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Year 2 LCRS > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

Define hypopituitarism

A

Hypopituitarism is the decreased production of all anterior pituitary hormones or the decreased production of specific hormones

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2
Q

Define panhypopituitarism

A

Panhypopituitarism is the decreased production of all anterior pituitary hormones.

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3
Q

What are the causes of panhypopituitarism?

A

It is a rare case caused by congenital defects or gene mutations in the genes involved in the development of the gland (e.g. PROP1). It can also occur after radiotherapy.

Most commonly caused by Simmonds disease, Sheehan’s syndrome, and Pituitary Apoplexy.

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4
Q

When is the disease considered a primary, secondary or tertiary endocrine disease?

A

Primary: disorder at the endocrine gland.
Secondary: disorder at the pituitary gland.
Tertiary: disorder at the hypothalamus.

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5
Q

Where does the pituitary gland sit in the skull?

A

The pituitary gland sits in the sella turcica of the sphenoid bone of the skull.

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6
Q

What is the aetiology, cause and symptoms of Simmond’s disease?

A

Simmond’s disease is slow loss of pituitary function caused by various things including infiltrative processes, pituitary adenomas, craniopharyngiomas (tumor derived from pituitary gland embryonic tissue), cranial injury and following surgery.

Symptoms are due mainly to decreased thyroidal (tiredness, waxy skin, loss of body hair, hypotension, etc.) , adrenal and gonadal function (oligomennorhoea, impotence) which is normally presented to the doctor.

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7
Q

What is the cause of Sheehan’s syndrome?

A

Sheehan’s syndrome is hypopituitarism specific in women and is relatively sudden in terms of onset. It develops acutely following post-partum haemorrhage, whereby blood loss and hypovolaemic shock causes vasoconstrictor spasm of the hypophysial arteries, leading to ischaemia and subsequent necrosis of the pituitary gland.

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8
Q

What is a Pituitary Apoplexy?

A

Pituitary apoplexy is a similar intra-­pituitary haemorrhage or infacrtion in the presence of a pituitary adenoma. It often has dramatic presentation with pre-­existing pituitary tumours which suddenly infarct.

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9
Q

How is a diagnosis of hypopituitarism made?

A

By measuring the values of pituitary hormones after a provocation test (e.g GnRH, Somatotrophin RH, CRH etc). Gold standard is to cause an insulin-induced hypoglycaemia for GH.

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10
Q

What are the names of the conditions caused by single pituitary hormone insufficiency?

A

lack of gonadotrophins (LH and FSH) leading to hypogonadism
lack of thyrotrophins (TSH) leading to hypothyroidism
lack of corticotrophin (ACTH) leading to hypoadrenocorticalism
lack of Somatotrophin leading to Hypopituitary Dwarfism

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11
Q

What are the causes of short stature?

A
  • Somatotrophin deficiency
  • Laron dwarfism (caused by GH receptor defect)
  • IGF1/2 receptor defect
  • Malnutrition
  • Emotional deprivation
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12
Q

What are the causes of somatotrophin deficiency?

A

CONGENITAL:

  • Deficiency of hypothalamic GHRH
  • Mutation of the GH gene
  • Developmental abnormalities (e.g aplasia or hypoplasia of the pituitary)

ACQUIRED:

  • Tumors of the hypothalamus or pituitary
  • Secondary to cranial irradiation of another tumor
  • Other intracranial tumours nearby (e.g optic nerve glioma)
  • Head injury
  • Infection or inflammation
  • Sever psychological deprivation appears to be associated with a lack of growth in children.
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13
Q

What can be administered to provocate the release of growth hormone from the pituitary?

A
  • GHRH (iv): limited availability
  • Insulin (iv): goldstandard test; dangerous in some patients who are elderly or have heart problems.
  • Arginine (iv)
  • Exercise
  • Glucagon (induces hyperglycaemia -> release of insulin )
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14
Q

What drugs can be administered to replace the pituitary hormones?

A
  • ACTH replaced by Hydrocortisone
  • TSH replaced by Thyroxine
  • LH/FSH (women) replaced by Ethinyloestradiol and Medrixyorigesterone
  • LH/FSH (men) replaced by Testosterone and udecanoate
  • GH replaced by GH
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15
Q

Describe the preparation, administration, pharmacokinetics and adverse effects of Growth Hormone relpacement.

A

Human recombinant GH (somatotrophin) administered subcutaneously or intramuscularly daily or 4-5 times a week.
Metabolism is hepatic or renal with a half-life of 20 minutes.
Adverse effects include lipoatrophy at injection side, intercranial hypertention, headaches, increased incidence of leukaemia.

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16
Q

What are the symptoms of growth hormone deficiency in adults?

A
  • reduced lean mass, increased adiposity and wast:hip ratio
  • reduced muscle strength and bulk
  • decreased HDL levels, increased LDL levels.
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17
Q

What causes hyperpituitarism?

A

Hyperpituitarism is usually due to isolated pituitary tumours but can also be
ectopic in origin

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18
Q

What are the symptoms of hyperpituitarism?

A

Excess production of adenohypophysial hormones:

  • Cushing’s disease
  • Thyrotoxicosis
  • Hyperprolacinaemia
  • Gigantism in children, Acromegaly in adults
  • Precocious puberty in children.

May also have bitemporal hemianopia if pituitary adenoma invades optic chiasm.

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19
Q

What causes hyperprolacinaemia?

A

Usually due to a prolactinoma (often microadenomas less than 10mm in diameter) of the lactrotrophs.

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20
Q

What symptoms are associated with hyperprolactinaemia?

A 
Women:
- Galactorrhoea
- Secondary amenorrhoea or oligomenorrhoea
- Loss of Libido
- Infertility
(last three due to hypogonadism)
Men:
- Galactorrhoea uncommon (as appropriate steroidal background inadequate)
- Loss of libido
- Impotence
- Infertility
(last three due to hypogonadism)

Also headaches and visual field defects if due to prolacinoma

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21
Q

What hypothalamic hormones control the release of prolactin?

A
  • DOPAMINE inhibits

- Thyrotrophin Stimulating Hormone stimulates production

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22
Q

What is the disease of excess somatotrophin called?

A

In childhood, excess growth hormone is gigantism. In adults, this is acromegaly.

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23
Q

What are the clinical manifestations of Acromegaly?

A

Slow onset, over many years. If untreated, it is associated with increased mortality and morbidity due to cardiovascular and respiratory disease.
Acromegaly involves increased growth of periosteal bone, cartilage, fibrous tissue, connective tissue, and internal organs
The metabolic effects include an increased plasma insulin response to oral glucose load, which leads to increased insulin resistance and diabetes.
Clinical signs include enlargement of supraorbital ridges and nose, hands + feet, thickening of lips (soft tissues)and general coarseness of features. Also excessive sweating due to increased metabolic activity. Mandible growth, Carpel Tunnel syndrome, Barrel chest and kyphosis. Hypertension.

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24
Q

What test is used to diagnose Acromegaly?

A

Suppression tests using oral glucose. Glucose should inhibit GH production; in acromegaly it does not.

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25
Q

What are the general treatment strategies for Acromegaly?

A
  • Chemotherapy including Dopamine and somatostatin agonists.
  • radiotherapy
  • Surgery to remove adenoma.
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26
Q

Describe the chemotherapy drugs that can be used to treat pituitary tumours.

A

Octreotide is a somatostatin analogue which may be used as a short-­term treatment before pituitary surgery, or a long-­term treatment in patients. Half life of 2-4 hours, administration I.V or I.M. Side effects: GI tract disturbances, transient hyperglycaemia.

Prolactinomas as treated with dopamine 2 agonists such as Bromocriptine and Cabergoline. Often decrease size of adenoma.

Bromocriptine taken orally with half life of 7h.
Cabergoline also has D1 affinity with longer half life. Taken orally once or twice a week. Drug of choice as has fewer side effects than Bromocriptine.

Unwanted effects of dopamine agonists include:

  • Nausea, Vomiting, Abdominal cramps
  • Dyskinesia
  • Psychomotor excitation
  • Postural hypotension
  • Vasospasm in digits. (Caution with Raynaud’s disease)
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27
Q

What is the principle effect of vasopressin?

A

The principle effect of vasopressin is antidiuretic. It acts on V2 receptors on renal and cortical medullary collecting ducts, where it stimulates the synthesis and insertion of aquaporin 2 into the apical membrane of principle cells. Acting to increasing water reabsorption from urine, increasing amount of water retained in the body?

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28
Q

What are the effects of vasopressin (apart from effects on principle cells)?

A
  • vasoconstriction through V1a receptors
  • corticotropin release (ACTH) through V1b receptors
  • production of Factor VIII and vonWillebrand factor through V2 receptors
  • central effects on behaviour such as contributions towards autism
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29
Q

What are the principle actions of oxytocin?

A
  • constriction of myometrium at parturition
  • milk ejection reflex
  • central effects
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30
Q

What condition is brought about by lack of vasopressin?

A

Diabetes Insipidus

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31
Q

What are the two types of diabetes insipidus?

A
  • Central/cranial DI is where the neurohypophysis cannot produce vasopressin. Usually due to damage to neurohypophyseal system such as surgery, cerebral thrombosis, tumours or granulomatous infiltrations of median eminence. Can also be idiopathic or familial.
  • Nephrogenic DI is where vasopressin is produced but there is end-organ resistance. Usually caused by drugs such as lithium, DMCT. Can also be familial.
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32
Q

What are the signs and symptoms of diabetes insipidus?

A

Polyuria, polydipsia, hypo-osmolar urine

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33
Q

What is the normal range of plasma osmolarity?

A

270-290 mOsm

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34
Q

How does diabetes insipidus affect plasma osmolarity?

A
  • DI puts patients on the higher end of the normal range.
  • Pshycogenic polydipsia means people will have lower-normal plasma osmolarity as they are drinking more water although their vasopressin works.
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35
Q

How can diabetes insipidus be diagnosed?

A

Fluid deprivation test and measure the plasma osmolarity. Normal people will be able to concentrate their urine (high osmolarity) as they functioning vasopressin system. Those with diabetes insipidus will not concentrate their urine and will dehydrate quickly so their weight is tracked for safety.

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36
Q

How can you clinically differentiate between central and nephrogenic diabetes insipidus?

A
  • Administer DDAVP (desmopressin). Those with central DI will respond to treatment, concentrating their urine, increasing its osmolarity. Those with nephrogenic DI will not respond
  • Administer intravenous saline and measure levels of vasopressin. Those with central DI will not be able to produce vasopressin, those with nephrogenic will.
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37
Q

What condition is brought about by an excess of vasopressin?

A

SIADH (Syndrome of Inappropriate ADH)

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38
Q

What are the consequences of SIADH?

A

Excess water reabsorption dilutes the plasma leading to hyponatraemia.

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39
Q

What are the signs of SIADH?

A
  • Raised urine osmolarity
  • Decreased initial urine volume
  • Hyponatraemia may present as weakness, poor mental function, nausea, confusion, coma
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40
Q

What are the causes of SIADH?

A

Tumour, Neurohypophsyial malfunction (due to meningitis, cerebrovascular disease etc), thoracic disease (e.g pneumonia), endocrine disease (e.g Addison’s disease), psychological factors, drugs or idiopathic.

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41
Q

How can you treat SIADH?

A

1) Immediate term: fluid destruction
2) Long term: use drugs that prevent vasopressin action in kidneys e.g lithium, di-methyh-chlor-tetracycline and V2 agonists.

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42
Q

Where are vasopressin receptors found?

A

V1: smooth muscle, anterior pituitary gland, liver, platelets and CNS
V2: kindeys and endothelial cells

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43
Q

What are the analogues of vasopressin?

A

Argipressin-1 (Arg-vasopressin), Terlipressin (V1) and Demopressin DDAVP (V2)

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44
Q

What are the pharmacological actions of Argipressin?

A
  • Natriuresis (secretion of sodium in urine) is V2 mediated but with unclear mechanism - only in high doses
  • Pressor action is V1 mediated
  • Contraction of non-vascular smooth muscle (V1a) (e.g gut motility)
  • Increased ACTH secretion (V1b)
  • Increased FVIII and vWF (V2)
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45
Q

What are the clinical uses of and pharmacokinetics of desmopressin?

A

Used in treating central diabetes insipidus, nocturnal enuresis and haemophilia. It is administered nasaly or orally. Distributed in the ECF. Metabolised in the kidneys and liver with a half-life of 5h

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46
Q

What are the side effects of desmopressin?

A

Hyponatraemia, abdominal pain, headaches and nausea.

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47
Q

What are the clinical uses of V1 analogues?

A

Terlipresin is used to treat oesophageal varices. Felypressin is used to prolong the action of local anaesthetics.

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48
Q

How can nephrogenic diabetes be treated?

A

With thiazines such as bendoflumethiozide. Although a diuretic as it inhibits Na+/Cl- transport in distal convoluted tubule, there is a compensatory increase in Na+ reabsorption from PCT causes increased H20 reabsorption.

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49
Q

Give an example of a V2 antagonist?

A

Vaptans are non-peptide vasopressin analogues

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50
Q

How does nicotine, alcohol or glucocorticoids affect vasopressin?

A

Nicotine increases vasopressin secretion

Alcohol and glucocorticoids decrease vasopressin release

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51
Q

What is the name given to the disease resulting in primary hypothyroidism due to autoimmune damage?

A

myxoedema

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52
Q

What are the symptoms of hypothyroidism?

A
  • deepening voice
  • depression and tiredness
  • cold intolerance
  • weight gain and reduced appetite
  • constipation
  • bradycardia
  • eventual myxoedema coma
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53
Q

What is cretinism?

A

A congenital deficiency of thyroid hormones

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54
Q

Why can tetraiodothyronine be considered a prohormone?

A

It is converted to the more active triiodothyronine (T3).

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55
Q

How is T4 converted to T3?

A

By deiodinase activity

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56
Q

Describe how T3 causes cellular change

A

T3 binds to intracellular thyroid hormone receptor which heterodimerises with retinoid x receptor. This complex then binds to the Thyroid Response Element which stimulates changes in gene expression, eventually increasing basal metabolic rate.

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57
Q

How is hypothyroidism treated?

A

Thyroid hormone replacement:

  • Levothyroxine sodium (usually drug of choice) is a synthetic thyroxine (T4) sodium.
  • Liothyronine sodium (more rapid action, and usually I.V for myxoedema coma) is a synthetic T3 sodium.
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58
Q

Why and how is levothyroxine sodium administered?

A

In the treatment for autoimmune primary hypothyroidism and iatrogenic hypothyroidism (post-thyroidectomy). Also used in the treatment of secondary hypothyroidism.

Oral administration once a day. In primary hypothyroidism, TSH can be used for guidance of dose, aiming to suppress TSH into a reference range. In secondary hypothyroidism, unbound T4 can be monitored for guidance.

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59
Q

What is the half-life of T3 and T4?

A

T4: 6 days
T3: 2-5 days

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60
Q

What percentage of T3 and T4 are bound to plasma proteins? And what is the significance of this?

A
  • 99.97% of T4 and 99.7% of T3 is bound to plasma proteins
  • Only unbound thyroxine or T3 is available to tissues
  • Plasma-binding proteins increase in pregnancy and on prolonged treatment with oestrogens and phenothiazines.
  • However, TBG falls with malnutrition, liver disease and certain drugs
  • Certain co-administered drugs compete for protein binding sites (e.g phenytoin and salicyclates)
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61
Q

What are the adverse effects of thyroid hormone over-replacement?

A
  • bone: increased bone turnover, reduction in bone mineral density, risk of osteoporosis
  • cardiac: tachycardia, risk of dysrhythmia
  • metabolism: increased energy expenditure, weight loss
  • increased beta-adrenergic sensitivity - tremor and nervousness.
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62
Q

List the causes of hyperthyroidism

A
  • Grave’s disease (autoimmune)
  • Pulmmer’s disease (benign adenoma)
  • Viral thyroiditis
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63
Q

What are the symptoms of hyperthyroidism?

A
  • Sweaty and hot
  • Weight loss with increased appetite
  • Body temperature climbs
  • Muscle wasting
  • Shortness of breath
  • Rapid pulse
  • Tremor
  • Palpitations
  • Eyelid lag
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64
Q

What is the aetiology of, and specific symptoms of Grave’s disease?

A

Autoimmune disease whereby antibodies bind to and stimulate the TSH receptor in the thyroid. The gland makes more thyroxine, becoming symmetrically enlarged (described as a smooth goitre).
Apart from usual hyperthyroidism symptoms, other antibodies stimulate of growth of muscles behind the eye causing exophthalmos. And others cause soft-tissue growth of shins - pretibial myxoedema.

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65
Q

What is the aetiology of, and specific symptoms of Plummer’s disease?

A

Benign adenoma presenting as a toxic nodular goitre producing thyroxine. Tumour results in asymmetric enlargement, seen on a scintigram. Can be multi-nodular..

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66
Q

What is responsible for the tachycardia, palpitations, lid lag and temor in hyperthyroid patients?

A

Thyroxine sensitises beta-adrenoreceptors. This makes catecholamines more potent.

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67
Q

Describe a medical emergency caused by hyperthyroidism

A

Thyroid storm has a 50% chance of mortality. Presentation of hyperpyrexia, accelerated tachycardia, cardiac failure, delirium, psychosis, hepatocellular dysfunction and jaundice.

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68
Q

What is the aetiology of, and specific symptoms of Viral thyroiditis?

A

Virus makes follicular cells produce more viral proteins than thyroxine. Thus there is zero iodine uptake by the cells (so a thyroid scan will be blank). Hyperthyroidism occurs because stored thyroxine is released from the colloid. Four weeks after the store runs out, a state of hypothyroidism occurs.

Patient presents with hyperthyroidism symptoms + dysphagia, pyrexia and raised ESR. They will also have tender pretracheal lymph nodes, and a palpable thyroid - usually enlarged more on one side.

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69
Q

How can a thyroid adenoma be treated?

A

Treatment is usually surgery or radioiodine ablation as well as enough thyroxine to suppress TSH release (as this stimulates thyroid cells to grow)

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70
Q

How can hyperthyroidism be treated?

A
  • Thyroidectomy
  • Radioiodine albation
  • beta-blockers (non-selective)
  • Thioamides
  • Iodine
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71
Q

How do thioamides work?

A

They inhibit thyroperoxidase and peroxidase transaminase and hence T3 and T4 synthesis and secretion.

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72
Q

Give examples of tionamides and their pharmacokinetic properties

A
  • Carbimazole is a pro-drug converted to methimazole. It has a half-life of 6-15h and has the ability to cross the placenta and be secreted in the milk.
  • Propylthiouracil is another example of a thionamide

They are metabolised in the liver and excreted in the urine. Taken orally.

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73
Q

How does iodine administration treat hyperthyroidism?

A

Usually as potassium iodide. Given in preparation of surgery or severe thyrotoxic crisis. It works through the Wolff-Chaikoff effect where iodide inhibits the iodination of thyroglobulin and thyroid peroxidase.
Iodide is also good in reducing the vascularity and some of the gland.

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74
Q

How is iodine administered in the treatment of hyperthyroidism?

A
  • Given orally (as potassium iodide) or in liquid form as Lugol’s iodine
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75
Q

How does radioidine treat hyperthyroidism?

A

Radio iodine is whereby radioactive iodine is taken up into the colloid where it emits beta-particles. It has a half-life of 8 days.

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76
Q

What precautions must be taken when hyperthyroidism is treated by radioiodine?

A

Can have teratogenic effect, so advised to avoid children and pregnant women

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77
Q

What are the clinical features of Cushing’s?

A
  • red cheeks
  • fat pads
  • moon face
  • thin skin
  • proximal myopathy
  • hypertension
  • red striae
  • thin arms and legs
  • poor wound healing
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78
Q

What are the causes of Cushing’s syndrome?

A
  • taking too many steroids
  • pituitary dependent Cushing’s DISEASE
  • ectopic ACTH from lung cancer
  • Primary adrenal adenoma secreting cortisol
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79
Q

What syndrome is a result of hypersecretion of aldosterone?

A

Conn’s syndrome

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80
Q

How can Cushing’s syndrome be investigated?

A
  • 24h urine collection for urinary free cortisol
  • measuring blood diurnal cortisol levels
  • low dose dexamethasone suppression test (healthy patient will stop ACTH production; cushing’s will still have large cortisol concentration)
  • high dose dexamethasone will suppress pituitary Cushing’s cortisol by 50% but not other causes.
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81
Q

What are the strategies in the treatment of Cushing’s syndrome?

A
  • hypophysectomy (for Cushing’s disease)
  • bilateral adre nalectomy
  • enzyme inhibitors
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82
Q

What enzyme inhibitors can be used in the treatment of Cushing’s syndrome?

A
  • Metyrapone inhibits 11-beta-hydroxylase
  • Trilostane inhibits 3beta-hydroxysteroid dehydrogenase
  • Ketoconazole inhibits CYP450
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83
Q

What is Metyrapone used to treat?

  • How does it do so?
  • What are its side effects?
A

Treat Cushing’s syndrome (e.g bronchial tumours inaccessible to surgery). It inhibits 11-beta-hydroxylase preventing production of corticosterone and cortisol. As 11-deoxycortisol has no negative feedback on the hypothalamus, ACTH secretion increases and plasma deoxycortisol levels are increased.

Side effects include:

  • nausea, vomiting, dizziness and sedation
  • hypoadrenalism and hypertension (long term_
  • hypertension caused by deoxycorticosterone accumulation in zona glomerulosa
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84
Q

What is Trilostane used to treat?

- What are its side effects?

A

Trilostane blocks activity of 3beta-hydroxysteroid dehydrogenase and therefore prevents the production of glucocorticoids, mineralocorticoids and sex steroids. Therefore treats Cushing’s syndrome and hyperaldosteronism. Also used in reduction of sex steroid hormone production.

Unwanted side effects include nausea, vomiting, diarrhoea and flushing.

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85
Q

What is Ketoconazole used to treat?

- What are its side effects?

A

Mainly used as an anti fungal agent. At higher concentration blocks cytochrome p450 enzymes, inhibiting steroidogenesis (thus glucocorticoids, mineralocorticoids and sex steroids). Can be used to treat Cushing’s syndrome.

Unwanted actions include nausea, vomiting, abdominal pain, alopecia, gynaecomastia, oligospermia, ventricular tachycardia, liver damage and reduced androgen production.

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86
Q

What is Conn’s syndrome?

A

Benign adrenal cortical tumour in the zona glomerulosa

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87
Q

What are the features of Conn’s syndrome?

A

Aldosterone excess leading to hypertension and hypokalaemia.

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88
Q

How is Conn’s syndrome diagnosed?

A
  • Measuring serum aldosterone levels. The RAS is often evaluated in patients with hypokalaemia or with hypertension to distinguish primary from secondary hyperaldosteronism. Those with primary hyperaldosetronism should have a suppressed RAS.
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89
Q

What can be used to treat hyperalderstronism?

A
  • Spironolactone
  • Trilostane
  • Eplerenone
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90
Q

What is spironolactone used to treat?

A

Conn’s syndrome, oedema, congestive heart failure, nephritic syndrome and cirrhosis of the liver.

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91
Q

Describe the pharmacokinetics of spironolactone

A
  • pro-drug converted to canrenone which is a competitive agonist for the mineralocorticoid receptor, therefore blocking Na+ absorption and K+ excretion.
  • orally administered, once or twice a day
  • highly protein bound and undergoes hepatic metabolism
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92
Q

How does spironolactone work and what are its side effects?

A

Competitively binds to mineralocorticoid receptors, blocking Na+ reabsorption and K+ excretion (thus K sparing diuretic)
Unwanted actions include: menstrual irregularities, gynaecomastia and GI tract irritation.
Therefore contraindications of use are renal and hepatic disease

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93
Q

Compare spironolactone to eplerenone

A

Eplerenone is similar to spironolactone, however it binds less to androgen and progesterone receptors and so is better tolerated.

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94
Q

What tumours of the adrenal medulla secrete catecholamines?

A

Pheochromocytomas

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95
Q

What are the features of pheochromocytoma?

A

Hypertension in young people and episodic severe hypertension. It is more common in certain inherited conditions. Severe hypertension can lead to myocardial infarction or stroke, and high adrenaline can cause ventricular fibrillation and death.

  • 10% are extra-adrenal, 10% are malignant and 10% are bilateral.
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96
Q

How are pheochromocytomas treated?

A

Treated with surgery. However, preparation needs to be done before anaesthetic administration:

  • alpha blockade is first therapeutic step
  • beta blockade is then added to prevent tachycardia
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97
Q

What are common causes of adrenocortical failure?

A
  • Tuberculosis Addison’s disease
  • Autoimmune Addison’s disease
  • Congenital adrenal hyperplasia
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98
Q

What are the symptoms of adrenocortical failure?

A

Hyperpigmentation (due to increased POMC), autoimmune vitiligo, weight loss, muscle weakness, hypotension.

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99
Q

What are the consequences of adrenocortical failure?

A
  • loss of salt in urine
  • hyperkalaemia
  • hypoglycaemia
  • increased pigmentation (POMC broken down to ACTH and MSH)
  • death to severe hypotension
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100
Q

How can addison’s disease be diagnosed?

A
  • If 9am cortisol is low and ACTH is high

- short synACTHen test - 200ug of synthetic ACTH is given intramuscularly, and the cortisol is measured.

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101
Q

What is the most common cause of congenital adrenal hyperplasia?

A

21-hydroxylase deficiency.

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102
Q

What are the types of 21-hydroxylase deficiency?

A

Complete and Partial 21-hydroxylase deficiency. Both result in a deficiency of cortisol and aldosterone.

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103
Q

What are the features of complete 21-hydroxylase deficiency?

A
  • patent only survives for less than 24h
  • neonate will present with Addisonian crisis
  • sex steroids and testosterone in excess
  • girls might have ambiguous genitalia (virilised by adrenal testosterone)
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104
Q

What are the features of partial 21-hydroxylase deficiency?

A
  • cortisol and aldosterone are slightly low
  • high ACTH and sex steroids (as build up of 17-hydroxyprogesterone)
  • present at any age
  • main problem in later life is hirsutism, virilisation in girls and precocious puberty in bonds due to adrenal testosterone
  • other problems include acne, variable pigmentation and muscular arms and legs.
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105
Q

Describe the features of congenital adrenal hyperplasia (NOT 21-hydroxylase deficiency)

A
  • In 11-hydroxylase deficiency, cortisol and aldosterone are deficient but 11-deoxy corticosterone, sex steroids and testosterone is in excess. As 11-deoxy-corticosterone can activate mineralocorticoid receptors, excess amounts cause hypertension and hypokalaemia. Sex steroids also cause virilisation.
  • In 17-hydroxylase deficiency, cortisol and sex steroids are deficient, while 11-deoxycorticosterone and aldosterone are in excess. This leads to problems included hypertension, hypokalaemia, sex steroid deficiency and hypoglycaemia.
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106
Q

What parts of the adrenal cortex produce the different steroids?

A
  • Glucocorticoids are produced in the zona fasciculata
  • Androgens and oestrogens are produced in the zona reticularis
  • Mineralocorticoids are produced in the zona glomerulosa
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107
Q

What two broad categories can the actions of cortisol be split into?

A
  • permissive actions (basal levels) maintain the body systems in a state able to respond to stress
  • protective actions (during stress) keeps the body’s stress response in check (e.g suppression of inflammatory mediator production to prevent shock)
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108
Q

Describe the properties of the corticosteroid receptors

A

Glucocorticoid Receptors:

  • wide distribution
  • selective for glucocorticoids
  • low affinity for cortisol

Mineralocorticoid Receptors:

  • discrete distribution
  • does not distinguish between aldosterone and cortisol
  • high affinity for cortisol
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109
Q

How are mineralocorticoid receptors protected from cortisol?

A

11-beta-hydoxysteroid dehydrogenase-2 converts cortisol to cortisone

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110
Q

Why does Cushing’s syndrome present with hypertension and hypokalaemia - symptoms of hyperaldesteronism?

A

11-beta-hydoxysteroid dehydrogenase-2 enzyme that normally converts cortisol to cortisone in the kidney is overwhelmed by high concentrations of cortisol. Remaining cortisol can bind to mineralocorticoid receptors.

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111
Q

What are the corticosteroid analogues?

A
  • Hydrocortisone (cortisol)
  • Prednisolone has glucocorticoid effects and weak mineralocorticoid activity
  • Dexamethasone is synthetic, with glucocorticoid but no mineralocorticoid activity
  • Fludrocortisone is an aldosterone analogue used as a substitute.
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112
Q

How can the corticosteroid analogues be administered?

A

All of them can be administered orally (apart from aldosterone and hence use of fludrocortisone). Hydrocortisone, prednisolone and dexamethasone can also be administered I.V or I.M

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113
Q

Describe the distribution of the corticosteroid analogues

A

Distributed via plasma proteins (Corticosteroid Binding Globulin and albumin).
Hydrocortisone is most bound > prednisolone > dexamethasone and fludrocortisone (only albumin)

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114
Q

How are the corticosteroid analogues metabolised?

A

Hepatic metabolism by reduction of the A ring + other modifications and conjugation before excretion via bile and urine.

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115
Q

Describe the duration of action of the corticosteroid analogues

A
  • Hydrocortisone and fludrocortisone - 8h
  • Prednisolone - 12h
  • Dexamethasone - 40h
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116
Q

How is primary adrenocortical failure treated with corticosteroid replacement?

A

Treat with titrated oral doses of hydrocortisone and fludrocortisone, with electrolyte and BP monitoring

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117
Q

How is secondary adrenocortical failure treated with corticosteroid replacement?

A

They have normal aldosterone because of functioning RAS. So only treat with titrated oral hydrocortisone.

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118
Q

How is acute adrenocortical failure treated with corticosteroid replacement?

A

Also known as Addisonian Crisis
Treated wit I.V saline and hydrocortisone (high dose to produce mineralocorticoid effect)
5% dextrose can be added if hypoglycaemic

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119
Q

How is congenital adrenal hyperplasia treated with corticosteroid replacement?

A
  • hydrocortisone to suppress ACTH production and replace aldosterone with fludricortisone
  • therapy is optimised by measuring adrenal androgens
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120
Q

How is iatrogenic adrenocortical failure treated with corticosteroid replacement?

A

This is when patients have a suppressed HPA axis due to long-term steroid treatment.

  • administer hydrocortisone.
  • increase dose when patients are vulnerable to stress. For minor illnesses this is x2 of normal dose. For surgery give i.m hydrocortisone with 6-8h intervals with oral once eating and drinking.
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121
Q

What are the glucocorticoids used for?

A
  • replacement therapy for patients suffering from adrenal insufficiency
  • replacement therapy and suppression of ACTH in congenital adrenal hyperplasia
  • differential diagnosis of Cushing’s syndrome
  • controlling inflammation e.g asthma
  • produce immunosuppression in hypersensitivity, autoimmune disease and transplant patients
  • treatment of neoplastic diseases
  • to mature foetal lung prior to pre-term birth
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122
Q

What are the characteristics of an inflammatory response?

A

Rubor, Calor, Dolor and Tumor

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123
Q

What brings about the characteristics of an inflammatory response?

A
  • damaged cells releasing histamine and other mediators leading to vasodilation of blood vessels (accounting for redness and heat)
  • exudation of plasma and leukocytes causes local oedema (swelling)
  • some inflammatory mediators activate sensory afferents causing pain
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124
Q

What innate immune system mechanisms lead to inflammation?

A

Vascular events:

  • histamine release –> vasodilation
  • increased capillary permeability –> plasma exudate
  • activation of enzyme cascades –> release of inflammatory mediators such as bradykinin –> pain, activation of phagocytic cells etc

Cellular events:

  • release of pro-inflammatory mediators from mast cells
  • involvement of tissue macrophages
  • release of vasodilators and other mediators from endothelial cells
  • migration of cells from the blood into tissue
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125
Q

What are the anti-inflammatory actions of glucocorticoids?

A
  • inhibit vasodilator response and reduce fluid exudation
  • reduce influx and activity of polymorphonuclear leukocytes
  • inhibit recruitment of monocytes
  • inhibit angiogenesis
  • blocking clonal proliferation of T-cells and inhibiting fibroblast function
  • inhibit the production of pro-inflammatory mediators including histamine, eicosanoids (protanoids, leukotrienes and PAF), cytokines, complement components and NO.
  • enhances production of anti-inflammatory proteins e.g annexin-1
  • Reduce production of ECM by: reducing matrix production and increase production of degrading enzymes.
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126
Q

What is the molecular basis of glucocorticoid anti-inflammatory action?

A
  1. Blockade of Eicosanoid Production.
    - They are arachidonic acid derivatives which act as signalling molecules involved in inflammations, immunity and in the CNS. It does this by increasing the function and synthesis of annexing A1 which suppresses phospholipase A2 and COX-2
  2. Inhibition of Cell-Mediated Immune Responses
    - immunosuppression by glucocorticoids mainly through the decrease in the function and number of B and T lymphocytes
    - inhibition of NF-kB transcription factor promoting the synthesis of cytokines and other mediators that promote immune response.
    - inhibition of genes coding for IL-2 (most importantly, but also other ILs), reducing T-Cell proliferation.
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127
Q

What glucocorticoids are used for their immunosuppressive qualities?

A

Hydrocortisone in large doses has mineralocorticoid effects. Therefore prednisolone and dexamethasone are used.

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128
Q

How is iatrogenic Cushing’s syndrome risk reduced when administering glucocorticoids for their immunosuppressive actions?

A
  • administer locally
  • use minimum effective dose
  • usa a GR-selective (glucocorticoid receptor) drug
  • use ACTH in children to reduce growth suppression
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129
Q

How are ostrodiol esters administered?

A

They are given intramuscularly in oil. The oil vehicle delays absorption, prolonging the duration of action.

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130
Q

What are the three types of oestrogen?

A
  • OESTRIOL is naturally occurring and orally active oestrogen - only produced by the placenta during pregnancy
  • OESTRONE sulphate is a conjugated oestrogen which is the main post-menopausal oestrogen (produced in fatty tissue). It is hydrolysed to the more active oestrogen within peripheral tissues.
  • OESTRADIOL: ethinyl oestradiol is a semi-synthetic oestrogen based on the same structure of oestradiol but with an ethinyl group on C17. This is resistant to metabolism and therefore the drug of choice in HRT
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131
Q

How are oestrogens administered?

A
  • transdermal skin patches as oestrogens readily cross membranes, and a skin patch avoids first pass metabolism
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132
Q

What are the types of clinically used progestogens? Give examples of each.

A
  • progesterone and its analogues - medroxyprogesterone acetate. progesterone is poorly absorbed, and is also rapidly metabolised in the liver. Can be given I.M or in an oily vehicle.
  • testosterone analogues - such as norethisterone. A variety of orally active synthetic analogues are available.
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133
Q

What are the types of female hormone contraceptives?

A
  • combined oral contraceptives (COCs)
  • progesterone oral contraceptives
  • emergency contraceptives
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134
Q

What are the physiological actions of oestrogens?

A
  • negative and positive (in high conc.) feedback controlling FH surge and ovulation
  • increase uterine and fallopian tube contractility
  • reduce viscosity of cervical secretions to favour sperm penetration
  • stimulates endometrial proliferation and glandular secretions
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135
Q

what are the physiological actions of progesterone?

A
  • changes mucosal secretions in fallopian tubes
  • thickens cervical mucus (hostile to sperm)
  • decreases myometrial contractility
  • stimulates development of lobules and alveoli in mammary tissue
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136
Q

What are the three reasons oestrogen is often administered with progesterone as a contraceptive?

A

Progestogen such as norethisterone suppresses ovulation by feedback of progesterone in the hypothalamus and pituitary, suppressing menstrual cycle. Progesterone also thickens cervical mucus.

  • Oestrogen is important to up regulate progesterone receptors
  • Oestrogen counteracts androgenic effect of synthetic progesterone, preventing masculinisation.
  • Oestrogen also contributes to the negative feedback by synergising with progesterone.
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137
Q

How are COCs taken?

A

Taken for 21 days, then stopped for 7

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138
Q

What are the effects of oestrogen?

A
  • increased clotting factors –> incidence of thromboembolic disease
  • increased proliferation of endometrium –> increased risk of endometrial cancer
  • may cause breast cancer
  • increased salt and water retention may cause oedema, and contribute towards hypertension
  • nausea and headache
  • increased weight gain (fat and oedema)
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139
Q

When are progesterone-only contraceptives used?

A

when oestrogen is contraindicated

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140
Q

What are emergency contraceptive pills?

A

Progesterone at higher doses. Taken twice, 12h apart and within 72h of intercourse.

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141
Q

Define menopause

A

Menopause is the permanent cessation of menstruation due to the loss of ovarian follicular activity.

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142
Q

What hormones are high in menopause and why?

A

Due to loss of ovarial follicular activity –> decreased oestrogen production –> less negative feedback on GnRH, FSH and LH and so those hormones are high then.

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143
Q

What is the average age of menopause?

A
  1. Range (45-55)
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144
Q

What is considered premature menopause?

A

When it occurs before the age of 40

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145
Q

What are the causes of premature menopause?

A

Autoimmune, surgery, chemotherapy or radiation

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146
Q

What are the symptoms of menopause?

A
  • hot flushes
  • urogenital atrophy
  • sleep disturbance
  • depression
  • decreased libido
  • joint pain
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147
Q

What are the main complications of menopause?

A
  • osteoporosis as oestrogen deficiency causes loss of bone matrix and x10 increase in fracture risk
  • cardiovascular disease as previously protected against CVD
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148
Q

Outline the three treatment options for menopause

A
  1. HRT (Hormone Replacement Therapy)
  2. Tibolone
  3. SERMs (Selective oEstrogen Receptor Modifying drugs)
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149
Q

Describe how HRT can treat menopause

A

Oestrogen and progesterone is used to treat vasomotor symptoms and delay osteoporosis. Oestrogen on its own would cause endometrial proliferation (this risk of endometrial carcinoma).
Oestrogen given daily, and progesterone every 12-14 days.

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150
Q

Describe how Tribolone can treat menopause

A

Synthetic pro hormone with oestrogen, progestognenic and weak androgenic actions. It reduces fracture risk, however is associated with an increased risk of stroke and breast cancer.

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151
Q

Describe how SERMs can treat menopause. Include two SERMs and their properties.

A

Selective Oestrogen Receptor Modifying Drugs can activate oestrogen metabolic pathway, but in some tissues block the ability of oestrogen.

  • Raloxifine is oestrogenen in bone (reduces risk of fractures) and anti-oestrogenic in breast an uterus. However increased risk of fatal stoke and VTE
  • Tamoxifen is anti-oestrogenic in breast tissue and can also therefore be used to treat certain breast tumours.
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152
Q

What is the nature of GnRH release from the hypothalamus?

A

GnRH is released in pulses, which stimulates release of LH and FSH from the pituitary

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153
Q

What effects do LH and FSH have on males?

A
  • LH stimulates testosterone production from the Leydig cells of the testis. Testosterone aids in spermatogenesis
  • FSH stimulates sertoli cells in the seminiferous tubules to stimulate spermatogenesis and the release of inhibin A and B
154
Q

Describe the negative feedback mechanisms of the male reproductive hormone system

A
  • Testosterone has a neg feedback on the release of LH from the pituitary, and a negative effect on the hypothalamus (to release GnRH)
  • Inhibin negatively feedback in the hypothalamus and pituitary gland (specifically on FSH release)
155
Q

How long is the female menstrual cycle?

A

28 days

156
Q

What phases can the menstrual cycle be split into?

A
  • Follicular phase
  • Ovulation
  • Luteal phase

Also proliferative and secretory phases

157
Q

What causes the spike in oestrogen before ovulation?

A
  • by day 10 the leading follicle develops into a mature Graffian follicle which relates large amounts of oestrogen.
158
Q

What causes the spike in LH before ovulation?

A

Initially oestrogen has a negative effect on LH and FSH. However, large amounts of oestrogen secreted by the Graffian follicle, causes a positive feedback mechanism which increases GnRH release as well as increased LH sensitivity to GnRH, resulting in a mid-cycle LH surge.

159
Q

Describe the state of oestrogen and progesterone levels after ovulation (assuming no fertilisation)

A

The Graffian follicle releases large amounts of progesterone as well as oestrogen. The large amounts of progesterone works with oestrogen it has a negative feedback on GnRH. Absence of fertilisation will see decrease of oestrogen and progesterone, which are no longer able to support the endometrium, causing menstruation.

160
Q

Define infertility

A

The inability to conceive after 1 year of regular unprotected sex.

161
Q

How many couples for infertility affect?

A

1 in 7

162
Q

What is the distribution of ‘blame’ for infertility within the couple?

A
  • 30% males
  • 45% females
  • 25% unknown
163
Q

Compare and contrast the hormone features of primary, secondary and tertiary gonadal failure

A

All have low sex steroids
Primary has HIGH LH, FSH and GnRH
Secondary has low LH and FSH while high GnRH
Tertiary has low LH, FSH and low GnRH

164
Q

What are the clinical features of male hypogonadism?

A
  • loss of libido
  • impotence
  • small testes and low secondary sexual characteristics
  • decrease in muscle bulk and testosterone is an anabolic hormone
  • osteoporosis as testosterone is normally converted to oestrogen, important for bone strength and health
165
Q

What are the hypothalamic-pituitary causes of male hypogonadism?

A
  • Hypopituitarism
  • Kallman’s Syndrome: embryologically GnRH neurones progress from olfactory bulb to hypothalamus. Any problem leads to low GnRH. Patients also present with anosmia, not going through puberty etc.
  • Illness/underweight puts one in an unfavourable reproductive state
  • hyperprolactinaemia - prolactin inhibits gonadotrophs in men and women
166
Q

What are the primary gonadal causes of male hypogonadism?

A
  • Kleinfelter’s Syndrome (XXY) - have non-functional testes
  • 5-alpha-reductase deficiency which normally converts testosterone to DHT
  • testicular torsion and chemotherapy
  • androgen receptor deficiency
167
Q

What laboratory investigations can be done to investigate male hypogonadism?

A
  • LH, FSH and Testosterone. This can point to a pituitary problem, primary gonadal failure or receptor defect
  • Prolactin: it inhibits GnRH, LH and FSH
  • Sperm count: Azoospermia is the absence of sperm in the ejaculate. Oligospermia is reduced numbers of sperm in the ejaculate. Also look at the morphology and motility of the sperm.
  • Chromosomal checks for Kleinfelter’s
168
Q

How is male hypogonadism treated?

A

Treating male hypogonadism involves offerting replacement testosterone. However, if they want to be fertile this will not work as testosterone will cause negative feedback on GnRH on the hypothalamus. For those patients, GnRH and LH/FSH is important.

A patient with hyperprolactinaemia can be treated with a dopamine agonist such as bromocriptine.

169
Q

What are the androgens?

A

Testosterone, androstenedione and dihydroepiandosterone

170
Q

Where are androgens produced?

A

Leydig cells, adrenal cortex (zona reticularis), ovaries, placenta and tumours.

171
Q

What are the functions of testosterone?

A
  • non-reproductive action such as increased muscle mass, deepening of voice, and male pattern of hair
  • works of Sertoli cells, aiding in spermatogenesis
  • converted to DHT (dihydrotestosterone) in specific tissues to aid in development of the male phenotype - development of male genital tract etc.
  • converted to oestrogens
172
Q

How is testosterone converted to DHT?

A

5-alpha-reductase enzyme in specific tissues

173
Q

Where is testosterone converted to DHT?

A

In the prostate, seminiferous tubules, seminal vesicles, brain and vesicles.

174
Q

What receptors do DHT have an affinity towards?

A

Androgen Receptors (more potent than testosterone)

175
Q

How and where is testosterone converted to oestrogens in the male body?

A

Converted to oestrogens via aromatisation reactions by the enzyme aromatase. This occurs in the adrenal glands, sertoli cells, liver, skin, ADIPOSE TISSUE and brain.

176
Q

What receptors do oestrogens have an affinity towards?

A

Oestrogen receptor (ER)

177
Q

Describe the distribution of testosterone bound in the blood

A

60% bound to SHBG (Sex Hormone Binding Globulin), 38% bound to albumin, 2% free.

178
Q

What are the unwanted effects of testosterone?

A
  • Acne and oily skin
  • Increased haematocrit
  • Exacerbates sleep apnoea
  • Accelerates prostate cancer
  • Alopecia
  • Excess can cause infertility
179
Q

Define amenorrhoea

A

The absence of periods.

180
Q

How does female hypogonadism present?

A

Amenorrhoea

181
Q

What is the difference between primary and secondary amenorrhoea?

A

NOT PRIMARY/SECONDARY HYPOGONADISM.

Primary amenorrhoea is the failure to begin spontaneous menstruation by the age of 16 years.
Secondary amenorrhoea is the absence of menstruation for 3 months in a woman who has previously had cycles.

182
Q

Define oligomenorrhoea

A

Irregular/infrequent cycles.

183
Q

What are the causes of amenorrhoea?

A
  • pregnancy/lactation
  • ovarial failure: premature ovarian failure tends to run in families, ovariectomy/chemotherapy, ovarian dysgeneisis due to Turners syndrome
  • PCOS (polycystic ovarial syndrome)
  • gonadotrophin failure: hypopituitarism, kallman’s syndrome, low BMI, or post-pill amenorrhoea
  • hyperprolactinaemia
  • androgen excess due to tumour
184
Q

What investigations can be done to investigate female hypogonadism?

A

1st!: Check if they are pregnant

  • LH, FSH and Oestrodiol can be measured.
  • Day 21 progesterone should be measured
  • Prolactin should also be measured
  • A thyroid function test
  • Test for excess androgens
  • Ultrasound of ovaries.
185
Q

How can female hypogonadism be treated?

A

Treatment available for certain causes like low weight.
Those with primary ovarian failure remain infertile.
GnRH or gonadotrophin are administered to treat hypothalamic/pituitary diseases.

186
Q

Describe the disease of PCOS

A

Polycystic Ovarian Syndrome affects 1 in 12 and is the most common female endocrine disorder.
It is a complex, heterogenous disorder of uncertain aetiology, however evidence shows i has a large genetic influence.
It is one of the leading causes of female sub fertility and is associated with increased CVS risk and insulin resistance.

187
Q

What are the clinical features of PCOS?

A
  • Anovulation resulting in irregular menstruation, ammennorhoea, ovarian-related infertility, and polycystic ovaries
  • Excessive androgenic hormonen results in acne and hirsutism.
188
Q

How can PCOS be diagnosed?

A
  • ultrasound identification of polycystic ovaries
  • oligo/anovulation
  • androgen excess
189
Q

How is PCOS treated?

A
  • metformin to combat insulin resistance, and therefore weight gain
  • clomiphene binds to and blocks oestrogen receptors in the hypothalamus, preventing normal negative feedback –> increase in GnRH to kick start periods
  • Gonadotrophin administration to replace LH/FSH in conjunction with IVF
  • Reverse circadian prednisolone suppresses pituitary ACTH production, which drives adrenal androgen production. This leads to regular cycles
  • To treat hirsutism, reduce testosterone, increase oestrogen
190
Q

What are the causes of hyperprolactinaemia?

A
  • Dopmaine antagonists such as anti-emetics or anti-psychotics
  • Prolactinomas
  • Pituitary adenomas can cause stalk depression, preventing dopamine getting through infundibulum to the lactotrophs
  • PCOS
  • Secondary hypothyroidism (increased TSH)
  • Oestrogens
  • Pregnancy, lactation
  • Idiopathic
191
Q

How is hyperprolactinaemia investigated?

A

Looking at drug history, serum prolactin, pregnancy test and thyroid function test. Also anterior pituitary function, MRI pituitary, visual fields test.

192
Q

Where is most seminiferous fluid reabsorbed?

A

Rete testes and early epididymis

193
Q

Under the control of what hormone does seminiferous fluid reabsorption occur?

A

Oestrogen

194
Q

Under the control of what hormone(s) are nutrients and other molecules secreted into the seminiferous fluid?

A

Androgens

195
Q

Why is nutrient and glycoprotein secretion into the seminiferous fluid necessary?

A
  • they provide energy for the journey ahead

- they coat the surface of the spermatozoa

196
Q

What part of the testes has smooth muscle that contracts in order to allow ejaculation?

A

The vas deferent has smooth muscle that is stimulated to contract by the sympathetic nervous system.

197
Q

Is the concentration of spermatozoa high or low at the vas deferens and why?

A

High. This is because most fluid has been reabsorbed by the rete testes and the early epididymis.

198
Q

What are the components of semen?

A
  • Spermatozoa
  • Seminal fluid
  • Leukocytes
  • Potentially viruses
199
Q

How many spermatozoa does semen contain?

A

15-120 x 10^6/ml

200
Q

How much seminal fluid is in semen?

A

2-5ml

201
Q

What organs do the seminal fluids originate from?

A
  • Prostate (1/3)

- Seminal vesicle (2/3)

202
Q

What does the seminal fluid contain?

A
  • Fructose
  • Fibrinogen
  • Citric Acid
  • Acid Phosphatase
  • Fibrinogenase
  • Fibrinolytic Enzymes
203
Q

What is the purpose for the clotting factors in semen?

A

Semen initially clots due to fibrinogens to get into the vagina. Then the fibrinolytic enzymes breaks this down.

204
Q

What is the difference between spermatozoa activation and capacitation?

A
  • From the vas deferens, spermatozoa are capable of limited movement (whiplash activity) and have only limited capacity of fertilising ovum - this is called activation
  • Full activity and fertilising capability is only achieved within the female tract - this is called capacitation.
205
Q

What percentage of the spermatozoa enter the cervix from the ejaculate?

A

1%

206
Q

What changes are involved in the process of spermatozoa capacitation?

A
  • The loss of a glycoprotein coat
  • Change in surface membrane characteristics leading to acrosome reaction when in close proximity to ovum
  • Whiplash movements of tail for movement within female reproductive tract
207
Q

What conditions are needed for spermatozoa capacitation processes?

A

The process requires oestrogen and Ca2+. They take place in the ionic and proteolytic environment of the oviduct.

208
Q

Describe the acrosome reaction

A

This reaction binds the acrosome of the sperm to the zona pellucid of the ovum via the ZP3 glycoprotein.

209
Q

What events after the acrosome reaction lead to the emptying of the acrosome?

A

Binding of the acrosome to the zona pellucida via the ZP3 glycoprotein causes Ca2+ influx into the sperm stimulated by progesterone.
This enables an exposed spermatozoon recognition site to bind to the second glycoprotein ZP2.
Subsequently the spermatozoon releases the contents of the acrosome.

210
Q

What does the acrosome contain?

A

Hyaluronidase and other proteolytic enzymes.

211
Q

Where does fertilisation normally take place?

A

The oviduct (Fallopian tube)

212
Q

What happens after fertilisation to prevent other sperm from reaching the egg?

A

After fertilisation, this results in the completion of the second phase of meiosis of the egg. This then results in the expulsion of the second polar body. This immediately causes the zonal reaction, where cortical granules release molecules which degrade the zona pellucid preventing the binding of other sperm.

213
Q

When after fertilisation does the conceptus move into the uterus?

A

3-4 days

214
Q

When does implantation occur?

A

9-10 days after fertilisation

215
Q

From where does the conceptus receive its nutrients before implantation?

A

Uterine secretions

216
Q

What prompts the conceptus from transferring to the uterus?

A

Increasing progesterone to oestrogen ratio

217
Q

What are the phases of implantation?

A
  • Attachment

- Decidualisation

218
Q

Describe the process of blastocyst attachment, with the hormones involved.

A

This is where the outer trophoblast cells will contact the uterine surface epithelium.

  • Leukaemia inhibitory factor (LIF) is secreted by endometrial secretory gland which stimulates adhesion of blastocyst to endometrial cells
  • IL-11 also from endometrial cells is released into the uterine fluid and is involved in the phase, along with many other molecules.
219
Q

Describe the process of uterine decidualisation, with the hormones involved.

A
  • invasion of the stroll tissue by the trophoblast cells of the blastocyst
  • increased vascular permeability in the invasion region, associated with oedema of tissues
  • localised changes in intracellular composition and progressive sprouting and growth of capillaries
  • factors include IL-11, histamine, certain prostaglandins and TGF(beta)
220
Q

Describe the levels of oestrogen and progesterone during pregnancy

A

Oestrogen and progesterone levels increase dramatically

221
Q

Describe the levels of prolactin during pregnancy

A

Prolactin will increase during pregnancy for lactation later.

222
Q

What is human placental lactogen?

A

It is a hormone produced from the developing placenta that has growth hormone and prolactin properties.

223
Q

Describe the reason for the rise of hCG during pregnancy.

A

hCG is essential for keeping the corpus luteum alive while LH and FSH levels are low at the beginning of pregnancy. At the end of the menstrual cycle, oestrogens and progesterones are high, inhibiting LH and FSH release. This would cause the corpus luteum to atrophy - but it is needed as oestrogen and progesterone (released by it) are essential for foetoplacental development.

Therefore the synctiotrophoblast of the blastocyst produces hCG, which has LH-like effects on the corpus luteum.

224
Q

Describe the reason for the fall of hCG during pregnancy.

A

Around day 40, the lutes-placental shift means that the main producer of gonadal steroids is now the placenta, not the corpus luteum. This means the corpus luteum does not need to be kept alive (LOL so ruthless).

225
Q

Describe how the conceptus produces sex hormones in early pregnancy

A
  • The mother and placenta produce prognenolone.
  • The foetal adrenal glands use this to make DHEA-S (Dehydroepiandrosterone-Sulphate)
  • The foetal liver conjugates this to 16-alpha-DHEA-S

The placenta converts DHEA-S to oestradiol and oestrone. The placenta also converts 16-alpha-DHEA-S to oestriol.

226
Q

What maternal hormones increase, and what maternal hormones decrease during pregnancy?

A

Increase:

  • thyrotrophin
  • corticotrophin
  • prolactin
  • somatotrophin
  • iodothyronines
  • adrenal steroids
  • PTH

Decrease:
- gonadotrophins

227
Q

Define parturition

A

Parturition is the contraction of the endometrial smooth muscle.

228
Q

How does the foetus cause parturition?

A

The foetus produces cortisol, which stimulates the placenta to release oestrogen that up regulates oxytocin receptors and phospholipase A2.

  • Phospholipase A2 will convert AA -> prostaglandin F2a, which increases intracellular calcium release via INTRACELLULAR stores of the myometrial cells.
  • oxytocin binds to the myometrium to allow EXTRACELLULAR calcium to enter the smooth muscle cell
229
Q

Why doesn’t cortisol normally lead to parturition?

A

In pregnancy, progesterone dominates and prevents oestrogen from causing contractions. Foetal stress in parturition leads to adrenals producing large amounts of cortisol which gets converted to oestrogen. This is then in high enough concentration to have effects.

230
Q

How does suckling lead to prolactin release?

A
  • Tactile mechanoreceptors in the great send nervous impulses to the neurohypophysis. This causes inhibition of dopamine relate and stimulation of TRH release to the adenohypophysis –> prolactin release.
231
Q

How do prolactin and oxytocin aid in lactation?

A
  • Prolactin release works on breast alveoli to stimulate milk synthesis.
  • Oxytocin works on the myoepithelial cells to stimulate milk ejection.
232
Q

What is the proper name of Vitamin D and Vitamin D3?

A

Calciferol and Cholecalciferol

233
Q

What is the molecular name of calcitriol?

A

1,25(OH)2D3

1,25-dyhydrocholecalciferol

234
Q

What is the active metabolite of vitamin D?

A

Calcitriol

235
Q

What are the effects of calcitriol?

A
  • Stimulate intestinal absorption of Ca2+ (and Mg2+) and PO4(3-)
  • Stimulate osteoclast and osteoblasts (bone remodelling)
236
Q

What disease occurs as a result of vitamin D deficiency?

A

Leads to lack of mineralisation in bone. This results in softening if bone, bone deformities and bone pain as well as severe proximal myopathy. In children this is called Rickets, while in adults, Osteomalacia.

237
Q

What can be the causes of a Vitamin D deficiency?

A
  • Inadequate diet. Normally found in fish, liver, cheese etc
  • Lack of exposure to UV rays, leads to decreased production of D3 precursors
  • Renal failure will affect production of 1-alpha-hydroxylase
  • GI malabsorption
  • Receptor defects
238
Q

What are the two pathways in which we acquire vitamin D?

A
  1. Under UV light, 7-deydrocholesterol in the skin is converted to cholecalciferol (D3)
  2. From our diet, we ingest ergocalciferol (D2)
239
Q

How and where is calciferol synthesised?

A

Vitamin D3 (cholecalciferol) is converted to 25-dehdryoxycholecalciferol by hepatocytes in the liver. This is done by enzyme 25-alpha-hydroxylase. 25(OH)D3 is stored in the body as a precursor hormone.

It is then converted to 1,25(OH)2D3 via enzyme 1-alpha-hydroxylase in the parenchymal cells of the proximal tubule.

240
Q

What are the diagnostic features of a vitamin D deficiency?

A
  • Plasma 25(OH)D3 is usually low (indicating a problem with one of the sources of making VitD rather than receptor problem)
  • Plasma [Ca2+] is low (unless hyperparathyroidism has been induced, when it may appear normal)
  • high PTH levels
  • Plasma PO4(3-) is low
  • Radiological findings e,g widened osteoid seams
241
Q

How is Vitamin D deficiency treated?

A

Treatment with ergocalciferol or cholecalciferol if kidney is functional.
If a renal failure patient, then give alfacalcidiol (as is 1-alpha-hydroxycholecalciferol)

242
Q

Explain how renal dysfunction leads to bone disease.

A

Renal dysfunction leads to a condition called Osteitis fibrosa cystica.

  • Calcitriol levels are low as kidneys not producing enough 1-alpha-hydroxylase enzyme –> decreased Ca2+ reabsorption.
  • Decreased phosphate excretion –> increased plasma phosphate –> extra-skeletal calcification.

Both factors lead to a state of hypocalcaemia. This causes increased PTH secretion, which in turn increases bone absorption and decreases formation.

243
Q

What is the sequelae of vitamin D intoxication?

A

Can lead to a state of hypercalaemia (stones, abdominal moans, and psychic groans), and hypercalciurea.

244
Q

What is Paget’s disease?

A

A very active, localised by disorganised bone metabolism.

245
Q

What are the disease characteristics of Paget’s disease?

A
  • slowly progressive
  • characterised by large abnormally active osteoclasts
  • significant genetic component, may have viral origin
  • more than 10% of 60+ are affected (but majority have no symptoms)
246
Q

What are the symptoms of Paget’s disease?

A
  • increased vascularity (felt by warmth over affected bone)
  • increased osteoclasts activity, followed by increased osteoblast activity
  • pelvis, femur, spine, skull and tibia most commonly affected.
  • fractures are common
  • bone pain due to nerve entrapment and joint involvement
247
Q

What are the diagnostic features of Paget’s disease

A
  • normal [Ca2+]
  • increased plasma [alkaline phosphatase] which is a sign of increased bone activity
  • radiology showing loss of trabecular bone, increased density, and deformity
  • radioisotope scanning indicating area of involvement.
248
Q

What are the roles of calcium?

A
  • neuromuscular excitability
  • bone mineralisation
  • intracellular secondary messenger
  • intracellular co-enzyme
  • hormone/neurotransmitter release coupling
  • blood coagulation (Factor IV)
  • excitable cells
249
Q

What is the distribution of calcium in the body?

A

95% in bone.
4% in plasma
1% intracellular

250
Q

What percentage of the bone is organic and what percentage is inorganic?

A

Organic (osteoid) is 35% of bone

65% is inorganic

251
Q

What forms the organic and inorganic component of bone?

A

Organic is mainly collagen. Inorganic is mainly calcium hydroxyapatite crystals.

252
Q

What do osteoclasts and osteoblasts do?

A

Osteoblasts synthesise osteoid and participate in mineralisation/calcification of osteoid.
Osteoclasts release lysosomal enzymes which break down bone.

253
Q

What is plasma calcium ion concentration?

A

2.3-2.6 mmol/l

254
Q

What is our average daily calcium intake and loss?

A

Intake is 1000mg

Loss via faeces is 850mg. Loss via urine is 150mg.

255
Q

What hormones are the regulators of plasma calcium concentration?

A
  • Plasma [Ca2+] is increased by PTH and subsequently 1,25(OH)2D3.
  • Plasma [Ca2+] is decreased by calcitonin
256
Q

How and where is PTH synthesised?

A

PTH is synthesised by the parathyroid glands, initially as pre-pro PTH.

257
Q

How big is PTH?

A

84 amino acids long

258
Q

Describe the receptor that PTH binds to

A

PTH binds to PTH receptors - G-protein coupled receptors which work through adenyl cyclase and possibly phospholipase C secondary messengers.

259
Q

How and where is calcitonin synthesised?

A

Parafollicular cells of the thyroid gland

260
Q

How big is calcitonin?

A

32 amino acids long

261
Q

Describe the receptor that calcitonin binds to

A

It binds to transmembrane G-protein coupled receptors which also work through adenyl cyclase and phospholipase C.

262
Q

What are the effects of PTH?

A

Bones:
- PTH receptors inhibit osteoblasts and stimulates production of Osteoclast Activating Factors (OAFs).
- OAFs bind to and stimulate oestoclasts
Therefore leading to increased calcium mobilisation

Kidneys:

  • enhances reabsorption of calcium and magnesium from distal tubules and thick ascending limb
  • increased excretion of phosphates
  • stimulates 1-alpha-hydroxylase activity which increases the synthesis of calcitriol.

(indirect) intestine increased calcium absorption

263
Q

What are the effects of calcitonin?

A
  • inhibits osteoclasts
  • increases Ca2+, Na+ and PO4 excretion from the kidneys
  • inhibits 1-alpha-hydroxylase enzyme
264
Q

What stimulates parafollicular cells to release calcitonin?

A

An increase in [Ca2+] in plasma stimulates calcitonin.

Gastrin also stimulates calcitonin production.

265
Q

How does hypocalaemia present?

A

CATs go numb:

Convulsions, Arrythmias, Tetany and Paresthesia in hands, mouth, feet and lips.

266
Q

What are two examination signs of hypocalaemia?

A
  • Chvostek’s sign is when tapping the facial nerve just below the zygomatic arch, a positive response is twitching of facial muscles to indicate hypocalaemia
  • Trousseau’s sign is when inflation of BP cuff for several minutes induces carpopedal spasm indicating neuromuscular irritability due to hypocalaemia.
267
Q

What are the causes of hypocalaemia?

A
  • Hypoparathyroidism (due to surgical removal of parathyroid, or autoimmune destruction)
  • Vitamin D deficiency
  • Renal failure (impaired 1-alpha-hydroxylation)
  • PTH resistance (pseudohypoparathroidism)
268
Q

What are the symptoms of hypercalaemia?

A

STONES = renal effects:

  • polyuria (calcium inhibits Na/Cl/K pump resulting in more Na+ in the nephron lumen) followed by polydipsia
  • Nephrocalcinosis (deposition of calcium salts in renal parenchyma), kidney stones, chronic renal failure

ABDOMINAL MOANS = GI effects:

  • Anorexia
  • Nausea
  • Dyspepsia
  • Constipation
  • Pancreatitis

PSYCHIC GROANS = CNS effects:

  • Fatigue
  • Depression
  • Impaired concentration
  • Altered mentation
  • Coma if >3mmol/l
269
Q

What are the causes of hypercalaemia?

A
  • Primary hyperparathyroidism
  • Tumours can secrete PTH-like peptide (PTHLP). This is the most common cause
  • Conditions with high bone turnover e.g hyperthyroidism and Paget’s disease
  • Vitamin D excess (rare)
270
Q

How can you biochemically investigate the cause of hyperparathyroidism?

A

Primary hyperparathyroidism will test as high [Ca2+] but with unsuppressed (high) PTH. Whereas malignancy releasing PTHLP would test with low levels of PTH, as parathyroid is functioning normally.

271
Q

Define osteoporosis

A

Osteoporosis is a condition of reduced bone mass and distortion of bone microarchitecture which predisposes to fracture after minimal trauma.
T-score of

272
Q

What does RANKL binding cause?

A

Stimulates the maturation of osteoclasts, therefore increase bone reabsorption.

273
Q

How is a T-score arrived at?

A

A T-score measures BMD (bone mineral density) against a young reference population. BMD is measured by DEXA (Dual Energy X-ray Absorptiometry)

274
Q

What conditions pre-dispose to osteoporosis?

A
  • Post-menapausal oestrogen deficiency.
  • Age (osteoclast senescence and raised PTH)
  • Hypogonadism
  • Endocrine conditions such as Cushing’s, Hyperthyroidism and Hypoparathyroidism
275
Q

Why is oestrogen protective against osteoporosis?

A
  • Oestrogen normally blocks PTH effects on osteoclasts preventing abnormal bone reabsorption.
276
Q

List the available treatments for osteoporosis

A
  • Oestrogen (HRT)
  • SERMs
  • Bisphosphonates
  • Denosumab
  • Teriparatide
  • Strontium ranalate
277
Q

How can bisphosphonates treat osteoporosis?

A

Bind to hyroxyapetite and injected by osteoclasts, impairing their ability to reabsorb bone and promoting apoptosis.

278
Q

Give examples of bisphosphonates

A

Alendronate and Sodium Etidronate

279
Q

What are the side effects of bisphosphonates?

A

Oesophagitis, flu-like symptoms, osteonecrosis of jaw, atypical fractures.

280
Q

How does Denosumab treat osteoporosis?

A

Binds to RANKL inhibiting osteoclast formation and activity

281
Q

How does Teriparatide treat osteoporosis?

A

Recombinant fragment of PTH, increases bone formation but also bone reabsorption?

282
Q

How does Strontium ranalate treat osteoporosis?

A

Stimulates bone formation.

283
Q

Define Type 1 Diabetes Mellitus

A

It is an organ specific autoimmune disease that leaves patients with an absolute insulin deficiency.

284
Q

Define Type 2 Diabetes Mellitus

A

It is insulin resistance that makes beta cells work harder to secrete more insulin, eventually leading to beta cell failure.

285
Q

What is the name of the condition when Type 1 Diabetes presents in adults?

A

Latent Autoimmune Diabetes in Adults (LADA)

286
Q

Why are the boundaries (in terms of presenting in the clinic) of Type 1 and Type 2 diabetes not clear?

A
  • A rise in childhood obesity has lead to type 2 presenting in children and adolescence
  • Advanced Type 2 diabetes can also present with ketoacidosis
287
Q

Describe the pathogenesis of Type 1 Diabetes

A

Interactions between genes and environment leads to autoimmune destruction of beta-cells in the islet of langerhans. There is a role of T-lymphocytes in this pathogenesis, as over time, effector T-cell levels increase, while T-reg levels decrease.

288
Q

Why is the autoimmune nature of Type 1 Diabetes Mellitus important to keep in mind?

A
  • Patients often also have other autoimmune conditions
  • Risk of autoimmunity in relatives
  • Autoimmune nature ensures a more complete destruction of beta-cells
289
Q

What evidence suggests that the environment triggers Type 1 diabetes mellitus?

A

Seasonal variations - highest presentation in spring and autumn, while a reduced presentation in summer and winter.

290
Q

What genes/alleles are protective, and what pose a significant risk in the development in Type 1 Diabetes Mellitus?

A

In the HLA-DR gene:

  • DR3 and DR4 allele pose a significant risk
  • DR2 has a protective effect
291
Q

What immune markers can me used to confirm the diagnosis of Type 1 Diabetes Mellitus?

A
  • Islet Cell Antibodies (ICA)
  • Insulin Antibodies
  • Glutamic Acid Decarboxylase Antibodies
  • Insulinoma-assoicated-2 antibodies
292
Q

What are the symptoms (not signs) of Type 1 Diabetes Mellitus?

A

Symptoms:

  • Polyuria and Polydipsia
  • Nocturia
  • Blurring of vision
  • Thrush
  • Weigh loss
  • Fatigue
293
Q

What are the signs (not symptoms) of Type 1 Diabetes Mellitus?

A
  • Dehydration
  • Cachexia
  • Hyperventilation due to metabolic acidosis
  • Smell of ketones
  • Glycosuria
  • Ketonuria
294
Q

Why does polyuria occur in Diabetes Mellitus?

A

Because sugar concentration is greater than 6mm/l, exceeding the ability of the PCT to reabsorb excess glucose –> glycosuria. This causes an osmotic diuresis as water follows the glucose.

295
Q

Why is thrush often occur in Diabetes Mellitus?

A

Candida (yeast) likes glucose environments.

296
Q

Why does weight loss occur in Type 1 Diabetes Mellitus?

A

There is a lack of insulin to suppress proteolysis and lipolysis.

297
Q

What would a state of glycosuria and ketonuria (simultaneously) point to?

A

Type 1 Diabetes Mellitus, as these two states don’t present at the same time normally. Ketones are produced in the absence of insulin as the liver is not suppressed to break down fatty acids (not a problem in Type 2 DM).

298
Q

What are the principles of a diet one should follow for Diabetes Mellitus?

A
  • Reduced calories as fat (to reduce risk of atherosclerosis)
  • Reduce calories as refined carbohydrates
  • Increase calories as complex carbohydrates (as they have a lower glycemic load with which insulin can cope with)
  • Increase soluble fibre (to increase time taken to absorb calories)
  • Balanced distribution of calories throughout the day
299
Q

Why is it difficult to administer the right level of insulin for a patient with Type 1 Diabetes Mellitus? How is this overcome?

A

Healthy individuals have a background level of insulin with peaks and mealtimes. A short acting insulin/analogue is taken with meals, while a longer acting (non-covalently bound zinc or protamine) is used to provide background insulin.

300
Q

How can Type 1 Diabetes Mellitus be treated apart from insulin analogues and diet?

A

Islet cell transplants require cells of two cadavers. They are transplanted to the patient’s portal vein embedded in the liver. Although given in the portal circulation, patient will still need immunosuppression.

301
Q

How can the treatment of Type 1 Diabetes Mellitus be monitored?

A
  • Capillary glucose monitoring kit

- HbA1c levels showing long-term glycemic control.

302
Q

Describe the use of HbA1c levels

A

HbA1c levels show long-term glycemic control. There is a correlation between mean [glucose] in blood and HbA1c. However, lots of factors can affect how reflective HbA1c is. Lowering HbA1c is associated with a lower risk of complication.

303
Q

How is diabetic ketoacidosis an acute complication in patients being treated for Type 1 Diabetes Mellitus?

A

Due to decompensation (when patients forget insulin). The condition is encompassed by hyperglycaemia and metabolic acidosis as well as osmotic dehydration and poor tissue perfusion.

304
Q

What is a major complication in the treatment of Type 1 Diabetes Mellitus?

A

Hypoglycaemia.

305
Q

Define hypoglycaemia

A

A plasma glucose level of

306
Q

What are the warning signs of hypoglycaemic events (in Type 1 Diabetes Mellitus)?

A

Autonomic symptoms:

  • Palpitations
  • Tremor
  • Sweating
  • Pallor
  • Anxiety
307
Q

How can hypoglycaemic events be treated?

A

IV dextrose (10%) and 1mg of Glucagon intramuscularly.

308
Q

Define Diabetes Mellitus

A

A state of chronic hyperglycaemia, sufficient to cause long-term damage to specific tissues. Notably the retina, kidneys, nerves and arteries.

309
Q

Describe the test used to diagnose Diabetes Mellitus?

A

Glucose tolerance test, where 75g of glucose is administered orally.

310
Q

What glucose blood levels diagnoses a patient with Diabetes Mellitus?

A

Fasting test: >7mmol/l

2h after glucose tolerance: >11.1mmol/l

311
Q

What are the consequences of having impaired glucose tolerance?

A
  • Increased risk for macrovascular complications

- Increased risk of developing Diabetes Mellitus

312
Q

What is the cause of Type 2 Diabetes Mellitus?

A

Genes, along with intrauterine and adult environment cause Type 2 Diabetes Mellitus. It is a result of insulin resistance and an insulin secretion defect. Insulin resistance is present for many years before blood sugar levels rise. Overworked beta-cells eventually lead to their failure and insulin secretion defect.

313
Q

Describe the aetiology of MODY

A

Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant condition, which has 8 forms. They all cause ineffective beta-cell insulin production. This is due to mutations of transcription factor genes or glucokinase genes.

314
Q

What causes insulin resistance?

A
  • Range of genes
  • Epigenetic effect
  • Intra-uterine Growth Restriction
  • Obesity and other fatty acid disorders
315
Q

How does insulin resistance cause health issues?

A

Insulin resistance leads to a state of dyslipidaemia and hypertension. This leads to macrovascular issues.

316
Q

How does beta cell failure cause health issues?

A
  • Diabetes symptoms

- Hyperglycaemia and worsened dyslipidaemia leads to microvascular issues.

317
Q

What health complications arise due to Type 2 Diabetes Mellitus?

A 
Microvascular:
- Retinopathy
- Neuropathy
- Nephropathy
Macrovascular:
- Ischaemic heart disease
- Cerebrovascular disease
- Renal artery stenosis
- Peripheral vascular disease
Metabolic:
- Lactic acidosis and hyperosmolar urine
318
Q

Which of Type 1 and Type 2 diabetes mellitus has a stronger genetic component?

A

Type 2!

319
Q

In terms of levels of insulin resistance and beta-cell failure, when can you be said to have Type 2 Diabetes Mellitus?

A

The more insulin resistant one is, the more insulin secretion is needed to maintain a correct glucose level. When enough insulin is not made, you are diabetic.

This is when insulin resistance and beta-cell failure lines cross.

320
Q

Why is weight loss rare in Type 2 Diabetes Mellitus?

A

There is enough insulin to suppress proteolysis.

NEFAs do not undergo Beta-oxidation in the liver.

321
Q

Why is there high circulating lipids in Type 2 Diabetes Mellitus?

A

Increased secretion of VLDL, as well as decreased clearance.

Obesity is often a precipitant in DM.

322
Q

Why is obesity a precipitant of Type 2 Diabetes Mellitus?

A

Fatty acids and adipocytokines play a huge part in the pathophysiology of T2DM as they modulate insulin resistance. In particular mental fat.

323
Q

What percentage of patients with Type 2 Diabetes Mellitus are obese?

A

80%

324
Q

What are the management principles for Type 2 Diabetes Mellitus?

A

Education, Diet, Pharmacy and Complication Screening

325
Q

What are four aspects of a Type 2 diabetic patient that needs to be monitored and treated?

A
  1. Weight
  2. Glycaemia
  3. Blood Pressure
  4. Dyslipidaemia
326
Q

How is a diabetic patient’s weight managed? Describe the drugs used, and their MOA.

A
  • Diet
  • Orlistat (inhibits GI lipase and reduces fat absorption
  • Rimonabant causes central fat loss and acts on central satiety.
327
Q

What family of drugs can be used to treat hyperglycaemia in diabetes?

A
  • Biguanides (e.g metformin)
  • Sulphonylureas
  • Metaglinides
  • Alpha-glucosidase Inhibitors
  • Thiazolidinediones
  • Glucagon like peptide-1
328
Q

How do Biguanides treat Diabetes? Give an example of such compound, along with possible side effects.

A

Metformin.

  • first-line treatment in patients who cannot be treated with diet alone
  • reduces insulin resistance by reducing hepatic glucose output and increasing peripheral glucose disposal
  • GI side effects and contraindicated in liver, cardiac and renal failure.
329
Q

How do Sulphonylureas treat Diabetes? Give an example of such compound, along with possible side effects.

A

Gibenclamide are insulin secretagogues, which block the ATP sensitive potassium channel on beta-cells, leading to the depolarisation of them –> insulin release.

  • Used in lean patients, where diet alone has not succeeded
  • hypoglycaemia and weight gain are side-effects
330
Q

How do Metalglinides treat Diabetes?

A

Same way as sulphonylureas but bind to a different site on the K channels (block the ATP sensitive potassium channel on beta-cells, leading to the depolarisation of them –> insulin release.)

331
Q

How do alpha-glucosidase inhibitors treat Diabetes? Give an example of such compound, along with possible side effects.

A

Acarbose prolongs absorption of oligosaccharides.

  • allows insulin secretion to cope, following first phase insulin
  • as effective as metformin but side-effects include flatulence.
332
Q

How do Thiazolidinediones treat Diabetes? Give an example of such compound, along with possible side effects.

A

Pioglitazone. They are peroxisome proliferator-activated receptor agonists (PPAR-gamma). They work as insulin sensitisers mainly peripherally (muscle).

  • Also cause peripheral distribution of adipocytes instead of central
  • Improvements in glycaemia and lipids
  • Side effects on older types included hepatitis and heart failure.
333
Q

How does GLP-1 treat Diabetes?

A

It is an incretin gut hormone secreted in response to nutrients in the gut. Transcription product of pro-glucagon gene.

  • stimulates insulin and suppresses glucagon
  • increases satiety
  • short half-life due to rapid degradation.
334
Q

What are the sites of microvascular complications in diabetes?

A

Damage to renal arteries –> diabetic retinopathy
Glomerular arterioles –> diabetic retinopathy
Damage to vasa nevorum –> diabetic neuropathy

335
Q

What factors influence the risk of developing microvascular complications in diabetes?

A
  • severity of hyperglycemia
  • hypertension
  • genetic influences
  • hyperglycaemic memory
336
Q

How does hyperglycaemia and hyperlipidaemia lead to microvascular damage?

A

There are various pathways activated in these states. The main are Advanced Glycosylated End-products (AGEs), oxidative stress, and hypoxia. These lead to local activation of pro-inflammatory cytokines and local inflammation, which damages the arteries/arterioles.

337
Q

What is used to examine the eye for diabetic retinopathy?

A

A fundoscope

338
Q

What are the types of diabetic retinopathy?

A
  • Background DR. Most common type; if fovoea is untouched, patients can see
  • Pre-proliferative DR.
  • Proliferative DR. Significant ischaemis to an area of the eye causes new vessel growth. This is dangerous as new vessels are prone to rupture. Vessels can penetrate vitreous humour, rupture then can cause instant blindness
339
Q

How can the different types of diabetic retinopathy be identified?

A

Background: has hard exudates (lipid deposition), microanuerysms or blot anuerysms.
Pre-proliferative: soft exudates (area of ischaemia)
Proliferative: obvious ischaemia, new vessel growth

340
Q

How can diabetic retinopathy be treated?

A

Background DR: improving glucose control
Pre-proliferative and Proliferative: Pan-retinal photocoagulation uses lasers to destroy soft exudates areas to prevent proliferation.
Maculopathy is treated with grid photocaugulation at the level of the macula to prevent acctidental damage to the fovea.

341
Q

How does diabetic nephropathy present?

A

With progressive clinical features:

  • progressive hypertension
  • Progressively increasing proteinurea
  • Progressively deteriorating kidney function
  • Classic histological featires
342
Q

Describe the ranges of proteinurea

A

Normal: 3000mg

343
Q

Why is diabetic nephropathy important to diagnose?

A

It is associated with a huge morbidity and mortality. This is because once microvascular problems present in the kindey, it is a marker for generalised vascular disease.

344
Q

What are the histological features of diabetic nephropathy?

A

Classically presents with glomerular changes such as:

  • Mesangial expansion
  • Basement membrane thickening
  • Glomerulosclerosis
345
Q

What is the pathogenesis of diabetic nephropathy?

A

Chronic exposure to glucose coupled with high blood pressure increases likelyhood for inflammation to occur.

346
Q

How can diabetic nephropathy be detected early?

A

Small increases in proteinurea, termed microalbuminuria. Also by abnormalities in blood pressure control.

347
Q

How can diabetic nephropathy be managed?

A
  • Diabetic control (reduce hyperglycaemia)
  • Blood pressure control
  • Inhibition of the renin-angiotensin-system (angiotensin has vasoactive effects, and causes glomerular hyperfiltration. blocking RAAS can aslo help control BP)
  • Stop smoking
348
Q

What is the most common cause of neuropathy?

A

Diabetes

349
Q

What are the small arteries that supply the nerves called?

A

The vasa nervorum

350
Q

What is the pathophysiology of diabetic neuropathy?

A

Several pathways leading to the damage of the vasa nervorum. This means the nerves become poorly perfused.

351
Q

What are the types of diabetic neuropathy?

A
  • Peripheral neuropathy
  • Mononeuropathy (affects one nerve)
  • Mononeuritis multiplex (randm combination sof peripheral nerve lesions)
  • Radiculopathy (pain over spinal nerves)
  • Autonomic neuropathy
352
Q

Describe peripheral neuropathy in Diabetes Mellitus

A
  • usually bilateral and symmetrical
  • longest nerves supply the feet and loss of sensation there is common
  • occurs more commonly in tall people
  • danger is that patients will not sense injury to foot (can lead to Charcot’s foot)
  • signs include absent ankle jerks and loss of vibration sense
  • use a monofilament examintaion to test sensation sin hands and feet and ask if patient can feel the pressure.
353
Q

Describe mononeuropathy in Diabetes Mellitus

A
  • usually noticed as sudden motor loss

- can present in cranial nerves too and cause cranial nerve palsies

354
Q

What type of CN III palsy is seen in diabetic patients and why?

A

Pupil-sparing CN III palsy. The loss of motor function to eye muscles is due to mononeuropathy. However, the eye will still respond to light. This is because the parasympathetic fibres are located outside somatic fibres and so the blood supply is not easily lost.

355
Q

What are the features of diabetic autonomic neuropathy?

A

Loss of sympathetic and parasympathetic nerves, so patient morbidity is very high.

  • dysphagia, delayed gastric emptying, constipation, bladder dysfunction
  • postural hypotension
  • sudden cardiac death
356
Q

What proportion of deaths arrises from CVD in diabetics?

A

> 75%

357
Q

What are the macrovascular complications of Diabetes Mellitus?

A
  • Ischaemic heart disease
  • Stroke
  • Renal artery stenosis
  • Cerebrovascular disease
  • Peripheral vascular disease

It is a systemic disease of MULTIPLE arterial beds.

358
Q

Describe the stages of development of an Atheroma

A
  1. Initial lesion - macrophage infiltration
  2. Fatty streak: mainly intracellular lipid accumulation
  3. Intermediate lesion: intracellular lipid accumulation with small extracellular lipid pools
  4. Atheroma: intracellular lipid accumulation and core of extracellular lipid
  5. Fibroatheroma: single or multiple lipid cores, also fibrotic/calcific layers
  6. Complicated lesions: a surface defect cases a thrombosis –> either occludes vessels or showers circulation with platelet fragments etc.
359
Q

What cluster of metabolic markers is hyperglycaemia normally associated with to cause macrovascular diseases?
(metabolic syndrome)

A
  • Insulin resistance
  • Inflammation
  • Hypertension
  • Increased waist circumference
  • HDL levels low
  • Microalbuminuea
360
Q

What is the ‘metabolic syndrome’ associated with diabetes?

A

Metabolic syndrome is a cluster of risk factors for CVD, which are a consequence of insulin resistance (and this hypertension and dyslipidaemia).

Includes:

  • Insulin resistance
  • Inflammation
  • Hypertension
  • Increased waist circumference
  • HDL levels low
  • Microalbuminuea
361
Q

Why do macrovascular complications occur more often and in younger patients in T2DM than T1DM?

A

T2DM is associated with insulin resistance which leads to the high blood pressure and dyslipidaemia, increasing rate of atherosclerosis development.

362
Q

What pathway leads to the development of diabetic foot?

A

Hyperglycaemia –>

  1. Motor neuropathy - leading to distorted foot shape
  2. Limited joint mobility - due to foot wearing away leading to abnormal distribution of pressure
  3. Autonomic neuropathy - low blood pressure in foot
  4. Trauma
  5. Sensory neuropathy
  6. Peripheral vascular disease - increase risk of infection
363
Q

By how much is the risk of foot amputation raised by, in diabetic patients?

A

up to x60

364
Q

What are the different types of diabetic foot?

A

Ischaemic, neuropathic and neuro-iscaemic

365
Q

What are the symptoms of diabetic foot?

A

Ischaemic: cold, pulseless, ulcers at foot margins
Neuropathic: numb, warm, dry, palpable foot pulses, ulcers at point of high pressure
Neuro-ischaemic: numb, cold, dry, pulseless, ulcers at point of high pressure and foot margins.

366
Q

What preventative measures must a diabetic take to prevent diabetic foot?

A
  • Inspect feet
  • Wear appropriate shoes
  • Never walk barefoot
367
Q

How are diabetic foot ulcers treated?

A
  • relief of pressure (bed rest, etc)
  • antibiotics
  • debridement (removal of dead tissue)
  • revascularisation (angioplasty, arterial bypass surgery)
  • amputation
368
Q

Describe the main central nervous region regulating appetite.

A

The hypothalamus contains the arcuate (infundibular) nucleus which projects neuronal populations to the paraventricular nucleus.

369
Q

What role does the arcuate nucleus play in appetite regulation?

A

An integrative role

370
Q

From where does the arcuate nucleus in the hypothalamus receive inputs from?

A

Brainstem and periphery, including circulating factors such as leptin, ghrelin, GLP-1 and PYY.

371
Q

How are the two main arcuate neuronal populations involved in appetite regulation?

A
  • POMC neurones are appetite inhibitory
  • Neuropeptide Y (NPY) and Agouti-related Peptode (AgRP) are appetite stimulating.
    They project to the paraventricular nuclei as well as other hypothalamic and extra-hypothalamic regions.
372
Q

What mutations of the appetite regulation pathways cause disorders?

A
  • No NPY or AgRP mutations are associated with appetite regulation issues as brains are plastic enough to compensate.
  • POMC deficiency and MCR-4 (POMC metabolite receptor in the hypothalamus) mutations have been shows to cause morbid obesity.
373
Q

Where is leptin secreted from?

A

White adipose tissue

374
Q

What is leptin secretion proportional to?

A

Circulates at concentrations proportional to fat mass and inhibits food intake.

375
Q

What are the orexigenic and anorexigenic neuropeptides in the arcuate nucleus?

A 
Orexigenic = NPY and AgRP
Anorexigenic = POMC
376
Q

Why are humans lacking leptin also infertile?

A

Leptin has a permissive effect on the HPG axis. Lacking leptin signalling means they become infertile due to hypogonadotrophic hypogonadism.

377
Q

Why is leptin ineffective as a weight control drug?

A

This is because obese people tend to have a degree of leptin resistance.

378
Q

What hormones circulate at concentrations proportional to fat mass?

A

Leptin and Insulin

379
Q

What is the body’s largest endocrine organ?

A

The GI tract - releases more than 20 different hormones.

380
Q

What GI hormone promotes hunger and how?

A

Ghrelin is released from the stomach by fasting, and inhibited by food intake. It stimulates food intake by inhibiting POMC neurones and stimulating NPY and AgRP

381
Q

What GI hormone promotes satiety and how?

A

PYY and Glucagon-like peptide-1 (GLP-1) are released after food intake, and inhibited by fasting.
By stimulating POMC neurones and inhibiting NPY.
GLP-1 also suppresses appetite but also has an incretin role.

Year 2 LCRS (5 decks)

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