Disorders of adrenocortical function

Question 1

Explain the inner structure of the adrenal gland

Answer 1

Think of the adrenal gland as having two main parts:

The outer part (Cortex): This part makes different types of steroid hormones:

Glucocorticoids (like cortisol): These help with things like stress response and managing blood sugar.
Mineralocorticoids (like aldosterone): These help control blood pressure and the balance of salts like sodium and potassium.

Sex steroids (like testosterone): These contribute to sexual characteristics.
The inner part (Medulla):
This part makes different hormones too:

Epinephrine (also known as adrenaline) and Norepinephrine (also known as noradrenaline): These are the “fight or flight” hormones that get your body ready for action

Question 2

How are different steroid hormones made in the sex organs

Answer 2

Starting point: Cholesterol gets turned into Pregnenolone.

Different paths: From Pregnenolone, things branch out:

Ovaries:
-Pregnenolone can become Progesterone, which then leads to Aldosterone (mainly in the adrenal gland’s zona glomerulosa).
Adrenal Gland (mainly zona fasciculata): Follow the orange arrow. Pregnenolone can also become 17 OH Pregnenolone, which can then lead to Cortisol.

Testes: 17 OH Pregnenolone can also become Androgens, and then specifically Testosterone. Testosterone can then be changed into other hormones like Oestrogens (with the help of an enzyme called Aromatase) or Dihydrotestosterone.

Question 3

Explain actions of cortisol

Answer 3

-increases plasma glucose levels
-inc gluconeogenesis
-dec glucose utilisation
-inc glycogenesis
-inc glycogen storage
-inc lipolysis
-provides energy

-proteins are catabolised
-releases amino acids
-Na+ and H20 retention
-maintains BP
-anti inflammatory
-increased gastric acid production

Question 4

Explain cushing’s syndrome

Answer 4

Clinical features of chronic exposure to excessive levels of the steroid hormone cortisol
-first described by Harvey cushing in 1932
-first person to describe the association between pituitary gland tumours and signs of excess steroid hormones

Question 5

Explain the epidemiology of cushing’s disease

Answer 5

-occurs in every 2 out of 1000 000
-3-15 female : 1 male
-onset at 20-40 years old

Question 6

Discuss definitions of Cushing’s syndrome and cushings disease

Answer 6

Cushing’s syndrome- excess cortisol in the blood

Cushing’s disease- excess cortisol in the blood due to an ACTH secreting pituitary tumour

Question 7

How does the protein (POMC) break down into smaller hormones

Answer 7

N-Terminal Fragment: This is one of the pieces cut off the beginning. It can be further processed into γ-MSH.

ACTH: This is another piece. It can be further cut into α-MSH and CLIP.

β-LPH: This is yet another piece. It can be further cut into γ-LPH and β-Endorphin. The γ-LPH can be further processed into β-MSH.

Question 8

List and explain the 3 stages of the investigation of cushing’s disease

Answer 8

1) screening:
-urinary free cortisol
-diurnal rhythm
-overnight dexamethasone suppression test

2) confirmation of the diagnosis:
-los dose dexamethasone suppression testing

3) differentiation of the cause:
-high dose dexamethasone suppression testing
-ACTH
-CRH test
-Localisation

Question 9

explain a differential diagnosis

Answer 9

1) Cushing’s disease:
-pituitary adenoma

2) Adrenal tumour:
-benign
-malignant

3) ectopic ACTH production:
-benign
-malignant

Question 10

List laboratory features

Answer 10

-hypokaleamia
-metabolic alkalosis
-hyperglycaemia

Question 11

How does aldesterone work

Answer 11

Aldosterone arrives: It travels to the cell.

Finds its receptor: Aldosterone binds to a specific protein inside the cell called the Mineralocorticoid Receptor. Think of it like a key fitting into a lock.

Signal is sent: When aldosterone binds to the receptor, it causes something to happen.
More sodium comes in: This signal leads to an increase in sodium (Na +) entering the cell (shown going into the blue oval labeled “Na+”).

Something blocks cortisol: The diagram also shows something called “11 β Hydroxysteroid Dehydrogenase 2”. This acts to prevent another similar hormone, cortisol , from binding to the mineralocorticoid receptor.
This makes sure aldosterone can do its job properly.

Question 12

How does the body handle cortisol and cortisone with MR

Answer 12

You have cortisol and cortisone. They are very similar.
The MR (where aldosterone usually binds, as we saw before) can also bind to cortisol.
You have two enzymes:

11$\beta$-HSD 2 changes cortisol into cortisone. Cortisone doesn’t bind well to the MR. This is like having a bodyguard that transforms cortisol into a less threatening form so it doesn’t bother the MR too much.

11$\beta$-HSD 1 can change cortisone back into cortisol.

Question 13

How to localise different glands

Answer 13

Pituitary
– MRI
– Inferior Petrosal sinus sampling IPSS

Adrenal
– CT or MRI

Ectopic
– Octreotide Scan
– ACTH Sampling

Question 14

Explain treatment for for adrenal adenoma, adrenal cancer and pituitary

Answer 14

1) Adrenal adenoma:
-surgery
-cortisol production blockers (e.g. metyrapone, ketoconazole)

2) Adrenal cancer:
-DXT three field or gamma knife
-CXT mitotane

3) Pituitary:
-TSS
-DXT
-following treatment patients may require replacement of other pituitary hormones too

Question 15

Explain treatment for steroid replacement therapy

Answer 15

-patients need to have steroid replacement tablets at the time of and following surgery

-the adrenal tumour suppresses the function of the normal gland

-many will not need the steroid tablets long term

Question 16

Explain Addison’s disease clinical features

Answer 16

gTiredness
gWeakness
gAnorexia
gWeight loss
gPostural hypotension
gMyalgia
gSalt Craving
gNausea Vomiting
gHyperpigmentation
gVitiligo

gHyponatraemia
gHyperkalaemia
gAcidosis
gHypercalcaemia
gHypoglycaemia
gIncreased urea and
creatinine
gEosinophilia
gLymphocytosis

Question 17

Discuss causes of Addison’s syndrome

Answer 17

gAutoimmune
gTB
gSteroid Withdrawal
gMetastases
gInfiltration
– Amyloid
– Haemochromatosis
gWaterhouse-
Freidrichson
gApoplexy
gInfection
– Fungal histoplasmosis
– Viral HIV
– Bacterial TB
gEnzyme defect
– Congenital Adrenal
hyperplasia
– Adrenolucodystrophy
– Adrenomyolneuropathy
gDrugs

Question 18

Discuss investigations for adrenal insufficiency

Answer 18

g 9 AM cortisol
g ACTH
g Electrolytes
g FBC
g Adrenal imaging
g Adrenal anti-bodies

g Investigations for other causes of
adrenal failure
g Infection screen
g Imaging for cancer
g Biochemical testing
for enzyme
deficiency

Question 19

List dynamic tests for adrenal insufficiency

Answer 19

-short synacthen (250mg)
-long synacthen test (1mg)
-insulin tolerance test
-glucagon test

Question 20

Explain the dosage needed for hydrocortisone and fludrocortisone

Answer 20

Hydrocortisone:
-10mg 5mg 5mg
-mimics the diurnal rhythm
-last dose before 6pm

Fludrocortisone:
-50-200mcg o.d

Question 21

Explain 21-hydroxylase deficiency (CAH)

Answer 21

-commonest form of CAH
-incidence 1:10 000 live births
-autosomal recessive
-HLA linked
Increased incidence in Yupik Eskimos

Question 22

How does our body make different types of steroid hormones

Answer 22

It all starts with Cholesterol. This is the basic ingredient.
Cholesterol gets turned into Pregnenolone. This is like the first major step.
From Pregnenolone, there are a few different paths that can be taken (shown by the yellow arrows).
One path leads to:

Progesterone
Then Deoxycorticosterone
Finally ending in Aldosterone. Aldosterone helps control blood pressure.
Another path from Pregnenolone goes to:

17-OH Pregnenolone
Then DHEA, which can eventually become Sex steroids (like estrogen and testosterone).
There’s also another branch that goes from 17-OH Pregnenolone to:

17-OHP
Then 11-deoxycortisol
Finally ending in Cortisol. Cortisol helps with stress response and many other things.

Question 23

Explain the role of ACTH in making steroid hormones

Answer 23

Cholesterol is produced
The arrow pointing towards Deoxycorticosterone and the blocked path after it (with the crossed-out symbol) suggests that something might be hindering the production of hormones down that specific path (which leads to Aldosterone).
The red shape near “Sex steroids” might be indicating an increased production or a different focus in that area.
ACTH at the top usually means that this whole process is being stimulated by this hormone. ACTH tells the body to make these steroid hormones.

Question 27

Explain 2–1 hydroxylase defiency (classical)

Answer 27

-excess sex steroids cause: -virilisation, hirsutism, premature adrenarche, infertility -no aldosterone, hence salt losing crisis (hyperkalaemia, hypotension) -high DOC -which is an agonist at MC receptors -hypertension and hypokalaemia

Question 28

Explain 11B-hydroxylase deficiency (non classical)

Answer 28

-accounts for approx 5% of reported CAH -incidence 0.5:100 000 live births -autosomal recessive -increased in Moroccan Jews (1:6000 live births) -HLA linked

Question 29

Describe the different pathways to making steroid hormones

Answer 29

One path goes from Cholesterol to Pregnenolone, then Progesterone, then Deoxycorticosterone, Corticosterone, and finally Aldosterone. Aldosterone helps control salt and water balance in the body. Another path goes from Pregnenolone to 17-OH Pregnenolone, then DHEA, which can then become Sex steroids (like estrogen and testosterone). There's also a path from 17-OH Pregnenolone to 17-OHP, then 11-deoxycortisol, and finally Cortisol. Cortisol helps with stress and other functions.

Question 30

Discuss synacthen test and prednisolone suppression

Answer 30

1) Synacthen test: -no cortisol rise -increased 17OH progesterone levels 2) Prednisolone suppression: -Androgens should fall into normal range

Question 31

Explain treatment for 11B-hydroxylase deficiency (non classical)

Answer 31

Both entities comprise a spectrum of disease – partial deficiencies complicate matters. -Rx of 11b- and 21- hydroxylase deficiency lies mainly in the use of glucocorticoid therapy – To replace cortisol – To inhibit ACTH production, reducing adrenal testosterone production -Surgery to virilised female genitalia. - Treatment of Mother to prevent foetal Virilisation - Fludrocortisone is used to replace absent mineralocorticoid activity

Question 32

Describe aldosterone

Answer 32

-produced in the zonal glomerulosa of the adrenal cortex -acts on the kidney via receptor binds glucocorticoids with equal affinity -intranuclear receptor (type 1)

Question 33

How does Aldesterone work

Answer 33

Aldosterone pointing towards a Mineralocorticoid Receptor. Aldosterone needs to bind to this receptor to do its job. When Aldosterone binds to the receptor, it causes something to happen. it's influencing what's happening with Na+ (sodium). "Na+" likely represents inside a cell, seems to be a channel or pump. The diagram also shows Cortisol and Cortisone. Notice how Cortisol is pointing towards the receptor as well, but there's also something labeled "11β Hydroxysteroid Dehydrogenase 2". This is an enzyme that can change Cortisol into Cortisone. Cortisone doesn't bind as well to the Mineralocorticoid Receptor as Aldosterone does. This is a way for the body to make sure Aldosterone can do its job on this receptor without being overpowered by Cortisol. The "H+" nearby might be related to other processes happening.

Question 34

How does the kidney control aldosterone

Answer 34

the Glomerulus, Proximal Convoluted Tubule, Loop of Henlé, Distal Convoluted Tubule, and Collecting duct. These are like different sections of the kidney's filtering system. You also see blood vessels: the Afferent Arteriole (blood going in) and the Efferent Arteriole (blood going out) of the glomerulus. There are some arrows. The black arrows seem to show the flow of something (likely blood or fluid). The yellow arrows pointing towards the "Renal Control of Aldosterone" title might indicate factors that influence Aldosterone production or action in the kidney.

Question 35

How does the kidney help control aldesterone production

Answer 35

There are parts of the kidney called the Macula Densa and Juxtaglomerular Cells that are close to each other. These cells can sense things like low salt levels or low blood pressure in the incoming blood (Afferent Arteriole). When they sense this, the Juxtaglomerular Cells release a signal (think of it as a "hey, we need more Aldosterone!") This signal eventually leads to the adrenal glands (not shown in detail here) making more Aldosterone. Aldosterone then tells the kidney to hold onto more salt and water, which helps increase blood pressure and salt levels back to normal.

Question 36

Explain control of aldosterone release

Answer 36

1) The liver makes a substance called Angiotensinogen. 2) When blood pressure is low (BP), or there's low salt (Δ Na+), the kidney releases an enzyme called Renin 3) Renin acts on Angiotensinogen and changes it into Angiotensin I. 4) Then, an enzyme called ACE (found in the lungs and kidneys) changes Angiotensin I into Angiotensin II. 5) Angiotensin II then tells the adrenal glands (part of the kidney system) to release Aldosterone.

Question 37

Explain aldosterone syndromes

Answer 37

gPrimary Excess: – High Aldosterone – Low Renin gConn’s Syndrome gBilateral Adrenal Hyperplasia gSteroid Treatable hypertension gAldosterone producing adrenal carcinoma gSecondary Excess – High Aldosterone – High Renin gWith Hypertension: – Renal artery stenosis – Renin Secreting Tumour – Malignant nephrosclerosis gNormal BP – CCF – Cirrhosis – Nephrotic syndrome – Dehydration

Question 38

What is the relationship between cortisone and cortisol in relation to blood pressure

Answer 38

Cortisone can be turned into Cortisol by an enzyme called "11β Hydroxysteroid Dehydrogenase 1". Cortisol can be turned back into Cortisone by another enzyme called "11β Hydroxysteroid Dehydrogenase 2". Too much Cortisol activity (perhaps because it's not being turned into Cortisone enough) can lead to "Steroid Responsive Hypertension" (high blood pressure that responds to steroids).

Question 39

Discuss Conn’s treatment

Answer 39

-Spironolactone/Eperelone -Amiloride / Triampterine -Potassium Supplementation -Treatment of the primary tumour -Surgery

Question 40

Give a summary of this lecture

Answer 40

1) Adrenal consists of 2 organs: -adrenal cortex -adrenal medulla 2) Adrenal over activity can be: -crushing’s syndrome -conn’s syndrome -adrenal hyperplasia 3) adrenal under activity: -Addison’s disease -CAH -secondary adrenal failure