Endocrinology: Physiology - The adrenal medulla and adrenal cortex

Question 1

Describe in brief the structure and function of the adrenal gland. What % of the gland does each portion represent?

Answer 1

Inner medulla responsible for catecholamine synthesis and secretion (epinephrine, norepinephrine, dopamine) 28%

Outer cortex responsible for steroid hormone synthesis and secretion, and consisting of layers:
- Zona glomerulosa (15%): mineralocorticoids (aldosterone), also produces new cortical cells
- Zona fasciculata* (50%): glucocorticoids
- Zona reticularis* (7%): sex steroids (androgens)

• both zone fasciculata and reticularis can produce glucocorticoids and sex steroids but this refers to their predominant production

Question 2

Describe the structure and function of the foetal adrenal cortex. What changes occur following birth?

Answer 2

20% permanent (adult) cortex
80% foetal adrenal cortex: produces androgens which are converted to oestrogens in the placenta

Following birth, foetal portion undergoes rapid degeneration

Question 3

Describe the blood flow of the adrenal gland

Answer 3

Arterial supply via small branches of phrenic and renal arteries, and the aorta
Venous drainage via central adrenal vein

Question 4

What is the effect of hypophysectomy on the various layers of the adrenal cortex?

Answer 4

Induces atrophy of zona fasciculata and reticularis

Initially function of zona glomerulosa is preserved due to action of angiotensin II
With longstanding hypopituitarism there is aldosterone deficiency due to absence of some pituitary factor that maintains responsiveness

Question 5

What is the effect of increased ACTH on the various layers of the adrenal cortex?

Answer 5

Hypertrophy of zona fasciculata and reticularis
Atrophy of zona glomerulosa

Question 6

What % of adrenal medullary cells secrete the various catecholamines?

Answer 6

90% secrete adrenaline
10% secrete noradrenaline

Question 7

Describe the five sympathomimetic effects of noradrenaline and adrenaline (including receptors which mediate these effects where relevant)

Answer 7

1. Positive inotropy and chronotropy (via B1)
2. Increased myocardial excitability
3. Vasoconstriction (via NA on a1) in most tissues
4. Vasodilation (via adrenaline on B2) in liver and skeletal muscles
5. Net decreased TPR (vasodilation > vasoconstriction)

Question 8

Compare and contrast the effects of noradrenaline vs adrenaline on: SBP and DBP, pulse pressure, HR, and cardiac output

Answer 8

NA: increased SBP and DBP, pulse pressured maintained, reflex bradycardia, decreased CO
Adrenaline: increased SBP and decreased DBP, widened pulse pressure, tachycardia, increased CO

Question 9

Describe seven metabolic effects of noradrenaline and adrenaline (including receptors which mediate these effects where relevant)

Answer 9

1. Increased BMR
2. Glycogenolysis in liver and skeletal muscle (via a and B receptors)
3. Increased insulin and glucagon via B-receptors, decreased insulin and glucagon via a-receptors
4. Initial hyperkalaemia (due to increased release from liver) with sustained hypokalaemia (due to increased uptake into skeletal muscle via B2-receptors)
5. Increased plasma lactate
6. Increased mobilisation of FFAs
7. Increased alertness

Question 10

How many times greater than normal resting values must the levels of adrenaline and noradrenaline be to exert its cardiovascular effects?

Answer 10

NA 5x normal resting
Adrenaline 2x normal resting

Question 11

Outline five effects of dopamine

Answer 11

1. Renal and mesenteric vasodilation
2. Vasoconstriction elsewhere (probably mediated via NA)
3. Positive inotropy (via B1)
4. Increased SBP, DBP unchanged
5. Natriuresis (may be via inhibition of Na+/K+ ATPase)

Question 12

How is secretion from the adrenal medulla regulated? What is the effect of emotional stress on catecholamine secretion?

Answer 12

Regulated via neural control: increased sympathetic discharge stimulates medullary secretion
Familiar emotional stress causes relative increase in NA secretion; unfamiliar stressors cause relative increase in adrenaline secretion

Question 13

What steroid hormones are secreted in physiologically significant amounts from the adrenal cortex? Which of these are secreted in free vs conjugated forms?

Answer 13

Mineralocorticoids: aldosterone (also deoxycorticosterone in similar amounts but is only ~3% as active as aldosterone)
Glucocorticoids: cortisol, corticosterone
Androgens: DHEA*, androstenedione

• majority conjugated with sulphate, other hormones tend to be released in free form

Question 14

Describe the difference in enzymes present between the layers of the adrenal cortex, and how this relates to the localisation of hormone production

Answer 14

Zona glomerulosa: contains aldosterone synthase (similar to 11B-hydroxylase in other zones)
Zona glomerulosa and reticularis: contain 11B-hydroxylase (which catalyses final stage of glucocorticoid synthesis) and 17a-hydroxylase (which catalyses sex hormone synthesis)
Zona fasciculata: contains more 3B-hydroxysteroid than zona reticularis (catalyses first step in glucocorticoid synthesis)
Zona reticularis: contains more of the required cofactors for 17a-hydroxylase, and contains adrenal sulfokinase which catalyses DHEA -> DHEAS

Question 15

What is the effect of ACTH on the adrenal cortex? Describe the intercellular signalling pathway utilised

Answer 15

Binds GPCR on plasma membrane of adrenocortical cells -> adenylyl cyclase activation -> increased cAMP -> increased production of pregnenolone and its derivatives
Over longer period also induces P450 enzymes involved in glucocorticoid synthesis

Question 16

What is the effect of angiotensin II on the adrenal cortex? Describe the intercellular signalling pathway utilised

Answer 16

Binds AT1 GPCR in zona glomerulosa -> phospholipase C activation -> increased protein kinase C -> increased conversion of cholesterol to pregnenolone, also facilitates aldosterone synthase -> increased aldosterone synthesis

Question 17

What is the cause of congenital adrenal hyperplasia?

Answer 17

Defects in enzymes leading to cortisol deficiency
Loss of negative feedback -> increased ACTH -> adrenal hyperplasia

Question 18

What are the two most common forms of congenital adrenal hyperplasia and what are the clinical syndrome observed in each? How are they treated?

Answer 18

21B-hydroxylase deficiency: decreased cortisol and aldosterone causes hypovolaemic hyponatraemia, ACTH feedback causes increased production of androgens leading to virilisation (adrenogenital syndrome)
11B-hydroxylase deficiency: virilisation and increased accumulation of 11B-deoxycortisol/11B-deoxycorticosterone (exerts mineralocorticoid effect -> hypernatraemia and HTN)

Treat with glucocorticoids: resolves deficiency and reduces ACTH feedback causing increased sex hormone production

Question 19

Glucocorticoid and mineralocorticoid activity of corticosterone relative to cortisol

Answer 19

Glucocorticoid: 0.3
Mineralocorticoid: 15

Question 20

Glucocorticoid and mineralocorticoid activity of aldosterone relative to cortisol

Answer 20

Glucocorticoid: 0.3
Mineralocorticoid: 3000

Question 21

Glucocorticoid and mineralocorticoid activity of deoxycorticosterone relative to cortisol

Answer 21

Glucocorticoid: 0.2
Mineralocorticoid: 100

Question 22

Glucocorticoid and mineralocorticoid activity of cortisone relative to cortisol

Answer 22

Glucocorticoid: 0.7
Mineralocorticoid: 0.8

Question 23

Glucocorticoid and mineralocorticoid activity of prednisolone relative to cortisol

Answer 23

Glucocorticoid: 4
Mineralocorticoid: 0.8

Question 24

Glucocorticoid and mineralocorticoid activity of dexamethasone relative to cortisol

Answer 24

Glucocorticoid: 25
Mineralocorticoid: 0

Question 25

Glucocorticoid and mineralocorticoid activity of 9a-fluorocortisol relative to cortisol

Answer 25

Glucocorticoid: 10
Mineralocorticoid: 125

Question 26

Which glucocorticoid has no mineralocorticoid activity?

Answer 26

Dexamethasone

Question 27

Which endogenous glucocorticoid (not aldosterone) has the highest mineralocorticoid activity?

Answer 27

Deoxycorticosterone
(9a-fluorocortisol has slightly higher mineralocorticoid activity but is a synthetic corticosteroid)

Question 28

Where are glucocorticoids produced? Which enzymes are important?

Answer 28

In zona fasciculata predominantly (also in reticularis)
Important hormones include 11B-hydroxylase and 3B-hydroxysteroid

Question 29

How are cortisol and corticosterone transported? What is the difference in half-life

Answer 29

Cortisol predominantly bound to transcortin (corticosteroid-binding globulin, CBG) and to lesser degree albumin
Corticosterone predominantly free in plasma

Therefore cortisol has longer half-life (60-90mins) compared with corticosterone (50mins)

Question 30

What is the normal plasma cortisol level?

Answer 30

13.5ug/dL (375nmol/L)

Question 31

What two factors increase CBG and what three factors decrease it?

Answer 31

Increased CBG: oestrogens, pregnancy
Decreased CBG: cirrhosis, nephrosis, multiple myeloma

Question 32

What is the effect of increased CBG on free cortisol and ACTH levels?

Answer 32

More free cortisol becomes bound, reducing free cortisol level
Feedback to pituitary causes increased ACTH level, which stimulates cortisol production to increase free plasma level back to normal
Results in increased total plasma cortisol without symptoms of glucocorticoid excess (as bound cortisol is physiologically inactive)

Question 33

Describe the metabolism and excretion of cortisol

Answer 33

Hepatic metabolism via glucuronidation
Excreted in urine predominantly, 15% in faeces

Question 34

Describe the mechanism of action of cortisol

Answer 34

Binds to glucocorticoid receptors
Receptor-steroid complex then acts as a transcription factor

Question 35

Describe ten physiologic effects of cortisol

Answer 35

1. Increased protein metabolism
2. Increased plasma BSL via:
   - Increased hepatic glycogenesis and gluconeogenesis
   - Increased glucose-6-phosphatase activity
   - Anti-insulin activity
3. Increased lipids and ketones in diabetics only (in normal individuals this is countered by increased insulin in response to raised BSL)
4. Permissive action: allows activity of glucagon and catecholamines
5. Needed for vascular reactivity
6. Role in CNS function
7. Needed for excretion of water load
8. Haematopoietic changes:
   - Decreased circulating eosinophils and basophils
   - Increased circulating neutrophils, platelets and RBCs
9. Inhibit ACTH release via negative feedback
10. Accelerate surfactant maturation in foetal lung

Question 36

Give two examples of ACTH-dependent causes of Cushing syndrome

Answer 36

ACTH-secreting pituitary tumours
Tumours of other organs (e.g. lung) secreting ACTH/CRH