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PHASE 2A MEDICINE - ANJALI createdd > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

Where are the Parathyroid glands

A

4 situated posterior to the thyroid

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2
Q

What is the structure of PTH?

A

84 amino acid hormone derived from 115 residue pre-prohormone

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3
Q

Where is PTH secreted from?

A

Chief cells of the parathyroid glands

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4
Q

When is PTH secreted?

A

In response to reduced serum ionized levels of Ca++. Detected by specific G protein coupled, Calcium sensing receptors on the plasma membrane of the Parathyroid cells

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5
Q

Where are the 3 main sites of action of PTH?

A
  • Kidney
  • Bone
  • Gut (indirect)
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6
Q

What is the function of PTH?

A

To increase serum calcium levels

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7
Q

What are the actions/effects of PTH?

A

Kidney

  • Increases renal tubular reabsorption of Calcium
  • Decreases phosphate reabsorption (increasing excretion of phosphate)
  • Increases 1alpha hydroxylation of 25-OH Vit D –> 1,25-DihydroxyvitD3

Bone
-Increases bone remodelling: Bone resorption > bone formation. Increases osteoclastic resorption of bone . Rapid effect

Gut: indirect effect
-Increased intestinal Calcium absorption bc of increased 1.25(OH)2VitD. Slow response

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8
Q

What is the relationship between serum Calcium and PTH?

A
  • Small changes in serum calcium –> big changes in PTH

- decrease in Calcium by 10 –> 10 fold increase in PTH to 100

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9
Q

How does Calcium circulate in the body?

A
  • Protein bound (35-50%) - mainly Albumin
  • Complexes (5-10%)
  • Ionised (50-60%)
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10
Q

What is the only type of Calcium that can have a biological effect?

A

Ionised. This is the type that is under tight homeostatic control to remain within narrow limits

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11
Q

How is Calcium measured in the blood?

A

2 measures:

  • Total serum calcium
  • Corrected serum calcium
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12
Q

Why is corrected serum Calcium calculated / used?

A

Bc serum albumin affects the total serum calcium level. Hence low serum albumin could give a low total serum calcium (but not actually be hypocalcemia).

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13
Q

What is the formula for corrected serum calcium?

A

Total serum calcium + 0.02*(40-serum albumin)

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14
Q

What is the normal range of corrected calcium?

A

2.20-2.60mmol/L)

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15
Q

What are the clinical features and complications of hypocalcaemia?

A

Neuromuscular irritability + neuropscyhiatric manifestations:

  • Parasthesia
  • Tetany: Muscle spams (hands and feet, larynx, premature labour)
  • Circumoral numbness (absent or reduced sensation around mouth)
  • Cramps
  • Anxiety

Complications

  • convulsions
  • Seizures
  • Laryngeal stridor
  • Dystonia
  • Psychosis
  • Basal ganglia calcification
  • Cataracts
  • ECG abnormalities (Long QT interval)
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16
Q

What are the classical clinical signs of Hypocalcemia and how do you test for them?

A

-Chovstek’s sign
Tap over the facial nerve –> twitches/spasms of the ipsilateral facial muscles

-Trousseau’s sign
Inflate blood pressure cuff to 20mmHg above systolic for 5 mins –> induce tetanic spasm of the finger and wrist into ‘chefs kiss’ like

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17
Q

What ECG abnormalities may hypocalcemia lead to?

A

Prolonger QT interval

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18
Q

What are the causes of Hypocalcemia and what are the common UK causes?

A

Increased phosphate levels:

  • Chronic Kidney Disease (common)
  • Phopshate therapy

Hypoparathyroidism

  • Surgical -after neck exploration (thyroidectomy, parathyroidectomy) (common)
  • Congential deficiency (DiGeorge’s syndrome)
  • Idiopathic (rare)
  • Severe magnesium deficiency
  • Autoimmune: polyglandular type 1
  • Infiltration: Haemachromatosis, Wilson’s disease

Vitamin D deficiency

  • Osteomalacia/rickets
  • Vit D resistance

Resistance to PTH
-Pseudohypoparathyroidism

Drugs

  • Calcitonin
  • Biphosphates

Other

  • Acute pancreatitis (quite common)
  • Citrated blood in massive transfusion
  • Low plasma albumin (malnutrition, chronic liver disease)
  • Malabsorption (Coeliac disease)
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19
Q

What are the causes of Hypocalcemia?

A

Increased phosphate levels:

  • Chronic Kidney Disease (common)
  • Phopshate therapy

Hypoparathyroidism

  • Surgical -after neck exploration (thyroidectomy, parathyroidectomy) (common)
  • Congential deficiency (DiGeorge’s syndrome)
  • Idiopathic (rare)
  • Severe magnesium deficiency
  • Autoimmune: polyglandular type 1
  • Infiltration: Haemachromatosis, Wilson’s disease

Vitamin D deficiency

  • Osteomalacia/rickets
  • Vit D resistance

Resistance to PTH
-Pseudohypoparathyroidism

Drugs

  • Calcitonin
  • Biphosphates

Other

  • Acute pancreatitis (quite common)
  • Citrated blood in massive transfusion
  • Low plasma albumin (malnutrition, chronic liver disease)
  • Malabsorption (Coeliac disease)
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20
Q

What are the most common causes of Hypocalcemia?

A
  • Chronic Kidney Disease (most common)
  • Severe Vit D deficiency - common in UK
  • Osteomalacia - common in UK
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21
Q

What is osteomalacia and how would it show on an X ray?

A

Osteomalacia is bone softening due to insufficient mineralisation of the osteoid secondary to any process that results in vitamin D deficiency or defects in phosphate metabolism:

X ray:
Looser zones or pseudofractures, the classic radiographic findings of osteomalacia are radiolucent bands perpendicular to the cortex that incompletely span the diameter of the bone. Mild to moderate sclerosis may be seen at the margins of these pseudofractures. Looser zones result from the focal deposition of uncalcified osteoid and may precede other radiographic changes. They are seen in characteristic sites such as the femoral neck ( Figures 35-2 and 35-3 ) below the lesser trochanter (subtrochantric region), the superior and inferior pubic rami, and the axillary margins of the scapula, ribs, and posterior margins of the proximal ulnae. Complete fractures may occur in the weakened areas. Pseudofractures typically appear bilateral and symmetric, which is another characteristic sign of osteomalacia and may be easily missed at early stages.

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22
Q

What are the causes of Hypoparathyroidism?

A
  • Surgical
  • Radiation
  • Syndromes
  • Genetic
  • Autoimmune: isolated, polyglandular Type 1
  • Infiltration: haemochromatosis, Wilson’s disease
  • Magnesium deficiency
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23
Q

What syndromes carry hypoparathyroidism as a component?

A
  • Di george (only important one)
  • HDR
  • Kenney-Caffey
  • Sanjad-Sakatie
  • Kearns-Sayre
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24
Q

What is DiGeorge’s syndrome?

A

Developmental abnormality of third and fourth brachial pouches. Familial syndrome. Hypoparathyroidism is associated with intellectual impairment, cataracts and calcified basal ganglia. Occasionally with specific autoimmune disease

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25
Q

Why does Magnesium deficiency cause hypoparathyroidism?

A

Functional hypoparathyroidism - can synthesis PTH but cant get it out of the glands

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26
Q

What is Polyglandular Type 1?

A

reccessively Inherited autoimmune condition that affects many of body organs. Rare. Chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency are associated with this.

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27
Q

What is pseudohypoparathyroidism (cause, clinical features etc)?

A

End organ resistance to PTH. Due to a mutation in the Gs alpha protein sub unit, which is coupled to the PTH receptor. One phenotype is Type 1 is Albright Hereditary Osteodsytrophy.

Clinical features/ complications:

  • Abnormalities in Calcium metabolism
  • short stature
  • Short metacarpals
  • Subcutaneous calcification
  • Sometimes intellectual impairment
  • Variable degrees of resistance involving other Gs receptors may be seen (TSH,LH,FSH)
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28
Q

Describe the levels of PTH, Calcium and Phosphate you would expect in Pseudohypoparathyroidism. Describe whether the PTH response is appropriate/innappropriate?

A

PTH: High
Calcium: Low
Phosphate: High
PTH appropriate

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29
Q

How do you diagnose Hypocalcemia and diagnose the cause?

A
  • Clinical history and picture
  • Confirmed by corrected low serum Calcium

Additional tests:

  • Serum+urine creatinine (renal disease)
  • PTH levels in serum (find cause of the hypocalcemia)
  • Parathyroid antibodies (present in idiopathic hypo)
  • 25-hydroxy Vit D serum level (low in Vit D deficiency)
  • Magensium level (functional hyperparathyroidism)
  • X rays of metacarpals (short fourth metacarpals occur in pseudohypoparathyroidism)
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30
Q

What is the management of Hypocalcemia?

A

If Vit D deficency –> Colecalciferol

Other causes –> alpha hydroxylated derivates of Vit D bc of shorter half life and especially in renal disease

During Tx, plasma calcium must be monitored frequently to detect hypercalcemia

Severe hypocalcemia presenting as an emergency –> IV calcium gluconate may be required

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31
Q

Describe the levels of PTH, Calcium and Phosphate you would expect in Hypoparathyroidism. Describe whether the PTH response is appropriate/innappropriate?

A

PTH - low
Calcium - Low
Phosphate - High
PTH - inappropriate

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32
Q

Is hypocalcemia or hypercalcemia more common?

A

Hypercalcemia

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33
Q

Why is hypercalcemia more clinically important?

A
  • More common

- More emergency presentation

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34
Q

What can cause appeared hypercalcemia?

A
  • Tourniquet on for too long (cell necrosis –> release of intracellular calcium)
  • Blood sample too old and haemolysed
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35
Q

What are the symptoms / clinical features / complications of hypercalcemia?

A

General: Tiredness, malaise, dehydration , depression

Renal: renal stones calculi (if chronic). Polyuria or nocturia, haematuria and hypertension.

Bones: bone pain. Hyperparathyroidism mainly affects cortical bone. Advanced disease - bone cysts and locally destructive brown tumours. May be more apparent when there is coexisting Vit D deficiency

Abdoemen: pain, constipation, nausea

Chondracalcinosis and ectopic classification - occasional

Corneal calcification - long standing hypercalcemia but causes no symptoms

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36
Q

What is the difference between mild and severe hypercalcemia?

A

Mild: adjusted Calcium <3mmol/L. Frequently asymptomatic

Severe: adjusted Calcium >3mmol/L. Usually associated with malignant disease, hyperparathyroidism, CKD or Vit D therapy

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37
Q

Why can hypercalcemia cause polyuria?

A

Hypercalcemia reduces the renal tubules concentrating capacity - a form of mild nephrogenic diabetes insipidus.

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38
Q

What ECG abnormality would be seen in hypercalcemia?

A

Short QT interval

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39
Q

What are the causes of hypercalcemia?

A
  • Malignancy
  • Primary hyperparathyroidism
  • Thiazides
  • Thyrotoxicosis
  • Sarcoidosis
  • Familail hypocalciuiric/benign hypercalcaemia
  • Immobilisation
  • Mild Alkali
  • Adrenal insufficiency
  • Phaeochromocytoma
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40
Q

What are the most common causes of hypercalcemia?

A

> 90% of cases due to:

  • Primary hyperparathyroidism
  • Malignancies
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41
Q

What malignancies can cause hypercalcemia?

A

Bone metastasis

  • Myeloma
  • PTHrP
  • Lymphoma
  • Bronchus
  • Breast
  • Oesophagus
  • Thyroid
  • Prostate
  • Renal cell carcinoma
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42
Q

What is PTHrP and what is relevance clinically?

A

Protein member of Parathyroid hormone family that is secreted by mesenchymal stem cells. Necessary in fetal development but does not have clearly defined roles in the adult.

Occasionally secreted by cancer cells - breast, lung. When a tumour secreted PTHrP it can lead to hypercalcemia. PTHrP has the same N terminal of PTH –> hence can bind to same receptor - Type 1 PTHR (PTHR1). PTHrP can stimulate most of the actions of PTH

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43
Q

How do some cancers cause hypercalcemia?

A

Most cases associated with:
-PTHrP secretion by the tumour

Lymphoma
-Mass of lymphoma contains macrophage lineage cell –> expresses alpha hydroxylase –> convert Vit D to active form –> Increased intestinal absorption of Calcium

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44
Q

How can thiazide diuretics cause hypercalcemia?

A

Increase calcium reabsorption in the renal tubules

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45
Q

What can thyrotoxicosis cause - hypo or hypercalcemia?

A

Hypercalcemia

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46
Q

How can sarcoidosis cause hypercalcemia?

A

uncontrolled synthesis of 1,25-DihydroxyVitD by Macriophages (similar to lymphom). granulomatous disorder

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47
Q

How can thyrotoxicosis cause hypercalcemia?

A

Thyroid hormones are known to cause bone resorption and mobilizing calcium from bone to circulation leading to hypercalcemia. High levels of interleukin-6 (IL-6) seen in hyperthyroidism stimulates osteoclastic activity and alter osteoblast osteoclast coupling.

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48
Q

What is familial hypocalciuric/ benign hypercalcaemia

A

Familial hypocalciuric hypercalcemia (FHH) is an inherited disorder that causes abnormally high levels of calcium in the blood (hypercalcemia) and low to moderate levels of calcium in urine (hypocalciuric). People with FHH usually do not have any symptoms and are often diagnosed by chance during routine bloodwork. Weakness, fatigue, issues with concentration, and excessive thirst (polydipsia) have been reported by some people with FHH. Rarely, people with this disorder experience inflammation of the pancreas (pancreatitis) or a buildup of calcium in the joints (chondrocalcinosis).[1][2]

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49
Q

How can immbolisation cause hypercalcemia?

A

Spinal injuries in young men –> still bone turnover but suddenly immobilised

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50
Q

What is milk-alkali syndrome?

A

Excessive calcium intake. Characterised by Hypercalcemia and metabolic alkalosis

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51
Q

Is adrenal insufficiency a cause of hypocalcemia or hypercalcemia?

A

Hypercalcemia

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52
Q

How can Addison’s disease cause hypercalcemia?

A

Pathophysiology is attributed to increased calcium mobilisation from bone stores, increased gut absorption, decreased eGFR secondary to hypovolaemia - and so increased calcium reabsorption in the proximal tubule concurrent with sodium uptake. Corticosteroid replacement results in calciuresis and improves creatinine clearance so calcium levels rapidly normalise.

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53
Q

What is a phaeochromocytoma?

A

Rare tumour of the adrenal medulla composed of chromaffin cells - also known as phaeochromocytes. Releases excess catacholamines

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54
Q

Is phaeochromocytoma associated with hypo or hypercalemia ?

A

Hypercalcemia

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55
Q

How can phaeochromocytoma cause hypercalcemia?

A

Sporadic pheochromocytoma may secrete calcitonin and cause hypercalcemia by non-parathyroid hormone-mediated mechanisms. The potential is clearly present for confusion with multiple endocrine neoplasia, type 2 (medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism).

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56
Q

What are the types of hyperparathyroidism?

A
  • Primary
  • Secondary
  • Tertiary
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57
Q

What is secondary hyperparathyroidism?

A

Physiological compensatory hypertrophy of all parathyroids bc of hypocalcemia (such as occurs in CKD and Vit d deficiency).

  • PTH levels are raised
  • Serum Calcium low or normal

PTH levels fall after correction of the cause of hypocalcemia

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58
Q

What is tertiary hyperparathyroidism?

A

Development of autonomous parathyroid hyperplasia AFTER LONGSTANDING SECONDARY HYPERPARATHYROIDISM.
-Most often occurs in renal failure

  • Plasma Calcium and Phopshate both raised (Phsophate v high)
  • Parathyroidectomy necessary
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59
Q

What is Primary Hyperparathyroidism and what is the cause?

A

One or more of parathyroid glands produce too much PTH

Usually an incidental finding on blood - rare clinically present these days .

Causes

  • 80% due to single benign adenoma of the parathyroid glands
  • 15-20% 4 gland hyperplasia (may be part of MEN I or II)
  • <0.5% malignant

Cause: unknown

  • appears that adenomas are monoclonal
  • Hyperplasia may also be monoclonal
  • Chromosomal rearrangements in the 5’ regulatory end of the PTH gene have been identified
  • May be the inactivation of some tomour suppressor genes
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60
Q

What is the Treatment for primary hyperparathyroidism?

A

-no effective medical therapies at present

Surgery is indicated if:

  • symptoms of hypercalcemia
  • end-organ disease (renal stones, fractures, osteoporosis)
  • adjusted serum calcium >2.85mmol/L
  • Parathyroidectomoy of one of the glands
  • Removal of all four hyperplastic parathyroids

Main danger after op = hypocalcemia

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61
Q

How do differentiate between hypercalcaemia of malignancy and primary hyperparathyroidism?

A

PTH is low in Hypercalcemia of Malignancy

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62
Q

Describe the levels of PTH, Calcium and Phosphate you would expect in Primary Hyperparathyroidism. Describe whether the PTH response is appropriate/innappropriate?

A

-PTH high
-Calcium high
-Phosphate low
inappropriate PTH response

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63
Q

Describe the levels of PTH, Calcium and Phosphate you would expect in Hypercalcemia of malignancy. Describe whether the PTH response is appropriate/innappropriate?

A

-PTH low
-Calcium high
-Phosphate (difficult to predict, not helpful measurement)
Appropriate PTH response

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64
Q

Describe the levels of PTH, Calcium and Phosphate you would expect in Secondary hyperparathyroidism. Describe whether the PTH response is appropriate/innappropriate

A

-PTH high
-Calcium low
-Phosphate low
Appropriate PTH response

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65
Q

What is the role of calcium in the body?

A 
Formation of bone and teeth
Muscle contraction
Normal functioning of many enzymes
Blood clotting
Normal heart rhythm
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66
Q

Describe the anatomy of the pituitary?

A

1cm diameter. Located in the Sella tursica (behind the nose). On an MRI can see the distinct anterior and posterior pituitary gland with the optic chiasm above it.

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67
Q

What is the blood supply to the anterior pituitary gland?

A

Portal circulation:

- No arterial blood supply but receives blood through a portal venous circulation from the hypothalamus

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68
Q

What are the functions of the pituitary/ what aspects does it control?

A
  • Growth
  • Thyroid
  • Puberty
  • Steroids
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69
Q

How did they discover hypothalamic hormones?

A

Using bioassays from animal hypothalami. TRH was discovered first in 1969

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70
Q

Why did it take soo long to discover GHRH?

A

Because SMS blocked the bioassays. But in 1982 two humans presented with tumours that were ectopically producing GHRH–> causing Acromegaly

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71
Q

Describe the HP axis for Thyroid hormones?

A
  • Thyrotropin-releasing hormone (TRH) secreted in the Hypothalamus  travels via the Portal system to the pituitary
  • TRH stimulates the thyrotrophs to produce Thyroid Stimulating hormone (TSH)  secreted into the systemic circulation
  • TSH stimulates increased iodine uptake by the Thyroid and stimulates synthesis and release of: Thyroxine (T4) and Triiodothyronine (T3)
  • Increased levels of T3 and T4 inhibit the Hypothalamus and Pituitary (negative feedback)  TSH production is suppressed  reduced T3 and T4 secretion
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72
Q

What is the more active Thyroid hormone?

A

T3

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73
Q

What are the effects of TSH?

A
  • Increases serum levels of T3 and T4

- Conversion of T4 –> T3 in peripheral tissues

74
Q

What serum level is commonly checked in clinical practice?

75
Q

What would the levels of TSH be if your thyroid was knocked out (e.g Hashimotos Thyroiditis)?

76
Q

What would happen to the levels of TSH in Thyrotoxicosis?

A

Low bc of negative feedback

77
Q

What is the TSH level in primary hypothyroidism?

78
Q

What is the TSH level in thyrotoxocicosis?

79
Q

Describe the HP-Gonadal Axis?

A
  • Gonadotrophin releasing hormone (GnRH) is released from the hypothalamus in pulses
  • GnRH  stimulates LH and FSH release from the anterior pituitary
  • Men: LH stimulates testosterone production and FSH stimulates spermatogenesis
  • Women: LH stimulates oestroadodial, FSH important in ovulation
  • Negative feedback: Testosterone and Oestrodial negatively feedback to the anterior pituitary and hypothalamus
80
Q

What happens to this axis on the oral contraceptive pill?

A
  • Oestrogen negatively feedbacks –> Decrease LH/FSH secretion–> prevents ovulation
81
Q

Describe the HPA Axis?

A
  • Hypothalamus produces CRH
  • CRH stimulates ACTH release from anterior pituitary
  • ACTH stimulates cortisol release from Adrenal
  • Negative feedback: Cortisol inhibits ACTH and CRH release
82
Q

Describe the GH/IGF-1 Axis?

A
  • Hypothalamus produces GHRH  Stimulates pulsatile GH release from Ant pituitary
  • Hypothalamus produces Somatostain (SMS)  inhibits GH release for ant pituitary
  • GH stimulates release of IGF-1 from liver
  • Negative feedback: IGF-1 inhibits Hypothalamus
83
Q

When are your major pulses of GH?

A

At night. In between GH very low/ undetectable

84
Q

Describe the Prolactin axis?

A

Under negative control by the hypothalamus.- Hypothalamus secretes DOPAMINE –> inhibits Prolactin release from ant Pituitary

  • Only anterior hormone that is under:Tonic inbibition by Dopamine
  • Forward feedback loops to switch on prolactin production when breast suckling
85
Q

What happens to Prolactin levels if you cut the pituitary stalk?

A

No dopamine received from hypothalamus–> Prolactin levels go up bc No negative control

86
Q

In clinical practice do we mainly look at pituitary or hypothalamic hormones?

87
Q

What is the most common lesion of the pituitary?

A

BENIGN PITUITARY ADENOMA

88
Q

What can cause disease of the pituitary?

A
  • Benign pituitary adenoma
  • Craniopharyngiomas
  • Trauma (car accident –section pituitary stalk –hypopituitarism)
  • Apoplexy/Sheehans
    Sarcoid/TB
89
Q

What is a craniopharyngioma?

A

Benign, epithelium like structures causing tumour, cystic, can grow quite large. Can cause inflammation and pressure on pituitary. More common in children. Difficult to operate on

90
Q

How can a craniopharyngioma cause apoplexy?

A

Pituitary tumour swells –> blocks off own blood supply

91
Q

What is Sheehans?

A

V rare now, large bleed after childbirth–>hypopituitarism

92
Q

What are the 3 main ways tumours cause pathology (endocrinology)?

A 
1-	Pressure on Local structures
•	Pressure on optic chiasm/ nerves -->bitemporal hemianopia/visual field defects 
2-	Pressure on normal pituitary 
•	Hypopituitarism 
3-	Functioning tumour (producing hormones)
•	Prolactinoma 
•	Acromegaly 
•	Cushing’s disease
93
Q

What are the clinical presentations of a pituitary tumour pressing on local structures?

A
  • Headaches (although majority of patients don’t have)
  • Hydrocephalus (v rare – obstructing IV ventricle)
  • Visual field defects, present to opticians
  • Cranial nerve palsy occasionally ( III, IV, VI)
  • CSF rhinorrhoeae (CSF leak from the nose)
94
Q

What visual field defects may a person with a pituitary tumour present with and why?

A

o Bitemporal Hemianopia (pressure on optic chiasm)
o Upper temporal Quadrantinopia ( tumour is growing up and pressing on the bottom of the optic nerves, cant see from upper temporal visual fields)

95
Q

Why do patients who have a pituitary tumour occasionally present with cranial palsies?

A

If the tumour is pressing up and growing in the cavernous sinus

96
Q

What is a presentation of CNIII palsy?

A

‘Down and out’ appearance of the eye

97
Q

How do you clinically measure visual fields?

A

With a red pin

98
Q

What will a tumour putting pressure on the pituitary lead to?

A

Hypopituitarism

99
Q

What are the clinical presentations of a patient with a tumour pressing on the pituitary itself (not local structures)?

A

Hypopituitarism presentation. Presents quite slowly:

  • Pale
  • No body hair
  • Central obesity
100
Q

What are the 3 main conditions associated with functioning pituitary tumours?

A
  • Prolactinoma
  • Acromegaly and Giagantism
  • Cushing’s Disease
101
Q

What is the incidence of raised prolactin levels and prolactinoma?

A

Quite common. Prolactinoma more common in women

  • Incidence 10 per 100,000
  • more common in women
  • Prevalance 90 per 100,000
102
Q

What are the reasons for a raised prolactin level?

A
  • Stress (prolactin is a stress hormone), mildly elevated after blood test etc  hence put a cannula in and take a series, should be normal
  • Interupption of the pituitary stalk (compression etc)
  • Certain drugs – Dopamine antagonists (anti-psychotics, some anti-emetics)
  • Prolactinoma
103
Q

What are the effects of raised prolactin levels and their clinical presentation/ effects?

A
  • Switches off Gonadotrophins - HYPOGONADISM present with secondary or primary amenorrhoeae , infertility , may bring milk into breasts (galactorrhoeae even in men)
  • Raised prolactin  inhibits pregnancy
104
Q

What are the contraceptive effects of prolactin?

A

Mild contraceptive after pregnancy

105
Q

What is the Tx for high prolactin levels?

A

Dopamine agonists

106
Q

What are the clinical presentations of a prolactinoma?

A
  • Galactorrhoeae
  • Amenorrhoeae
  • Infertility
  • Loss of libido
  • Visual field defect
107
Q

What is the treatment for a Prolactinoma?

A

Dopamine agonist e.g. Cabergoline once or twice a week or bromocriptine. V responsive the therapy. Therapy:
• Stops Prolactin production and also
• Shrinks the tumour

If not responding to dopamine agonist –> Surgery

108
Q

Why could David kill goliath?

A

He couldn’t see him. Goliath had bitemporal hemianopia (giant bc of GH exces due to pituitary adenoma)

109
Q

What is gigantism?

A

A pituitary tumour producing GH in childhood. Very rare

110
Q

What normally stops growth?

A

Fusion of epiphysis in long bones when we go through puberty

111
Q

What causes gigantism?

A

GH release and pause of puberty:
- Pituitary tumour produces GH and presses on the normal pituitary–> don’t go through puberty (bc hypopituitarism) –>continue to grow

112
Q

What happens if you take a normal child (not GH deficient) and give them GH?

A

They do not grow much taller at all

113
Q

What is Acromegaly?

A

In adult life: Due to pituitary tumour producing GH

  • Long bones (arms) cant grow due to fusion of epiphysis but
  • Membranous bones like jaw can grow
114
Q

What are the clinical presentations of acromegaly?

A

SLOW ONSET

  • Big jaw (clench teeth and bottom teeth above top) ‘Prognathism’
  • Frontal bossing
  • Thick skin
  • Enlarged pituitary fossa
  • Big feet, sweaty feet, increase in shoe size
  • Sweat a lot
  • Enlargement of the tongue
  • Big hands ‘have you had to change the size of your ring
  • Sleep apnea if oropharynx obstructed
  • Hypertension
  • Diabetes - insulin resistance, glucose intolerance
  • hypogonadism: Amenorrhoeae, Erectile dysfunction, loss libido
115
Q

What is Cushing’s?

A

Excess Cortisol production from adrenal gland

116
Q

What are the causes of Cushings?

A
  • Pituitary tumour producing too much ACTH –> stimulates cortisol from adrenal. All the features of excess steroids (glucocorticoids) - CUSHINGS DISEASE
  • Adrenal tumour producing too much Cortisol –≥ CUSHINGS SYNDROME
  • Ectopic production of ACTH from another tumour (particularly lung)
  • Exogenous steroids
117
Q

What tumour can cause ectopic production of ACTH?

118
Q

What are the clinical presentations of Cushings?

A
  • Thin skin
  • Bruising of skin
  • Stretch marks , marked stria around umbilicus, red and purplish
  • Fat in abdomen
  • Weak muscles – muscle wastage
  • In children – stop growing
  • Moon face
  • Buffallo hump
  • Central obesity
  • Severe osteoporosis
119
Q

What is the initial screening test for Cushing’s syndrome?

A

DEXAMETHASONE SUPPRESSION TEST

  • Give 1mg Dextamethasone at nigh and measure cortisol level during next day
  • In normal people there should be suppression of plasma cortisol levels
  • People with Cushings fail to show complete suppression
120
Q

What might interfere with cortisol levels in the Dexthamethasone test?

A
  • Patients on oral contraceptive pill: high Cortisol binding globulin (CBG)  false positive dexthamethasone suppression test
  • Stress / depression
  • Alcoholics – look cushinoid, fail to suppress
121
Q

When does a patient present with gigantism?

A

If they have GH excess due to a pituitary tumour during the teenage years before fusion of epiphyses in long bones – Gigantism

122
Q

What is the difference between acromegaly and gigantism?

A
  • Acromegaly: in adulthood, when long bones epiphyeses have fused, can no longer grow in stature. Increase in membranous soft tissue
  • Gigantism: In childhood, before fusion of epiphyses, increase in stature
123
Q

What is the pathophysiology of acromegaly?

A

Due to a pituitary tumour (usually macroadenoma >1cm)

  • Pituitary tumour secretes excess GH
  • GH exerts effect predominantly by stimulating release of IGF-1 from liver
  • IGF-1 level increases greatly –> peripheral effects of excess GH
124
Q

What are the pathological effects of excess GH?

A

Bone growth, soft tissue increase, enlargement of pretty much all organs, cardiomegaly, cardiomyopathy, insulin resistance

125
Q

Why might patients with acromegaly develop diabetes?

A

Due to insulin resistance as IFG-1 normally offsets and opposes the actions of insulin

126
Q

What is the incidence and prevalance of Acromegaly?

A

Not that common:

  • Incidence: 3.3 per million
  • Prevalance: 58 per million
127
Q

What is the age of onset of Acromegaly?

A

Mean age at diagnosis is 44 years

128
Q

What is the mean duration of symptoms?

A

8 yrs, often a delayed diagnosis

129
Q

What co-morbidities are associated with acromegaly?

A
  • Hypertension
  • heart failure
  • Insulin resistance diabetes
  • Cerebrovascular events and headaches
  • Arthiritis
130
Q

Why can you get arthiritis from acromegaly?

A

Swelling in synovium and increased fluid in joint spaces

131
Q

What is the prognosis of patients with acromegaly?

A

Lower survival than general population. If with co-morbities, worse. Overall 10 yr reduction in life expectancy

132
Q

Does treatment of Acromegaly help prognosis?

133
Q

How do you make a diagnosis of acromegaly?

A
  • Clinical features (often gradual onset)

- Biochemical diagnosis: Measuring GH and IGF-1

134
Q

What is the circadian rhythm and how is GH released?

A

Pulsatile fashion:

  • Very low levels
  • Pulsatile spikes
  • Between pulses, GH is very low/ undetectable
135
Q

What is GH secretion in acromegaly like?

A
  • Levels of GH never return to baseline – never v low

- Not so elevated spikes

136
Q

When should GH be measured and why?

A

Multiple samples across the day

137
Q

What would the GH results be like in acromegaly?

A
  • If detectable in each sample across the day (bc in normal they should be so low sometimes they are not detectable)
138
Q

What are the investigations done for suspected Acromegaly?

A
  • GH levels
  • Glucose Tolerance test
  • IGF-1 levels
  • Visual field examination

If above tests normal:
-MRI scan of pituitary

  • Pituitary function
  • Prolactin levels
139
Q

What is the glucose tolerance test in Acromegaly and what is a normal response and what is the result in patients with Acromegaly?

A

Give patient 75g of glucose (usually Lucozade) and measure GH .

Normal subjects:
- After glucose is given ,GH should be rapidly suppressed and levels should decrease. Suppress to below 1ug/L ( now almost 0.2 bc the assays are very sensitive)

Acromegaly patients:

  • No GH suppression
  • In 30% of patients, there is a paradoxical rise
140
Q

What is the criteria for diagnosis of Acromegaly?

A

Acromegaly excluded if:
-Random GH<0.4 ng/ml and normal IGF-1

If either abnormal proceed to:
75gm Glucose Tolerance test

Acromegaly excluded if:
-IGF-1 normal and GTT nadir GH<1ng/ml

141
Q

What are the objectives of therapy in acromegaly?

A
  • Restoration of basal GH and IGF-1 to normal levels
  • Relief of symptoms
  • Reversal of visual and soft tissue changes
  • Prevention of further skeletal deformity
  • Normalization of pituitary function
142
Q

What are the 3 main Tx options for Acromegaly?

A
  • Pituitary surgery
  • Medical therapy
  • Radiotherapy on pituitary
143
Q

What is the first line Tx for Acromegaly?

A

Trans-sphenoidal surgery

144
Q

Why is surgery the primary treatment for Acromegaly?

A
  • Prospect of cure (especially with smaller adenomas)
  • rapid fall in GH
  • Decompression of pituitary
  • Cost-effective
  • Fewer complications

Clinical remission in 60-90% of cases

145
Q

What are the determinants of successful pituitary tumour surgery?

A
  • Size of tumour

* The surgeon (how good they are, how specialised and practiced)

146
Q

What complications can there be in pituitary surgery?

A

-anaesthetic complications
-Carotid artery injury
-CNS Injury
-Haemorrhage
-Loss of vision
etc etc

147
Q

When is radiotherapy indicated for Acromegaly?

A
  • Surgery not possible

- Surgery not fully effective

148
Q

How does radiotherapy treat Acromegaly?

A

Changing the area that receives the radiotherapy into scar tissue

149
Q

How long does radiotherapy take to have an effect in treating Acromegaly?

A

Long time – often many years for GH levels to change

150
Q

What types of radiotherapy are there?

A
  • Conventional: multi-fractional, smaller dose but around surrounding tissues, still tries to preserve optic nerve
  • Stereotactic: single fraction, less radiation to surrounding tissues – particularly the optic nerve
  • Gamma knife:
  • Linear accelerator LINAC: stereotactic dosage in 3D
  • Proton beam: protons, can manipulate the charge and speed of particle density of tissue pass through- stop at particular depth, deposition exactly where it needs to be in the pituitary. Much less access in the UK (only 2 sites)
151
Q

What determines the efficacy of conventional radiotherapy in treating Acromegaly?

A
  • GH levels

- Tumour extension

152
Q

What are the disadvantages of conventional radiotherapy in treating Acromegaly?

A
  • Delayed response (takes years to decrease GH levels)
  • Hypopituitarism – deficiency in other pituitary hormones: TSH, ACTH, Gonadotrophins
  • Rare secondary tumours
  • Rare visual field defects
153
Q

What are the 3 main drugs/ approaches in medical therapy to treat Acromegaly?

A
  • Dopamine agonists – Cabergoline
  • Somatostatin analogues
  • Growth Hormone Receptor antagonist
154
Q

How do dopamine agonists work to treat Acromegaly?

A
  • Dopamine agonists bind to D2 receptors – present on GH releasing cells in the Pituitary
  • Switches off secretion of GH
155
Q

How do somatostatin analogues work to treat Acromegaly?

A
  • Binds to Somatostatin type 2 receptor  switches off production of GH
156
Q

What are the goals of medical therapy in treating Acromegaly?

A
  • Control GH
  • Control IGF-1
  • Improve well being
157
Q

What dopamine agonists are available to treat Acromegaly?

A

Bromocriptine (10%), Cabergoline (37%) – more active, fewer side effects

158
Q

What is the typical dosage of Dopamine Agonists for Acromegaly Tx?

A

• Cabergoline 2x a week

159
Q

What are the advantages OF Dopamine agonist Tx in Acromegaly?

A
  • No hypopituitarism,
  • oral administration,
  • rapid onset
160
Q

What are the disadvantages of Dopamine agonists as Acromegaly Tx?

A

Relatively ineffective (compared to other Tx), side effects

161
Q

When are Dopamine agonists indicated for Tx of Acromegaly?

A

Only when levels of GH after surgery remains modest

162
Q

What determines the effectiveness of Dopamine agonist Tx in Acromegaly?

A
  • Milder acromegaly has a better response to treatment ( in this graph, lowered serum levels to target)
163
Q

What is the most effective Medical Tx for Acromegaly?

A

GH receptor antagonist (Pegvisomat) > Somatostatin analogues >Dopamine agonists

164
Q

What is the mode of action of somatostatin analogues in Tx if Acromegaly?

A
  • Binds to Somatostatin receptor (type 2 in GH secreting cells)
165
Q

What are the advantages of Somatostain analogues in Tx of Acromegaly?

A
  • Inhibit multitude of hormones
166
Q

What are its disadvantages of traditional somatostain analogues in Tx of Acromegaly and what has been developed to overcome this?

A

Traditional:

  • Very short half life – 3 minutes n
  • Binds to all 5 receptor sub-types (1,2,3,4,5)

New - Octreotide and Lanreotide:

  • Longer half life
  • No rebound
  • Routine agents used for treatment
167
Q

How effective are Somatostatin analogues in Tx of Acromegaly?

A

More effective than dopamine agonists, less affective than GH receptor antagonists:

  • Control GH (60% of patients)
  • Control IGF-1 (65% of patients)
  • Clinical improvement
  • Tumour shrinkage

Efficacy determined by:
GH level, tumour size, SMS receptor expression

168
Q

What are the disadvantages of Somatostain Tx in Acromegaly?

A
  • Injectable (monthly basis)

- Side effects (GI upset, gallstones in long run, reducing pancreatic exocrine function)

169
Q

What is Pegvisomant?

A

Competitive GH receptor antagonist. Best medical Tx for Acromegaly

170
Q

How do GH receptor antagonists (Pegvisomant) work?

A

Blocks the GH receptor on the liver as it is a GH analogue –> lowers IGF-1 levels
-serum GH cannot be used as a disease marker as levels still high in these patients but its not having its effectt through IGF-1

171
Q

How does GH receptor antagonists affect GH and IGF-1 levels?

A

GH levels still high but IGF-1 low as its blocking the GH receptor in the liver

172
Q

How effective are GH receptor antagonists (Pegvisomant) in medical Tx of Acromegaly?

A

VERY EFFECTIVE: After 12months, IGF-1 levels at target

- With doses up to 40 mg, 97% normalisation of IGF-1

173
Q

Why is use of GH receptor antagonists (Pegvisomant) tightly controlled?

A

VERY EXPENSIVE

174
Q

What is a Prolactinoma?

A

Lactotroph cell tumour of the pituitary

175
Q

What is the only anterior pituitary hormone under inhibitory control solely?

A

Prolactin

-Tonic inhibition by Dopamine

176
Q

When is Prolactin production switched on (physiologicaly)?

A

Breast suckling.

- Forward feedback loops to switch on prolactin production when breast suckling

177
Q

What is the function of Prolactin?

A

Milk production in the breast

178
Q

What are the types of Prolactinoma and what are their features?

A
  • Macroprolactinoma (can be massive, produce local tumour effects)
  • Microprolactinoma (virtually always stay small)
179
Q

What are the clinical presentations of a prolactinoma due to?

A
  • Local effect of the tumour (macro adenoma)

- Effect of Prolactin - Hypogonadism

180
Q

What are clinical presentatios of the local tumour effects of a prolactinoma?

A
  • Headache
  • Visual field defect (bi-temporal hemi-anopia)
  • CSF leak (RARE)
181
Q

What are the clinical presentations of the high prolactin levels of a prolactinoma?

A 
Hypogonadism:
•	Menstrual irregularity/ amenorrhoeae
•	Infertility 
•	Galactorrhoeae
•	Low libido 
•	Low testosterone in men
182
Q

What is the efficacy of Dopamine agonists in Tx of Prolactinoma?

A
  • Remarkable shrinkage usual with macroadenoma – patients can see again
  • Microadenomas usually responds to small doses of Cabergoline just once or twice per week

PHASE 2A MEDICINE - ANJALI createdd (9 decks)

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