Endocrine Flashcards
Catecholines
Derived from tyrosine Noradrenaline, adrenaline, dopamin Insoluble - do not enter cells Exert their actions by binding to plasma membrane receptors Rapid onset
Thyroid hormones
Derived from tyrosine Thyroxine (T4) and tri-iodothyronin (T3) Lipid soluble and so can enter cells Receptors are located within cell nucleus Slow onset
Indoleamines
Derived from tryptophan
Serotonin, melatonin
Bind to plasma membrane receptors
Exert actions rapidly
Hypothalamus
Basal part of diencephalon
Appetite, HR, body temp, sexual appetite, stress response
Vascular link between median eminence and anterior pituitary
Somatostatin
Hypothalamus and delta cells of the endocrine pancrease
Potent inhibitor of GH secretion
Potential therapeutic to treat GH tumours
Thyrotrophin releasing hormone
Key regulator of TSH production in the pituitary
Dopamine
Catecholamine
Tonic inhibitor of prolactin secretion of pituitary
Corticotrophin releasing hormone
Key regulator of stress response
CRH mutations results in impaired stress response and front lobe epilepsy
Anterior posterior
Master gland
Controls function of numerous other glands
Situated in bony cavity at the base of the skull
5 cell types: gonadotroph, lactotroph, somatotroph, corticotroph, thyrotroph
Secretes: FSH, LH, GH, TSH, ACTH, PRL
Regulated by hypothalmic factors
Growth hormone
In response to GHRH and Ghrelin, inhibited by somatosytation
Effects on liver and muscle are mediated by the release of insulin-like growth factor
Acromegaly: GH-secreting tumour causing inappropriate growth, giantism and diabetes
GH insensitivity/deficiency: dwarfism, short stature, Laron’s syndrome
Thyroid stimulating hormone
Released in response to TRH stimulator and acts at thyroid gland to regulate the production of T4/T3 - regulate growth and metabolism
Thyrotropinomas: secrete high levels of TSH, treated by SST analogues, surgery and irradiation
TSH production is regulated by T4/T3 feedback at TRH neurons and at thyrotrophs
Prolactin
Secreted in response to TRH, oestradiol and VIP/PACAP and tonic inhibition by dopamine
Regulate lactation in oestradiol-primed mammary glands
Prolactinomas: cane be large - surgery
Adrenocorticotrophin hormone (ACTH)
Secreted from corticotrophs in response to CRH
Key regulator in stress response - regulates glucocorticoid production
Corticotrophinomas: Cushing’s syndrome - excessive glucocorticoid syndrome - surgery
Tpit mutations lead to ACTH deficiency - low glucocorticoids, weight loss, anorexia, low bp
Adrenal cortex
Paired gland, on top or near kidneys
Cortex: 80-90% gland volume
Medulla: 10-20%, highly vascularised
Zona glomerulosa: lies under capsule, 5-10% of cortex, cells are small and round, few lipid droplets, aldosterone
Zona fasciculata: 60-75% of the cortex, ZF cells are bigger than ZG, contains numbers of lipid droplets, cortisol
Zona reticularis: 20-30% of the cortex, intermediate size, relatively few lipid droplets, adrenal androgens
Actions of ACTH
Acute:
- Deplete ascorbic acid
- Stimulate steroid synthesis
- Increase blood flow to gland
Chronic:
- Increase adrenal weight
- Increase both cell number and size
- Induce synthesis of enzymes involved in steroid synthesis undos a consequence increase steroid synthesis
Transport of corticosteroids
In plasma bound vesicles to protein
Normal circulating volume: >90% of glucocorticoid are bound to transcortin or corticosteroid binding globulin (CBG)
Protein bound steroids - not biologically active
Aldosterone is not normally bound to specific proteins
Actions of glucocorticoids
Specific glucocorticoid receptor (GR)
Affects carbohydrate, lipid and protein metabolism
- Anabolic actions in the liver and catabolic actions in muscle and fat cells
- Protein breakdown and lipolysis (fat and muscle cells)
- Glycogenesis and gluconeogenesis (liver cells)
- Protein synthesis (liver cells)
Inhibit growth (young), anti-inflammatory, immunosuppressive, protection against stress, negative feedback on ACTH release
Clinical disorder of the adrenal cortex
Rare - usually female, middle aged - old dogs
Excessive quantities of glucocorticoids
Excessive secretion of cortisol may be due to increased secretion of ACTH
Cortisol excess due to hypersecretion of pituitary or extra pituitary-dependent hyperadrenocorticism (90%) or adrenal tumours (10%)
Actions of mineralocorticoids
Via specific mineralocorticoid receptors
Increase the reabsorption of Na in the kidney
Na ions are exchanged H and K ions leading to decreased Na and increased K excretion - increased acidity
No feedback effects on pituitary ACTH release
Aldosterone - excess primary hyperaldosteronism
Conn’s syndrome
Autonomous secretion of aldosterone due to presence of single adrenal adenomas in the zona glomerulosa
High levels of aldosterone:
- Hypertension - increase water and Na retention
- Hyperkalemia - muscle weakness, cardiac arrhythmias
Aldosterone - excess secondary hyperaldosteronism
Increased aldosterone secretion in response to increased levels of angiotensin II due to increased renin secretion from juxtoglomerular cells
Physiological reflex designed to conserve sodium in cases such as haemorrhage, salt and water depletion
ACTH stimulation test
Normal response: 2-3 fold increase over the pre-ACTH level of cortisol
Pituitary-dependent hyperadrenocorticism: exaggerated response (>660mmol/L)
Adrenal tumours: may hyper-respond or have very high resting cortisol levels with little or no change after ACTH
Addison’s: lack of response
Low dose dexamethasone suppression test
Normal response is a decrease in cortisol levels to
Steroids as treatment
Replacement for adrenal insufficiency
Anti-inflammatory therapy
Immunosuppressive therapy
Shock treatment
S/E: adrenal gland atrophy, hyperadrenocorticism, iatrogenic Cushing’s, PU/PD (ADH actions), polyphagia (anti-insulin effects), hepatomegaly (glycogen deposition in liver), fat deposition in abdomen, skeletal muscle weakness (muscle protein breakdown), thin skin and hair loss (effects on hair cycle and collagen synthesis)
Thyroid anatomy
Two lobes joined by an isthmus
12 weeks of gestation: synthesises and secretes thyroid hormones under influence of foetal hypothalamic/pituitary axis - normal growth and development
HIghly vascularised, sympathetic and parasympathetic innervation
Functional unit: follicle - single layer of cuboidal cells surround clear mucus-like fluid (colloid)
- Elongate upon stimulation
- Growth and development of follicle is independent of TSH initially
Also contain larger epithelial cells know as clear cells - synthesise and secrete calcitonin - a hormone which regulates plasma
Thyroid hormones
Tri-iodothyronine - T3
- Smaller amounts secreted but provides almost all thyroid hormone activity in target tissues
Thyroxine (tetraiodothyronine) - T4
- Converted to T3 in target tissues
Unique hormones: incorporate iodine into an organic structure made from tyrosine
Thyroid hormone transport
Transport: thyroxine-binding globulin (TBG), thyroxine-binding pre-albumin (TBPA), albumin
Free hormone fraction - responsible for activity
Thyroid hormone receptors
Alpha 1 and 2 expressed mainly in the brain (lower levels in the kidneys, skeletal muscle, lungs, heart and liver)
Beta1 - kidneys, liver, brain, heart and thyroid
Beta2 - brain, retina and inner ear
Beta3 - kidney, liver and lungs
Metabolic action of thyroid hormone
Calorigenesis: increased energy production and consumption, increased BMR
Intermediate metabolism: Increased hepatic gluconeogenesis/glycognelysis, increase lipolysis
CVS effects: Increased cardiac muscle contractility, increased slow Ca2+ channels, increased beta adrenergic receptors (and in skeletal muscle, adipose tissue - increased sensitivity to catecholamines)
Thyroid hormone metabolism
Liver, kidney, brain and muscle - deiodination enzyme
15-20% of T4 and 100% of T3 forms conjugates and excreted in faeces and urine
Hypothyroidism
Signs:
Weight gain, scaly skin, seborrhoea, hyperpigmentation, alopecia, increased cholesterol in the blood, lipid accumulation in the liver, bradycardia
Causes:
- Idiopathic atrophy - larger dog breeds
- Immune mediated thyroiditis - binding of autoantibodes to thyroglobulin
- Less common: bilateral non-functional thyroid tumours, sever iodine deficiency, destructive lesions in the pituitary gland
Hyperthyroidism
Hyperplasia, adenomas, autoimmune response (Grave’s disease)
Signs: weight loaa, sweating, tremor, goitre, agitated and nervous, fast HR, atrial fibrillation
Most common endocrine condition in old cats (usually benign thyroid adenoma): weight loss, V/D, rapid HR, PD
Other causes:
- Genetic enzymatic defect: can’t produce T3 or T4 e.g. congenital dyshormogenetic goitre in certain breeds of sheep
- Iodine deficiency: foals, pigs, lambs, goats
- Iodine excess: interferes with one or more steps in thyroxine synthesis, dried seaweed
- Goitregenic substances: interfere with T3/T4 synthesis
Drugs that act on the pituitary to affect TSH secretion
Protilerin: synthetic TRH - stimulates TSH release (and prolactin and FSH) - diagnosis of thyroid dysfunction
Thyroxin and tri-iodothyronine (T3 and T4): inhibit secretion and synthesis by negative feedback, used for diagnostic testing of thyroid gland function
Drugs that influence thyroid hormone secretion or secretion
Thyrotrophin (TSH): increase metabolic activity of the gland - increase T3/T4, not licensed
Radioisotopes of iodide: selective radiation therapy of hyperactive tissue - treatment of hyperthyroidism
Anti-thyroid drugs:
- Perchlorate and thiocyanate: compete with organic iodide for uptake by pump
- Thioureylenes (methimazole, carbimazole, propylthiouracil) - orally active, potent inhibitors of throidal perioxidase/TG, block iodine incorporation into tyrosol
- Inorganic iodide: large amounts over a brief period (10d) reduce size/vascularity of gland, management of hyperthyroidism in cats (prior to/instead of surgery)
Drugs with mimic or inhibit thyroid hormone action
(MIMIC) Thyroid hormone replacement therapy synthetic prep:
- Dose adjusted according to clinical response or base on serum (T4)
- Care should be taken in animals with concurrent heart disease
(INHIBIT) Propanolol:
- To functionally antagonise some of the CVS actions of excessive thyroid hormones - increase number of beta receptors in myocardium
- Used in cats with hyperthyroidism - slows HR, decreases myocardial O2 demand and is anti-dysrhythmic
Pancrease anatomy
Right side of abdomen - attached to caudal surface of stomach and cranial flexure of duodenum
Site within greater omentum and mesoduodenum
Right and left lobes
Exocrine (99%) and endocrine segments - 1.5g of patches spread out among exocrine area
Islets of Langherhans
Endocrine cells of the pancreas
- Alpha cells secreting glucagon (5-30%): raise blood sugar, breaks down glycagon in liver, also affected by symp NS, adrenaline/noradrenaline
- Beta cells secreting insulins (60-80%): lower blood sugar, stimulate skeletal muscle fibre to take up blood glucose and convert it to glycogen, insulin binds to insulin receptors imbedded in plasma membrane, also produce IGF2 (mainly and some IGF1)
- Delta cells secreting somatostatin (
Insulin secretion
NS, retina, erythrocytes and germinal epithelium of gonads require glucose
Excess glucose - negative osmotic effects
Insulin secreted when there is high blood glucose - enhance acutely by blood fatty acids, amino acids, ketones
Increlin hormones:
- GI hormone - cause increase in the amount of insulin released from beta cells
- Slow rate of absorption of nutrients by reducing gastric emptying
- Reduce glucagon release from alpha cells
Autonomic NS
GH, glucagon and glucocorticoids may increase insulin secretion chronically
Acromegaly
Hypersomatotrophism
Growth hormone - elevated levels of IGF1
Cats: nearly always pituitary tumour
Dogs: increased GH secretion for mammary tissue
Juveniles: increase length of long bones
Treat:
- Dogs: remove progesterone influence
- Cats: consider dopamine agonists, local irridation, somatostatin analogues
Dwarfism
Hyposomatotrophism
Congenital malformation of the pituitary adenohypophysis (cystic Rathke’s pouch) or possible malformations in trophic hormone producing cell lines
Reduced secretion of GH and possibly also TSH
Occasionally, reduced gondaotrophin secretion may also be present
Small stature, immature hair coat, 6-8w, persistent oestrous, normal life expectancy
No treatment need, consider progestin therapy
Diabetes insipidis
Reduced vasopressin (ADH) secretion from the posterior pituitary
Occasionally secondary to an expanding mass lesion of congenital abnormality but usually idiopathic
Lack of ADH means collecting tubules remain impermeable to water, consequently urine is persistently and very hyposthenuric
PU >200ml/kg/24h, obvious PD
USG
Parathyroid hormone related peptide
PTH like factor that is secreted by some neoplastic cells and is an important cause of the hypercalcaemia associated with malignancy
Hypercalcaemia
PU/PD, anorexia, dehydration, weakness/lethargy, vomiting
Facial pruritis, oral discomfort, cardiac arrhythmias, seizures/twitching, acte renal failure and death
Primary hyperparathyroidism: signs often attributed to old age
High calcium interferes with kidney’s ability to concentrate urine so patients may be dehydrated with a pre-renal azotaemia but with a low USG
Transient inconsequential: hypoadrenocorticism, haemoconcentration, hyperproteinaemia
Pathologic: malignancy (especially lymphoma, anal sac adenocarcinoma), primary hyperparathyroidism (Keeshunds, parathyroid adenoma - u/s), renal failure, hypervitaminosis D (some rat poisons, psoriasis cream), granulomatous disease (fungal infections, lungworm), toxic (vitamin D analogues), skeletal lesions, idiopathic (cats)
Treat specific disease, when undiagnosed can lower serum calcium temporarily:
- Diuresis with 0.9% NaCl
- Bisphosphonates therapy e.g. palmidronate
- Calcitonin
- Furosemide
- Peritoneal dialysis
- Glucocorticoids - last resort
Hypocalcaemia
Concurrent low albumin
Common problem in farm: milk fever
Muscle tremors/cramps, stuff gait, behavioural change, panting, hyperthermia tachycardia, hypotension, death
Small animals: chronic renal failure, eclampsia. acute pancreatitis, iatrogenic, ethylene glycol toxicity, intestinal malabsorption, primary hypoparathyroidism
10% calcium gluconate, oral calcium supplementation, supplement with vitamin D metabolite:
- Ergocalciferol (cheap but long half life)
- Dihydrotachysterol (middle ground)
- Calctriol (most expensive, shortest half life)
Pituitary adenoma
Produce ACTH
May obliturate the gland and cause hypopituitarism - diabetes insipidus
Can also cause Cushing’s in horses but not in all cases
Addison’s
Hypoadrenocorticism - common and underdiagnosed
- Destruction of adrenal glands
- Idiopathic bilateral adrenocortical atrophy
- Increased excretion of Na and Cl
- Increased K in the blood
- Generalised tissue underperfusion
- Reduction of glucocorticoids
Canine diabetes mellitus
Normal insulin sensitivity, esp winter, esp 7-12y, severe loss of Islets, rapid onset 3-5w
Tibetan terrier, Cairn terrier, Samoyed
Less likely: Boxer, GSD
Hyperthyroidism treatment
Inexpensive: carbimazole, methimazole 100-200/year
Middle: unilateral thyroidectomy 500
Expensive: bilateral thyroidectomy 750-1000
Tops: thyroid irradiation 1700-2000
Hypothyroidism
Congenital or acquired
Lethargic, disinterested, 30% overweight, may be exercise tolerant and have muscle or joint pain, alopecia, hyperpigmentation with thickened skin, infertility, neuro problems
Mild non-regenerative anaemia, elevated serum cholesterol, elevated serum CK, protein uria
Treat: thyroxine
