Lab Investigation of Endocrine Disorders

Question 1

Hypothalamic Pituitary Axis

Answer 1

1. TRH is secreted from the hypothalamus will bind to the anterior pituitary gland and cause the secretion of TSH
2. TSH is responsible for the production of thyroid hormones (T3 and T4) from the thyroid gland
3. These then act on multiple peripheral tissues.
4. Circulating T3 and T4 under the control of negative feedback control the hypothalamic-pituitary levels
5. T4 is the main hormone secreted by the thyroid gland, however T3 is more biologically active,

Question 2

How is T3 formed?

Answer 2

By the peripheral conversion from T4

Question 3

The function of thyroid hormones

Answer 3

• Essential for normal growth and development
• Increase BMR and affect many metabolic processes
• Synthesized in thyroid via a series of enzyme-catalyzed reactions
• These reactions begin with the uptake of iodide into the gland
• Synthesis and release is controlled by TSH
• T4 is the main hormone secreted by the thyroid but T3 is more active and is made by the conversion of T4 to T3
• Effects are mediated via activation of the nuclear receptor because

Question 4

Euthyroid

Answer 4

Normal range thyroid function

Question 5

Hypothyroid

Answer 5

Below average function

Question 6

Hyperthyroid

Answer 6

Above average function

Question 7

Primary hyper/hypothyroidism

Answer 7

Dysfunction is in the thyroid gland

Question 8

Secondary hyper/hypothyroidism

Answer 8

Problem with the pituitary

Question 9

Tertiary hyper/hypothyroidism

Answer 9

A problem in the hypothalamus

Question 10

Hyperthyroidism

Answer 10

• Excessive production of thyroid hormones = thyrotoxicosis
• Clinical features: weight loss, heat tolerance, palpitations, goitre, eye damage. In extreme cases, thyroid storm also occurs.

Question 11

Causes of hyperthyroidism

Answer 11

• Graves’ disease - most common
• Toxic multinodular goitre
• Toxic adenoma
• Secondary causes can include excess TSH production which is rare

Question 12

Thyrotoxicosis

Answer 12

Excessive production of thyroid hormones

Question 13

Hypothyroidism

Answer 13

• Deficient production of thyroid hormones
• Clinical features: weight gain, cold intolerance, lack of energy, goitre. Congenital development abnormalities
• Investigations: raised TSH, and reduced T4. Reduction in TSH and T4 suggests a secondary hypothyroidism which means it is to do with hypo-functionality of the pituitary gland

Question 14

Causes of hypothyroidism

Answer 14

• Auto-immune thyroiditis = Hashimoto’s
• Via thyroid peroxidase antibodies
• Iodine deficiency
• Toxic adenoma
• If it is secondary, it can be lack of TSH.

Question 15

Division of the adrenal gland

Answer 15

• Zona Glomerulosa
• Zona Fasciculata
• Zona Reticularis

Question 16

Function of the Zonas of the adrenal cortex

Answer 16

All three are responsible for synthesising different types of hormones.
ZG = responsible for minerocorticoids
ZF = responsible for glucocorticoids
ZR = responsible for adrenal androgens

Question 17

What substrate do the hormones start off with?

Answer 17

Start with the same substrate which is cholesterol, and they then follow different pathways with different enzymes that help them differentiate.

Question 18

How does functional zonation of the cortex occur?

Answer 18

• Blood flows from the cortex to the inner medulla.
• Layer specific enzymes are responsible for steroid synthesis in one layer and can inhibit different enzymes in subsequent layers.
• Results in functional zonation of cortex with different hormones made in each layer

Question 19

Which gene is absent in congenital hyperplasia?

Answer 19

CYP21A

Question 20

What is the function of CYP21A?

Answer 20

A gene fro 21-hydroxylase which is the enzyme responsible for converting progesterone into aldosterone.

Question 21

Aldosterone

Answer 21

• A mineralocorticoid
• The function is to balance the water and salt levels in the body in order to maintain plasma volume which is linked to maintenance of blood pressure over a long time
• It maintains extracellular water levels by reabsorbing Na+ from the kidneys and therefore water follows as well due to osmosis.
• It is signalled via a drop in blood pressure and therefore blood volume and the RAAS system.

Question 22

Cortisol

Answer 22

• Glucocorticoids
• Function to control metabolism and immune function
• Stress increases release but minimal levels are essential for normal function

Question 23

Action of cortisol on the CVS

Answer 23

• Very important for blood pressure
• No cortisol means low blood pressure
• This is because it counteracts the effects of NO
• Therefore, prevents too much vasodilation from occurring

Question 24

Action of cortisol on glucose metabolism

Answer 24

• Acts to spare glucose which means it allows to maintain high glucose levels
• It will promote insulin resistance in skeletal muscle
• This is an adaptive response in order to preserve glucose and use other energy sources such as fat.
• Promotes gluconeogenesis by the liver and promotes the oxidation of fatty acids
• These effects will lead to an increase in blood glucose levels and therefore promoting insulin secretion which will promote lipogenesis
• Therefore, the 2 ways to counteract each other, this is why excess cortisol can lead to fat deposition in certain areas of the body.

Question 25

How is cortisol secretion controlled?

Answer 25

• Synthesis and release regulated by HPA axis

- CRH and ACTH

Question 26

How is aldosterone secretion controlled?

Answer 26

Controlled by RAAS

Question 27

How are adrenal androgens controlled?

Answer 27

ACTH and not gonadotrophins

Question 28

Cortisol and circadian rhythm

Answer 28

• Cortisol secretion in a circadian rhythm which means a random plasma cortisol reading would not work.
• It would not exclude abnormalities unless way outside the normal range.
• The levels typically rise in the morning
• Therefore, to study levels of cortisol a 24-hour urine sample is needed.

Question 29

ACTH receptor

Answer 29

Present on the adrenal glands: a Gs protein-coupled receptor, so via cAMP stimulates cholesterol uptake and steroid synthesis.

Question 30

Conn’s disease

Answer 30

• Aldosterone excess
• This leads to hypertension and NOT hypernatremia because it reabsorbs both sodium and water.
• Secondary hyperaldosteronism can be caused by anything that stimulates the RAAS system
• Kidney enzymes convert cortisol to cortisone, which prevents the activation of the mineralocorticoid receptors by cortisol.
• Therefore, anything that inhibits this enzyme could produce hyperaldosteronism

Question 31

Cushing’s syndrome

Answer 31

• Cortisol excess
• This is caused by anything that leads to excess cortisol.
• Whereas Cushing’s disease is caused by an adenoma in the pituitary gland.
• ACTH secreting tumours are secondary, and negative feedback is still present.
• However, because the mass of cells has increased the threshold for negative feedback has also increased.

Question 32

Dexamethasone

Answer 32

An exogenous steroid, so it is used as an analogue for steroids.

Question 33

Action of dexamethasone

Answer 33

If injected in a normal person, low doses should suppress ACTH via negative feedback.

Question 34

Dexamethasone suppression test

Answer 34

• In Cushing’s disease: there is no suppression because due to the pituitary adenoma and the mass of the cells growing, the threshold to reach the negative feedback limit has also increased. A higher dose, however, should lead to suppression because the threshold has been reached.
• In an ectopic source of ACTH, there will be no suppression during both the higher and the lower dose. This is because the tumour must be somewhere else such as in the lungs and has nothing to do with the pituitary gland.
• In an adrenal tumour, at a low dose, there is no suppression and at a higher dose, there is suppression also.

Question 35

Adrenocortical insufficiency: Primary adrenocortical failure

Answer 35

Example: Addison’s disease is typically autoimmune.
- The adrenal cortex stops functioning and therefore, there is no production of both cortisol and aldosterone which leads to primary adrenal failure.

Question 36

Adrenocortical insufficiency: Secondary

Answer 36

• If there is impaired ACTH release such as during heat trauma, tumour, surgery or steroid withdrawal.
• The biggest symptom of Addison will be hypotension
• There will be high ACTH due to no negative feedback.

Question 37

Use of dynamic tests of adrenal function

Answer 37

This assesses the ability of adrenal glands to produce cortisol in response to ACTH.

Question 38

Short synacthen test

Answer 38

• Measure baseline cortisol at 9am and 30mins after 250ug of synacthen.
• In a normal person, this should lead to the production of cortisol.
• So if the cortisol level increases to more than 200nmol/L then adrenal insufficiency can be excluded.

Question 39

Long synacthen test

Answer 39

• The adrenal cortex shuts down if there is no ACTH production overtime.
• And therefore, in secondary adrenal insufficiency, a 3-day stimulation with synacthen is done.
• And if the levels do not increase it is present.