhythm Cytokines

Question 28

What are mineralocorticoids?

Answer 28

Synthesised in the zona glomerulosa Aldosterone is produced by the adrenals Salt and water homeostasis Mineralocorticoid receptor activation

Question 29

Describe mineralocorticoid receptor specificity

Answer 29

The same for mineralocorticoids and cortisol | Both exert the same effect

Question 30

What is apparent mineralocorticoid excess?

Answer 30

Severe hypertension, hypokalaemia, low renin and aldosterone levels. Caused by a block in cortisol to cortisone conversion. Plasma cortisone levels are undetectable. Normal circulating cortisol levels. Increased urinary THF/THE ratio and cortisol/cortisone 11betaHSD2 eliminated and cortisol freely binds MR (also mimicked in liquorice excess)

Question 31

What is the role of 11beta hydroxysteroid dehydrogenase?

Answer 31

Conversion of cortisol to cortisone and back 11betaHSD1: predominantly cortisone to cortisol, liver, adipose and bone 11betaHSD2: only cortisol to cortisone, kidney, colon and salivary gland

Question 32

What happens if cortisol levels are lowered?

Answer 32

Aldosterone activates the mineralocorticoid receptor

Question 33

Describe pre-receptor regulation by 11betaHSD

Answer 33

High levels of 11betaHSD2 present in the kidney All cortisol is converted to cortisone Only mineralocorticoid receptor activation is by aldosterone

Question 34

What is obesity-metabolic syndrome?

Answer 34

Prevalent 25% of UK BMI of 30+ Premature mortality Hypertension, insulin resistance, diabetes mellitus type 2, hyperlipidaemia, CVD, central obesity

Question 35

What is the link between 11betaHSD1 and adipogenesis?

Answer 35

Cortisol causes adipogenesis (Cushing's disease) Adipose cells in vitro grow most in the presence of cortisol Cortisone causes slight increase in growth (11betaHSD1) 11betaHSD1 inhibitor LJ2 prevents this Overexpression = obesity KO = poor glucose clearance

Question 36

What clinical drugs inhibit 11betaHSD1?

Answer 36

Amgen Biovitum Carbonexalone