Endocrinology Flashcards
1
Q
Describe the Development of the pituitary
A
- Downgrowth of the neuroectoderm and Theres and outgrowth from the buccal ectoderm forming Rathkus pouch.
- Rathkus pouch forms a vesicle
- Vescicle fuses with the downgrowth from the neuroectoderm.
Rathkes pouch is the origin of the Anterior pituitary
Neuroectoderm is the origin of the Posterior pituitary
2
Q
Describe the link between the hypothalamus and the pituitary
A
- Anterior pituitary has NO neuronal link with hypothalamus. Hormones are deposited into the medial eminence, where they drain into the Hypothalamo - pituitary portal vessels.
- Posterior pituitary receives blood from Inferior hypophyseal artery. No hormones are received this way. Has neuronal input from hypothalamus
3
Q
Explain why pituitary tumours can often have no clinical signs or lead to loss of vision
A
Pituitary sits in a bony cavity known as the pituitary fossa. This means tumours have no where to grow except for upwards. Can lead to compression of the optic nerve
4
Q
Describe the histology of the pituitary
A
- Pars distalis - Makes up the AP.
- Pars intermedia - Boundary between two areas.
- Pars nervosa - Makes up PP
- Pars tuberalis - Produces TSH, Also has high amount of melatonin receptors. After melatonin release big increase gene expression
5
Q
Name 2 possible transcription factors that could be mutated in the pituitary
A
- SF-1: Drives differention of the gonadotrophs. mutations can lead to failure to develop gonads
- PIT-1: Needed for the development of growth hormone secreting cells. mutations will cause growth disorders
6
Q
What are the 5 cell types of the pituitary, what do they secrete and what are they regulated by
A
- Somatotrophs - Secrete Humane growth hormone (GH). GH acts via JAK-STAT pathway. causes the release of insulin like growth factor. This is caused by release of GHRH from hypothalamus in a pulsultile manner. Inhibited by somatostatin
- Lactotroph - Prolactin secreted for milk production. TRH (thyropin releasing hormone) promotes secretion. Dopamine release is the main control of PRL. Must decrease dopamine to increase PRL.
- Corticotroph - Adrenocorticotropic hormone (ACTH), stimulate release of glucocorticoids. Also releases MSH. Release of ACTH is due to corticotropin releasing hormone (CRH)
- Thyrotroph - secretes thyrtropin releasing hormone (TRH). Inhibited by somatostatin
- Gonadotrophs - FSH & LH secreted. Released due to stimulation by pulsultile release of GnRH.
7
Q
Describe properties of protein & peptides
A
- Synthesised as pre hormones & undergo post translational modification.
- Stored in granules and released by exocytosis
- Water soluble
- Small difference in amino acid sequence causes big difference in physiological function
8
Q
Describe properties of steroidal hormones
A
Synthesised in adrenal cortex, testis & ovary. 3 six membered rings and 1 five membered ring. ALL derived from cholesterol. 4 classes:
- Corticosteroid - cortisol & aldosterone
- Pregnans - Progesterone
- Androgen - testosterone
- Oestrogens - Oestradiol-17
9
Q
What are the properties of amine hormones
A
Derived from tyrosine. Have a rapid onset and no species differentiation. Short half life. E.gs adrenaline and dopamine.
Can also be derived from tryptophan, same properties. E.g serotonin
10
Q
What are the properties of eicosanoids
A
2 major classes both derived from arachidonic acids. Rate limiting step is amount of free amino acids from phospholipids by phopholipase A2.
- Leukotriens - 5-lipoxygenase converts arachidonic acid into leukotriens
- Prostaglandins - Converted by Cyclooxygenase (COX)
11
Q
Why do some hormones bind to carrier proteins in blood
A
- Increases hormones aqueous solubility
- protects hormone against metabolism by proteolytic enzymes.
When bound hormones are biologically inactive. steroids and thyroid hormones
12
Q
Describe structure of hypothalamus
A
- Basal part of diencephalon
- Hormones released into median eminence and then into hypophyseal portal system (anterior pituitary)
- Medial hypothalamus has connections to amygdala (anxiety/mood)
- afferent conncetions to the hippocampus
13
Q
What hormones are released by the hypothalamus
A
GnRH
- neurones are born in vomeronasal organ & migrate to hypothalamus.
- Key regulator in reproduction, released in pultultile manner controlling LH & FSH secretions
- Controlled by E2 in negative feedback loop
- The GnRH receptor has no C-terminal tail, meaning it never switches off
- Causes increase in cAMP
Somatostatin (SS)
- 5 isoforms of receptor, inhibit cAMP production
- potent inhibitor of GH secretions. used therapeutically for GH tumours
- Neurones in the periventricular (Pev) hypothalamus
Thyrotrophin releasing hormone (TRH)
- Neurones in Paraventricular nucleus.
- Key regulator of TSH
- Increases phosphoinositidase C production in pituirary
Dopamine
- Produced from tyrosine residues by Tyrosine hydroxylase & DOPA decarboxylase
- Neurones in hypothalamic tubero-infundibular system
- Tonic inhibitor of PRL secretions from pituitary. Only way to increase PRL is to decrease dopamine
Corticotrophin releasing hormone (CRH)
- Neurones in the Paraventricular nucleus & regulated by Glucocorticosteroids
- Receptors stimulate cAMP production in pituitary to generate ACTH - stress response
- CRH mutation = Imparied stress response
14
Q
Describe the structure of the adrenals
A
- Medulla - Central, Synthesis of adrenaline
- Cortex is comprised of 3 areas:
- Zona glomerulosa - Lies under capsule, cells arranged circularly. Makes aldosterone
- Zona fasciculata - makes up 60-70% of cortex. Large numbers of lipid droplets. syntheses cortisol
- Zona reticularis - Cells are intermediate in size between zf & zg. synthesis androgens
15
Q
Cholesterol is the precursor for progesterone, ostrediol, aldosteron & cortisol. What are the sources of cholesterol?
A
- Cholesterol esters - In lipid droplets. Catalysed by cholesterol ester hydrolase ( activated by ACTH)
- Cholesterol in lipoproteins in blood
- Synthesised from acetate via HMG CoA reductase
16
Q
How does cholesterol become pregnenolone
A
- Cholesterol cant pass into the inner mitochondrial membrane Without the StAR protein.
- Here is where the enzyme cholesterol side-chain cleavage (cscc) is located
- Cscc cleaves 6 carbon side chain off cholesterol to form pregnenolone
17
Q
What carrier proteins are bound to cortisol in the blood
A
Transcortin
Corticosteroid binding protein
Biologically inactive
18
Q
What are the actions of the glucocorticoids
A
- Raise plasma glucose
- Protein breakdown & lipid lipolysis
- glucogenesi & gluconeogenesis
- Increased expression of gluconeogenic enzymes
- Decrease in IGF-1
- Increase anti inflammatory cytokines, IL-4, IL-10
19
Q
What are the maturational effects of glucocorticoid on the fetus
A
Lungs
- Surfactant production
- Beta adrenic receptors
Liver
- Gluconeogenic enzymes
- IGF gene expression
GIT
- Acid secretions
- Digestive enzymes
- Mucosal growth
Kidney
- Glomerular filtrate rate
- Tubular Na reasbsorption
20
Q
What is the difference between cushings syndrome and cushings disease
A
Cushings syndrome - Excessive quantitites of glucocorticoids.
Cushings disease - Cortisol excess due to hypersecretion of pituitary or extra pituitary ACTH (tumour)
21
Q
What is the action of aldosterone
A
Causes the expression of new protein channels into the kidney which increases Na+ absorption and K+ secretion
22
Q
What is primary and secondary hyperaldosteronism
A
Primary hyperaldosteronism
- Autonomous secretions of aldosterone due to presence of adrenal adenomas in zona glomerulosa
- Results in hypertension, muscle weakness & cardiac arrythmias due to hypokalaemia
Secondary hyperaldosteronism
- Increase in aldosterone due to increase in angiotensin II because of increased renin secretions
23
Q
Describe the causes, clinical signs and diagnosis of hypoadrenocorticism (addisons)
A
Causes:
- Idiopathic bilateral adrenalcortical atrophy
- Immune mediated
- Pituitary lesion
Clinical signs:
- Hypovalaemic shock (dehydration due to increased Na+ secretion decreased aldosterone)
- Increase in K+ (decreased aldosterone) = bradycardia
- increased negative feedback = Increased ACTH & MSH = hyperpigmentation
Diagnosis
- ACTH stimulation test (no cortisol increase)
- Hyperkalaemia
24
Q
Describe the causes, clinical signs and Diagnosis of hyperadrenocortism (cushings)
A
Causes
- Active pituitary tumour (85%)
- Active adrenal tumour
- Iatrogenic due to glucocorticoid therapy
Clinical signs
- Cortisol interfers with ADH to cause polyuria and thus polydypsia
- Induces gluconeogenesis => hyperglycaemia can cause secondary D.melitus
- stimulates protein catabolism => muscle weakness & poor wound healing
- inhibits growth phase of hair = bilateral symmetric alopecia
- Lipolysis and redistribution of fats in abdomen => pot belly
Diagnosis
- Lymphocytopenia (low lyphocytes), cortisol is anti-inflammatory
- Low dose dexamethasone test - pituitary dependant and normal animals will show suppression cortisol after 3 hours. Adrenal dependant cortisol remains high
25
What enzyme converts T4 into T3
T4 converted into T3 in peripheral tissues by
**_5'-deiodinase_**
26
Describe the synthesis of T4/T3
1. **TSH** binds to cell surface receptor causing intracellular increase in **cAMP =\> pKa**
2. pKa **phosphorylates Iodine pump** allowing I- into epithelial cell & it diffuses into colloid.
3. Enzyme **Thyroperoxidase** allows **addition** of **iodine** to tyrosine residues from **thyroglobulin**
4. Produces **Monoiodotyrosin** and **diiodotyrosine**. Combine to form either T4 or T3
5. Products are **endocytosed** into epithium. **Proteases** later break down endosome allowin release into the blood
27
How are thyroid hormones transported in blood
Bind to carrier proteins in blood.
* Thyroxin binding globulin (TBG)
* Thyroxin binding pre albumin
* Albumin
Inactive while bound
28
What are the actions of thyroid hormone and how is it metabolised
**_Actions_**
* **Calorigenesis** - Increase **BMR** & produce **heat**
* Increase hepatic **gluconeogenesis** & **lipolysis**
* Increase amount of **Beta adrenoreceptors** - increase HR and contractility
**_Metabolism_**
* **Deiodinasation** enzymes in liver/kidney.brain
* 20% of T4 & 100% of T3 **conjugated** to **sulphuric acid**, then undergoes **oxidative deamination** & **decarboxylation** to be **excreted**
29
What are the causes, clinical signs and diagnosis of hypothyroidism
**_Causes_**
* Iodiopathic follicular collapse
* Lymphocytic thyroiditis
**_Clinical features_**
* Weight gain with a normal appetite
* infertility
* **Bradycardia**
* Bilaterally symmetrical alopecia
* **myxoedema** - deposition of mucinous material, causing thickened skin and tragic facial expression
**_Diagnosis_**
* measure T4 levels (low)
* Measure **cholesterol** which should be high (**hypercholesterolaemia**), due to decreased activity of *lipoprotein lipase*
30
What are the causes, clinical signs & diagnosis methods for hyperthyroidism
**_Causes_**
* Nodular hyperplasia / **Thyroid adenoma**
* Thyroid carcinoma
**_Clinical signs_**
* **Tachycardia** (increased 02 consumption)
* **Weight loss despite polyphagia**
* Polydypsia/polyuria
**_Diagnosis_**
* T3 suppression test
* Increased ALP or ALT
31
What is goitre and what are its causes
Non neoplastic & no inflammatory enlargement of the thyroid
**_Causes:_**
* **Genetic enzymatic defect** - inability to produce T3/T4
* **Iodine deficiency**
* **Iodine excess**
32
What ways can you affect disorders of the thyroid therapeutically
**_Affect TSH secretion_**
* Protirelin - synthetic TRH
* T4/T3 - Inhibit TSH
**_Act on thyroid_**
* Radioisotope of iodine - absorbed by thyroid mainly, destroys cells
* thioureylenes - inhibit thyroidal peroxidase
**_Mimic thyroidal hormones_**
*Beta blockers (propranolol) antagonise some CVS actions oh hyperthyroid cats.*
33
What drugs affect adrenals
1. Affect **hypothalamus** to **decrease CRF** - *Bromocriptine*
2. Affecting **pituitary** to affect **ACTH secretions** - *Glucocorticoid Analogues*
3. Synacthen - **ACTH analogue**
4. **Inhibit cortisol biosynthesis** - *Aminoglutethimide*
Drugs which mimic cortisol
* Replacement therapy, anti inflammatory, immunosuppresive.
* Side effects are it will suppress ACTH, Adrenal gland atrophy and iatrogenic cushings
34
Explain how insulin is synthesised and explain its biphasic release
**_Synthesis_**
* Synthesised initially as a **pre-prohormone**
* Processed in thew **ER** into **prohormone**
* Mature insulin then formed in **gogli** by ***Prohormone convertase enzymes***.
* C-peptide cleaved off
**1st phase** of release occurs in **3-5 mins** from readily releasable granules close to plasma membrane. **2**nd in **15mins-2hours**. From **newly** synthesised granules
Insulin is a large Peptide, ***species specific***
35
Explain the secretion mechanism of insulin and the actions it has on the body
**_Secretion_**
* Stimulated by high blood glucose
* **GLUT-2** transports glucose into B-cells
* **Glucokinase phosphorylates glucose** to produce **pyruvate** making **ATP**.
* Atp dependant **K+ channels open** =\>**outflux** of K+
* **Depolarisation** causes opening of **Ca**=2 =\> exocytosis
**_Actions_**: Increased...
* Glycogen synthesis
* Glycolysis
* Lipogensis
* Protein synthesis
Relaxes smooth muscle of resistance vessels
36
What are the actions of glucagon and how are these achieved
* **Lipolysis** by the **phosphorylation** of **hormone sensitive lipase** to break downs TAG's into free fatty acids
* **Phosphorylation** of **phosphorylase B** to **a** promotes **glycogenolysis**
37
What is the effects of somatostatin
* **Paracrine** effects to **inhibt** insulin & glucagon secretions
* Stimulated by **nutrient ingestion** & **increased blood glucose**. maintains a constant nutrient supply
38
What is secreted from C cells of thyroid and what are its affects
* **Calcitonin**
* Secreted in responce to **hyperkalcaemia**
* **Inhibits osteoclast activity**
* Neoplasms can occur here, and if malignant spread to Lymph nodes
39
What is the role of parathyroid hormone
Secreted by **chief cells** in responce to **hypokalcaemia.** Increases osteoclast activity, causing **bone resorption,** mobilising Ca+2 stores. Also **increases phosphate excretion** in kidney
40
What is the causes & clinical signs of hypoparathyroidism
**_Causes_**
* **Lymphocytic parathyroidism** - infiltration of lymphocytes **destroying chief cells**
* Metastic neoplasm
* **Chronic hypercalcaemia** - **atrophy** of parathyroid
* Iatrogenic damage during surgery on thyroid
**_Clinical signs_**
* Tachycardia
* **Decrease in Ca+2 increases** permeability of **Na+** in neuronal membranes causing depolarisation =\> **tetany**
41
What are the causes of hyperparathyroidism, what are the different types and what are the clinical signs
**_Causes_**
* **_Primary_** - Functional parathyroid **hyperplasia** or **neoplasm** (adenoma or carcinoma)
* Tumours associated with **paraneoplastic hyperparathyroidism** are ***Lymphoma, Plasma cell tumour*** and ***anal sacapocrine gland adenocarcinoma.***
**_Secondary_**
* Due to **_chronic renal failure_**. imparied glomerular filtrate causes a **hyperphosphotaemia**. Phosphate binds to calcium forming **salts** which **deposit** in **kidney**. Decreased calcium causes **increased PTH** secretion=\> **hyperplasia**. But kidney damaged therefore phosphate retained.
* **_Nutritional_**. Due to increased Phosphorus intake, causing relative calcium deficiency by binding to calcium in the gut and **decreasing its absorption.**
***_Fibrous osteodystophy_** - Breakdown of bone and removal of Ca+2 . Bone replaced by fibrous tissue in areas of mechanical stress. susceptible to lameness and fracture.*
42
What is the consequences of adenoma in the pituitary
1. **_Paraneoplastic effects_** - Can be active **producing hormones** E.g Producing ACTH=\>cushings or producing GH=\> gigantism
2. **_Compression & atrophy of adjacent pituitary_** - will cause a **decrease** in **hormones secreted** causing **atrophy** of distint glands e.g ***Adrenals.*** Compression of the **Posterior pituitary** can cause a **decrease in ADH**, causing **polyuria** and **polydypsia**
43
What would occur if there was an adenoma of the Pars intermedia?
If its **inactive** can compress onto the pituitary and hypothalamus causing **intermitten fevers, sweating and polydypsia & polyuria**
If active can secrete **MSH** (*hyperpigmentation*), **ACTH** (*cushings*) and Beta endorphins
44
What is the most common type of Diabetes melitus in domestic animals and what are the clinical signs
Type 1 is more common in domestic animals
**_Clinical signs_**
* **Weight loss despite Polyphagia** - Inadequete uptake of glucose
* Also weight loss due to **decreased muscle mass** due to **gluconeogenesis**
* Polydypsia and **polyuria** because **glucose exceed renal threshold**
* **cateract** as **metabolism** of **lens** altered to **compensate** for hyperglycaemia
* Higher risk of infection because less glucose for leukocytes
High blood glucose and glycosuria common indecators
45
What is diabtes insipidous
Characterized by **inedaquate** amounts of **ADH**. Occurs for two reasons
1. **_Central_** - inedaquate release of ADH. No ablity to concentrate urine. Polydypsia and polyuria
2. **_Nephrogenic_** - Failure of nephrons to respond to ADH.
3. **_Phychogenic polydypsia_** - neurological disorder triggering excess thirst. Functional lack of ADH as animal is over hydrated so no ADH released.
46
