7.16 Adrenal Gland Function and Dysfunction

Question 1

Where are the adrenal glands located?

Answer 1

They are pyramidal shaped glands that sit ontop of the kidneys.

The left is shaped like a semicircle while the right is shaped like a party hat

Question 2

Describe the structureof the adrenal gland

Answer 2

Like the pituitary, the adrenal gland can be thought of as two embryologically and functionally distinct glands that fused during development

There is an adrenal medulla (outer) and an adrenal cortex (inner)

Question 3

Compare the adrenal medulla to the adrenal cortex in terms of major functions

Answer 3

Adrenal medulla:

• A modified sympathetic ganglion
• Neurohormones
• Secretes catacholamines

Adrenal cortex:

• True endocrine gland
• Classical hormones
• Secretes steroid hormones

Question 4

Describe the major histological parts of the adrenal cortex and what each part is responsible for

Answer 4

“G.F.R”

Zona glomerulosa –> Aldosterone secretion

Zona fasciulata –> Glucocorticoids

Zone reticularis –> Sex hormones

(note there is some overlap between the zona glomeruosa and the zona fasciulata)

Question 5

Describe the Hypothalamic-Pituitary-Adrenal Axis and the main outputs from each component

Answer 5

• The hypothalamus secretes corticotrophin releasing hormone CRH which travels through the hypothalamic hypophyseal portal to the anterior pituitary
• The anterior pituitary gland (corticotroph cells) secrete adrenocortitotrophic hormone (ACTH) which travels through the blood to the adrenal glands
• The adrenal cortex cells respond by secreting cortisol
• Cortisol acts via a long negative feedback loop to the hypothalamus and the pituitary

Question 6

What are the main sex hormones from the adrenal cortex?

• What layers produce them?

Answer 6

Androgens, oestrogens, dehydroepiandosterone (DHEA)

They are produced primarily in the zona reticularis (but also in the fasciculata)

Question 7

What regions of the adrenal cortex produce cortisol?

• What is the trigger for secretion?

Answer 7

The primary zone is the zona fasciculata (but also in the zona reticularis)

• Cortisol production and secretion is trigger by the hypothalamic-pituitary-adrenal axis (HPAA)

Question 8

Where are the mineralocorticoids produced?

What stimulates it?

Answer 8

Only the zona glomerulosa produces the mineralocoriticoids (aldosterone)

• It is stimulated by the RAAS pathway and increasing levels of plasma K

Question 9

How is there a difference in what hormone the cells of the adrenal cortex produce?

Answer 9

Different zones of the cortex have slightly different cells as they each possess different enzymes that are able to cause the production of the different hormones

Question 10

What is the major common backbone for steroid hormone synthesis?

Answer 10

Cholesterol backbone which is converted to pregnenolone

Question 11

Draw the (simplified) pathway from cholesterol to the three steroid hormones (include enzymes)

Answer 11

• Purple = Classic female sex hormones
• Blue = Classic male sex hormones
• Green = Glucocorticoids
• Pink = Mineralocorticoid

(Note there a more steps/enzymes in between the ones shown)

Question 12

What is a major consequence of having a shared synthesis pathway?

Answer 12

They are chemically related leading to a possible cross over effect of their actions

Eg. Mineralocorticoid and Glucocorticoid receptor actions (especially if there is an excess amount of one of them)

Question 13

What are the higher brain centre functions that trigger/impact the tonic release of CRH from the hypothalamus?

Answer 13

• The circadian rhythm
• Stress

Question 14

What are the major functions of cortisol in the body?

Answer 14

• Immune system suppression
• Stimulates gluconeogenesis in the liver
• Muscle protein catabolism (substrate for gluconeogenesis)
• Enhances lipolysis of adipose tissue (Fatty acids for energy)
• Causes a negative calcium balance (decreases absorption, increases excretion and causes bone breakdown)
• Influences brain function
• Adaptation to stress

Question 15

CRH and ACTH have other functions on the body. What are these?

Answer 15

They have stress-related functions in the immune system and the nervous system:

• Inflammation and immune responses
• Inhibition of appetite (through urocortion, a brain neuropeptide)
• Signals for the onset of labour
• Mood disorder effects

Question 16

What is POMC (pro-opiomelanocortin)?

Answer 16

A large protein that exists in the pituitary glands that is the precursor protein to ACTH

Proteolysis yields several bioactive peptides (in addition to ACTH)

Question 17

What are the main bioactive products coming from the proteolytic cleavage of POMC in the pituitary gland?

Answer 17

POMC is broken down to form ACTH and beta endorphin (an endogenous opiod that blocks pain perception) as well as other fragments

Question 18

Post-translational processing of POMC outside the pituitary creates more active peptides. What are they?

Answer 18

Outside the pituitary gland, the ACTH produced is further cleaved to create alpha MSH (melanocyte stimulating hormone) which results in a decrease in food intake (appetite) and increase in skin melanin and may also affect mood.

Question 19

What are the melanocortins?

Answer 19

The family name for the MSH Hormones (and ACTH)

• They have a wide variety of effects which depend on the melanocortin receptor subtype that is stimulated

Question 20

Can a person survive without cortisol?

Answer 20

We can survive for several days only - once a stress is placed upon a person they will not cope.

It is essential for life as it helps the body cope with long-term stress

Question 21

Why is cortisol important for life and survival?

Answer 21

Because it helps the body cope with stress (Especially in the long term)

• It protects against hypoglycemia by stimulating catabolism of energy stores
• It is permissive (ie. required) for glucagon and catecholamine actions to occur

Question 22

Describe the use of cortisol as a therapeutic drug

Answer 22

Glucocorticoids are readily used as an anti-inflammatory drug

• It suppresses the immune system (transplant rejection prevention)
• Inhibits the inflammatory response (stings, allergies, asthma)

Question 23

What are the side effects of long term use of glucocorticoids (cortisol) as a therapeutic drug?

Answer 23

It results in the inhibition of the Hypothalamic-Pituitary-Adrenal Axis because of the impact of negative feedback.

Introduction of an exogenous cortisol causes negative feedback to the hypothalamus and pituitary to cease production of CRH and ACTH eventually leading to atrophy of cortisol secreting cells

It is important to taper off doses gradually to prevent the individual from going into adrenal crisis

Question 24

Are the steroid hormones stored in the adrenal gland?

Answer 24

NO

They are made on demand in response to stress and feedback pathways

Question 25

Fill in the following table for cortisol

Answer 25

Question 26

What are the two major causes of **hyperaldosteronism?** (primary and secondary)

Answer 26

* Primary hyperaldosteronism (**Conn’s syndrome** - when the adrenal gland is excessively producing them) * Secondary hyperaldosteronism (RAAS) - over stimulation of the adrenal glands due to the Renin-Angiotensin-Aldosterone System

Question 27

What are the consequences of hyperaldosteronism?

Answer 27

* Hypernatremia (increased Na retention) * Hypokalemia * Hypertension (Na and water imbalances)

Question 28

If a person has excess cortisol in their system, what are they said to have?

Answer 28

Cushing's syndrome

Question 29

What are the 4 major causes of **Cushing's syndrome?** (Hypercortisolism)

Answer 29

* Primary adrenal cortex tumours automously secreting cortisol * Secondary **pituitary tumour (CUSHING'S DISEASE)** that autonomously secretes ACTH * Hyperstimulation by CRH or ACTH by some other means * Iatrogenic hypercortisolism by excess cortisol therapy

Question 30

What are the major consequences of hypercortisolism (Cushing's syndrome)

Answer 30

* Excess glucose * Protein shortage * Abnormal fat distribution

Question 31

What is the major causes of **adrenogenital syndrome**? (Excess androgen and oestrogen)

Answer 31

Lack of enzyme in the cortisol steroidogenic pathway (the main cause is lack of 21-hydroxylase shunting more precursor to the sex hormone pathway)

Question 32

What are the consequences of adrenogenital syndrome?

Answer 32

Inappropriate masculinisation (except in adult males)

Question 33

What is the major treatment for adrenogenital syndrome?

Answer 33

Treat by giving exogenous cortisol/glucocorticoids This repairs the deficiency in the glucocorticoids and mineralocorticoids as well as providing the negative feedback to inhibit ACTH (reducing steroid secretion and thus reducing adrenogen/oestrogen secretion)

Question 34

What are the main signs and symptoms of Cushing's Disease?

Answer 34

* Excess gluconeogenesis leading to hyperglycemia thus it **mimics diabetes** * Muscle protein breakdown and lipolysis leads to **wasting** * Paradoxical **fat deposits** in the neck, trunk and face due to an increase in appetitte * Straie * Moon Face * Excess glucocorticoid has effect on mineralocorticoid receptor activity leading to salt and water retnetion, oedema, weakness and hypertension * Bone resorption leads to osteoporosis * Mood elevation and then depression, difficulty learning and with memory * Poor wound healing and bruisability (ecchymoses)

Question 35

Describe the differences, and draw the pathway for primary and secondary pathologies. What is the main way to differentially diagnose them? * Primary hypersecretion due to problem with the adrenal cortex * Secondary hypersecretion due to pituitary problem * Secondary hypersection due to a hypothalamic problem

Answer 35

Main means of differentiation is to look at the relative levels of cortisol, ACTH and CRH

Question 36

Adrenocortical insufficiency results in **hyposecretion** of the steroid hormones; it is less common than hypersecretion. What is the main **primary** adrenal insufficiencies?

Answer 36

**Addison's disease** = this is an attack on the **whole** adrenal cortex leading to hyposecretion of **all** the steroid hormones

Question 37

What are the major effects seen in Addinson's disease?

Answer 37

* Autoimmune destruction of the adrenal cortex * Decreased aldosterone (hyponaturemia, hyperkalemia- risk of arrhythmia, hypertension) * Decreased cortisol (decreased stress response and hypoglycemia)

Question 38

What is a major hereditary cause of hypocoritoslism and hyperaldosteronism?

Answer 38

Steroidal **enzyme deficits** These cause an increase in the androngens and **adrenogenital syndrome**

Question 39

What secondary deficits can occur to cause adrenocortical insufficiency (hyposecretion)?

Answer 39

Only **cortisol is affected** by secondary deficits * Abnormal hypothalamus or pituitary problems leading to decreased CRH or ACTH. * Mineralocorticoids are not affected by this pathway

Question 40

Describe the adrenal medulla in terms of function and secretions

Answer 40

* It is a modified part of the SNS (ie. it is the **post-ganglionic cell)** * It is involved in the flight-or-fight response * It releases **Catecholamines** * Adrenaline * **​**Noradrenaline * Dopamine

Question 41

What is the main cell of the adrenal medulla important for the neurohormonal effect?

Answer 41

The **chromaffin cell** It secretes and **stores** the neurohormones

Question 42

What is important about adrenaline synthesis in terms of the adrenal medulla

Answer 42

The enzyme that converts noradrenaline to adrenaline, **Phenlethanolamine-N-methyltransferase PMNT,** is **only present in the adrenal medulla**

Question 43

What are the main actions of the adrenomedullary catecholamines?

Answer 43

* Flight or fight: ↑HR, ↑Contractility, ↑TPR, ↑BP * Metabolism: ↑glucose and free-fatty acid release, ↑BMR * Central: ↑arousal and ↑alertness * Stress responses

Question 44

What are the hyposecretory catecholamine disorders?

Answer 44

There are none recognised

Question 45

What are the hypersecretory catecholamine disorders?

Answer 45

**Pheochromocytoma** (tumour of the adrenal medulla) * These are very rare and potentially deadly (hypertension) * The only treatment is removal of the tumour

Question 46

What are the 2 broad types of stresses that disrupt homeostasis?