Week 5 Flashcards
What does the adrenal cortex synthesize?
Two classes of hormone corticosteroids (glucocorticoids and mineralocorticoids) & androgens
What are mineralocorticoids?
Electrolyte-balance regulating e.g. aldosterone which regulates K+ and Na+ levels in the distal tubules of the kidney, causing them to absorb more sodium and water from the urine… therefore more potassium is secreted in exchange
** stimulates H+ secretion in the collecting duct, regulating plasma bicarbonate and acid/base balance
* can also act on the CNS via the posterior pituitary gland to release ADH- conserves water by direct actions on renal tubular resorption
What do glucocorticoids do?
* essential for survival in a fasting animal
* cortisol is a glucocorticoid that affects carbohydrate and protein metabolism
* Protects glucose dependent tissues e.g. brain & heart
* Increases plasma glucose by enhancing mobilizaton of amino acids from proteins in many tissues
* Enhances the ability of the liver to convert these amino acids and glycerol into glucose by activating gluconeogenesis and to store glucose as glycogen
* In the periphery, glucocorticoids diminish glucose utilization and uptake, activate lipolysis, and increase protein breakdown
* Targets most body tissues, including CNS, bone, skin, liver, fat, and muscle
What is an example of an androgen precusor and function?
dehydroepiandrosterone (DHEA)- converted to testosterone and estradiol in peripheral tissues
What are the three zones of the adrenal cortex and each function?
- Zona glomerulosa- produces aldosterone
- Zona fasiculata- produces cortisol and androgens
- Zona reticularis- produces cortisol and androgens
What regulates glucocorticoid secretion?
Regulated via hypothalamus- pituitary axis- CRH & ACTH
* CRH is released as a consequence of hypoglycaemia, stress, physical trauma, hypoxia, ADH, infection and diurnal secretion (dogs and cats episodic release)
** CRH binds cell surface receptors on corticotrophs and via G proteins and cAMP releases ACTH from the anterior pituitary
** Feedback inhibition– cortisol inhibits pituitary and hypothalamus. ACTH inhibits neuronal cells in the hypothalamus.
How are adrenocortical hormones transported and removed?
* Transported in the blood bound to globulin (trancortin) and albumin. 90% of glucocorticoids are bound to protein and have a relatively long half life ~60-90 minutes
* Inactivated by the liver, conjugated with sulphates and glucuronides- decreasing their ability to bind to blood proteins and makes them more water soluble- for excretion in the urine
What is the steroid mechanism of action?
* Cortisol and aldosterone bind to glucocorticoid receptor (GR) or mineral corticoid receptors (MR) in the cytoplasm that translocate to the nucleus and modulates transcription in multiple tissues after hormonal binding
What are metabolic actions of glucocorticoids?
* Defence against hypocalcaemia: raise blood glucose by increasing liver output of glucose
- decrease utilization of glucose by muscle and adipose tissue
- promotes gluconeogenesis (by inducing synthesis of enzymes)
- promotes proteolysis and inhibits protein synthesis to free up amino acids for gluconeogenesis
- liver synthesis of enzymes involved in the metabolism of amino acids- facilitating conversion to carbohydrates
- In muscle facilitating break down of muscle protein therefore providing amino acid substrate to the circulation and to the liver
* Mobilization of fat from subcutaneous adipose tissue
* Enhance release of glucagon from pancreas alpha cells
* Antagonizes the action of insulin on muscle and adipose tissue
* cortisol must be present for catecholamines to stimulate hormone sensitive lipase
Glucocorticoids and inflammation
* inhibit PGs and Leukotriene production (from endothelial cells, macrophages, mast cells, etc.)
* decrease release of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha)
* Reduces IL-2 production therefore inhibiting lymphocyte proliferation
* Reduced proliferation of fibroblast- therefore slow wound healing
What is Cushing’s Disease?
Hyperadrenocorticism
* Excess secretion of corticosteroids due to:
- pituitary tumour (85% of cases) over secreting ACTH- normally have two large adrenal glands
- Adrenal tumour
- excess administration of cortico-steroids (iatrogenic) (cortisone = cortisol, predinisone 4 x cortisol, dexamethasone 30 x cortisol)
What are the symptom’s of Cushing’s Disease?
* Bulging sagging (pot-bellied) belly
* muscle weakness, loss of muscle mass
* Hair loss and thinning of skin
* weak bones
* bruising
* polyphagia
* PU/PD
* poor wound healing
* Weight gain or redistribution of fat
* susceptibility to infections particularly bladder
* exercise intolerance
Why are about 10-20% of dogs with Cushing’s Disease also Diabetic?
* Glucocorticoids decrease utilization of glucose by muscle and adipose tissue and lower sensitivity of these tissues to insulin
What is Addison’s disease?
* Insufficiency of adrenocortical hormones
* Rare- autoimmune disease
* Signs: lethargy, weakness, dehydration, collapse
* Low plasma Na+, increased K+, increased BUN (blood urea nitrogen)
What does the adrenal medulla secrete? What is the medulla?
* catecholamines: adrenalin and noradrenalin (short half life 10-15 seconds- up to 90% of catecholamines removed from blood on single passage)
* medulla is a modified ganglion- a component of the sympathetic NS
What are the major stimuli of the adrenal medulla? How?
* hypoglycaemia, stress, and exercise
* Stimulation of nicotinic ACh receptors opens Ca2+ ion channels on chromaffin cells that produces a localized depolarization and entrance of Ca2+ resulting in exocytosis of adrenaline and noradrenaline
Where and from what are adrenalin and noradrenalin synthesized?
Chromaffin cells
* Tyrosine, dopa, dopamine, noradrenalin, adrenalin
What are the functions of adrenoceptors?
alpha- 1: increased vascular smooth muscle contraction, mydriasis (constricts radial muscle)
alpha-2: muscle relaxation, sedation, and analgesia (effects on CNS), hypertension, vasoconstriction of arteries to the heart
Beta 1: heart and kidney- increased force cardiac contraction and heart rate, renin release
Beta 2: bronchodilation by relaxation of smooth muscles in bronchi, uterine muscle relaxation, liver- glucose metabolism, smooth muscle relaxation
Beta 3: enhanced lipolysis
Metabolic actions of adrenalin
Where do large emobli tend to become trapped in the brain? Why are venous occlusions uncommon in the brain?
* Leptomeningeal vessels (where they divide into perpendicular branches)
*at the grey-white matter junction
* venous occlusions are rare because verebral veins are abundant and have many anastamoses
What is diploe?
Spongy bone present between two layers of compact bone in the parietal, occipital, and temporal bones of the skull– one of the ways the skull can absorb considerable shock forces (cranial sutures help too and the internal bony ridges of the skull)
What are the factors that influence the consequences of skull trauma?
Physical rigidity of bone (age, nutrition, presence of metabolic disease), mass, velocity, and direction of the applied force, the ability of the impacted tissues to move in response to the applied force
Why is cerebral trauma often fatal?
Due to the confined space of the cranial cavity. Normally only a narrow space separating the brain from the dura mater. If ICP increases, cerebral structures such as the medulla oblongata and the cerebellar vermis may herniate caudally.
Clinical signs of increased ICP
Aniscoria, mydriasis (pupillary dilation), non-responsive pupils, dull mentation, or altered state of consciousness, rigid paresis, abnormal respiration pattern, bradycardia, and coma
What is the adenohypophysis? What 3 parts does the adenohypophysis consist of?
Adenohypophysis- anterior lobe of the pituitary
- pas distalis- bulk of endocrine cells which secrete trophic hormones
- pas tuberalis- endocrine cells– mainly acts as a scaffold for the portal blood vessels coursing from the median eminence to the pas distalis
- pars intermedia- junction between the pas distalis and the pars nervosa and contains endocrine cells (separated by a cleft- not in horse- the residual lumen of Rathke’s pouch)
What is the neurohypophysis?
* Posterior lobe of the pituitary
What are acidophils?
* secretory endocrine cells of the adenohypophysis– secretory granules stain red with H& E
* somatotrophs= cells secreting growth hormone (somatotropin)
* luteotrophs= cells secreting luteotropic hormone (LTH) (prolactin)
What are basophils in the adenohypophysis?
Secretory granules stain blue with H& E stain
* gonadotrophs= cells secreting luteinising hormone (LH) and follicle stimulating hormone (FSH)
* thyrotrophs= cells secreting thyroid stimulating hormone (TSH)
What are chromophobes?
* secretory endocrine cells of the adenohypophysis– not discernible with H& E stain
* Corticotrophs= cell secreting adrenocorticotropic hormone (ACTH)
* melanotrophs= cells secreting melanocyte stimulating hormone (MSH)
* degranulated acidophils and basophils
* undifferentiated stem cells
* non-secretory cells
What are the endocrine cells of the adenohyphophysis under control of?
Corresponding releasing hormone derived fro neurons of the hypothalamus by neurosecretion
* the releasing hormones are transported along the axonal processes of the secretory neurons to the median eminence–> release into capillaries–> transport by blood vessels of the pituitary protal system–> target endocrine cells in the adenohypophysis which rapidly release their secretory granules into the blood
What is the control of most pituitary trophic hormones?
Negative feedback control achieved by the blood concentration of the hormone produced by the target endocrine glands e.g. thyroxine from the thyroid glands, cortisol from the adrenal cortices, oestrogen or progesterone from the ovaries, androgens from the testes, etc.
** negative feedback is exerted either on the hypothalamic neurosecretory neurons or on the adenohypophyseal trophic hormone secreting cells or both
How do GH, prolactin (LTH), and MSH stimulate secretion of a hormone?
NOT by acting on target endocrine organs but by means of releasing inhibitory hormones produced by hypothalamic neurons.
* dopamine is the main releasing factor for prolactin (LTH)
* somatostatin is the main release inhibiting factor for GH (somatostatin is also produced by pancreatic islet cells)
What are supraoptic nuclei?
Neurons of these nuclei in the hypothalamus synthesise antidiuretic hormone (ADH; vasopressin)
What are paraventricular nuclei?
Neurons of these nuclei in the hypothalamus synthesise oxytocin
How is ADH secreted into general circulation?
* ADH and its corresponding binding protein (neurophysin I) are packaged into neurosecretory granules and transported to the pars nervosa of the pituitary gland by axonal processes of the hypothalamic neurosecretory neurons; the axons terminate on fenestrated capillaries in the pars nervosa, permitting release of ADH directly into general circulation
What is the function of ADH?
Acts on distal tubules and collecting ducts of the kidneys to cause water resorption from the glomerular filtrate and hence increased urine concentration
What is the function of oxytocin?
Contraction of smooth muscle fibres in the uterus and myoepithelial cells in mammary tissue
What are the three parts of the neurohypophysis?
- median eminence: site where axons of the hypothalamic neurosecretory neurons release hypothalamic releasing hormones/ factors into capillaries to influence the endocrine cells of the adenohypophysis
- infundibular stalk= pituitary stalk: composed on non-myelinated axonal processes from the hypothalamic neurosecretory neurons of the supraoptic and paraventricular nuclei… joins the pars nervosa to the overlying hypothalamus
- pars nervosa- contains numerous capillaries which are termination sites for the axonal processes of the hypothalamic neurosecretory neurons producing oxytocin and ADH
pituitary gland (arrow)
Later term human foetal brains in which there has been failure of successful differenation of the prosencephalon into derivative structures (holoprosencephaly= prosencephalic hypoplasia)
Cyclopia- most severe expression of holoprosencephalon (excessive wool growth reflects prolonged gestation due to partial or complete failure of development of the hypothalamus and/or posterior pituitary. Therefore a delay in or complete absence of the foetal cortisol surge which triggers the parturition process.
Veratrum californicum (lamb’s bane, skunk cabbage)- steroidal alkaloids induce holoprosencephaly in foetal lambs if their dams consume the plant between days 9 and 14 of pregnancy
Foetal calf with cessation of growth and development at approximately 7 months of gestation due to hypoplasia of the adenohypophysis and hence inadequate pituitary tropic hormone production
Cauliflower saltwort in Africa- last 50 days of pregnancy may have parturition delayed by 10-20 days, possibly by inhibition of release of foetal hypothalamic releasing hormones
Development of the pituitary gland
* down growth of neuroectodermal tissue from diencephalon
- gives rise to posterior pituitary… has to grow ventrally and make contact with organ up growth (ectodermal tissue from the oropharynx)– ultimately when it joins up and matures–> gives rise to anterior pituitary—> eventually separated from oropharyngeal ectoderm because bone forms (sphenoid bone).
* Rathke’s pouch refers to the up growth
Arrow? What can happen if this stays open?
A residual cleft (arrows) that is the remnant of the embryonic Rathke’s pouch detectable microscopically. If Rathke’s pouch stays open–> PITUITARY CYST
Pituitary cyst
Pituitary cyst– gradually enlarges
Litter mates.
What’s the problem? What are the causes?
Pituitary Dwarfism- over represented in German Shepherds. Autosomal recessive. Inadequate growth hormone. Usually becomes apparent from approximately 2 months of age.
** pituitary cyst, craniopharyngioma (ectodermal remnants of Rathke’s pouch)
Pituitary abscess in a calf – purulent exudate tracking along the ventral floor of the cranial vault to the foramen magnum
** grass awns tracking along the optic nerve from the orbit or circle of willis or bacteria can ascend from superficial skin infections along the deep valveless veins of the face into the cranial vault
Non-functional tumours of the pituitary
Space occupying- compression of surrounding structures.
Visual deficits, central blindness, pupillary dilation issues, trigeminal nerves
What are some of the signs and symptoms of hypothalamic pituitary disorders?
* example: infertility due to not enough FSH/ LH produced
* obesity: polyphagic- pressing on appetite and satiety centers
* space occupying mass in a tight space = neurological signs due to ICP
* OR pituitary cachexia can also occur due to lack of growth hormone
pituitary macroadenoma in a dog
Functional pituitary tumours- Pars distalis (sometimes pars intermedia)
* in the pars distalis can get really big– easily compress CNs
* Producing too much ACTH will cause bilaterally enlarged adrenal cortices– overproducing cortisol– therefore hyperadrenocorticoid
Cushing’s Disease (tumour) vs. Cushing’s Syndrome (iatrogenic due to corticosteroids)
Pituitary Pars Intermedia Dysfunction (PPID)
** EXCESS pro-OLMC precursor produced by chromaphobe cells of the tumours in horses– serum cortisol and ACTH concentrations are only mildly increased or NORMAL–
* polyphagia, PU/PD, weight gain (pot-bellied), docility/ sleepiness, failure of seasonal shedding of the hair coat, excessive sweating, chronic recurrent laminitis
* due to compression of the hypothalamus by a tumour
Clinical presentation of PPID
* less peripheral effects, but issues with sphenoid bone (lysis) and compression of overlying structures
Acromegaly due to development of the functional acidophil tumour of the pituitary
* visual effects, polyphagia, PU/PD, eventually become diabetic because they are eating more–> pancreas produces more insulin–> insulin resistant diabetes
Where do the adrenal cortex and medulla derive from? What is the ratio?
What parts of the adrenal gland secrete what?
Salt, sugar, sex–> the deeper you go, the sweeter it gets
Amyloid deposition or adrenal mineralization
Why is adrenal haemorrhage common?
Thin walled- so susceptible to haemorrhage especially horses who have died on the race track.
* neonates who have been “squeezed out”
* DIC
* septicaemia (if they survive, they can end up with adrenal insufficiency- rare)
Adrenal haemorrhage
Adrenalitis- common, sequestered from the immune system to some extent
** autoimmune disease as well- common in dogs
What are the two most common drugs causing adrenal toxicity?
Nodular hyperplasia vs. adenoma
Hyperplasia is a normal response, whereas adenomas have abnormal stimulus
Signs and symptoms of Hyperadrenocorticism
Calcinosus cutis
Hyperadrenocorticism in cats signs and symptoms
Hyperadrenocorticism in horses or pituitary pars intermedia dysfunction (PPID)?
What are haematology findings with Hyperadrenocorticism (HyperA)?
Persistent stress leukogram
Routine urinalysis findings with HyperA
(UTI prone due to suppressed immune system)
Testing Options for HyperA
** keeping in mind stressed animals at the vets may have abnormal levels – overdiagnosed
Low dose dexamethasone suppression test (LDDST)
Measure levels before and after giving exogenous corticosteroids… if they have pituitary dependent hyperA or adrenal dependent hyperA… normal dog SHOULD SUPPRESS PRODUCTION for about 8 hours… Why do we do a 3 and 8 hours?? To differentiate between pituitary dependent PDH and adrenal dependent….
* high sensitivity (95%)– most dogs will be detected with this test!! Problem is: normal stress (drive to produce cortisol is overriding the feedback mechanism****)
* Moderate specificity (44-73%)
* adrenal tumours show lack of suppression
* pituitary dependant hyperA (PDH) can show partial suppression (75%) or no suppression (25%)
* Partial or no suppression with stress
What is the unique thing about horses interpreting overnight DST?
ACTH stim test
Stimulates adrenal glands to make more cortisol. Depending on the size of the adrenal gland, it will depend on how the animal will respond. Great big= respond more than an animal with smaller.
** more false negatives– lower sensitivity than LDDST BUT not as many false positives
** does not differentiate PDH from ADH
Haematological findings with Addison’s disease in dogs
* lack of stress lymphopenia but they are sick!! (may be the only sign you have)
Biochem findings with Addison’s Disease
How do you test for Addison’s Disease?
** may run a basal cortisol level** (exclusion test, not confirmatory)
What is the eosinophilic material contained within the follicles of the thyroid?
Colloid- which is the storage form of thyroid hormone.
Colloid is a glycoprotein called
thyroglobulin, the storage or intermediary form of thyroid hormone
What are the hormones that are released from the pars nervosa?
Oxytocin and ADH (peptide hormones).
** synthesized in the cell bodies of the supraoptic nucleus (ADH) and paraventricular nuclei (oxytocin) of the hypothalamus
What would you see with an LDDST with PDT? Why?
Partial or no suppression at 4 hours- then kicking up again at 8 hours
**Dexamethasone is a corticosteroid not detected by the cortisol assay that causes suppression of CRH and ACTH release, leading to a marked decrease in cortisol release from adrenal glands. In normal dogs, this suppression lasts 8 hours– but in a pituitary dependent hyperA dog– the excess secretion of ACTH causes marked adrenal gland enlargement (cortical hyperplasia) and hence greater release of cortisol… and with the LDDST we will see either no suppression (total loss of normal negative feedback of pituitary adenoma continues to release ACTH, so cortisol levels do not significantly fall)– same response as in adrenal tumours (25% of PDH cases), OR early escape from suppression– lowers it but cortisol levels rebounded by 8 hours, OR partial suppression of CRH and ACTH release- leading to a mild decrease in cortisol release from the adrenal glands… they do not fall below 30 nmol/L
What will you see with LDDST with ADH? Why?
Failure to suppress. Due to a functional tumour of the adrenal glands pumping out cortisol without the requirement for ACTH release. Typically ACTH levels in these dogs are extremely low…. so the negative feedback mechanism has no effect.
How do you test for Addison’s Disease?
Primary adrenal gland failure or Iatrogenic (sudden withdrawal)
** Haematology- lack of stress leukogram in a sick dog
** Biochemistry- low sodium, high potassium, low glucose, high calcium, azotaemia
