Endocrine 1 Flashcards
Hypothalamus and pituitary where located, composed of and parts
Hypothalamus
- Functionally diverse region of the brain
- Located in the diencephalon below the thalamus and above the pituitary
- Composed of anatomically distinct nuclei
• Pituitary gland
- Complex endocrine organ
- Located in the sella turcica at the base of the brain inferior to the hypothalamus
○ Only way to access through the roof of the mouth
- Two parts
○ Anterior pituitary -> collection of endocrine cells (adenohypophysis)
○ Posterior pituitary -> made up of neural tissue (neurohypophysis)
what are the 2 hormones secreted from the posterior pituitary
1) Anti-diuretic Hormone (ADH)
2) Oxytocin
ADH how synthesized and the 2 main functions
- Synthesis
- peptide hormone (9 aa)
- Produced in hypothalamus
» supraoptic and paraventricular nuclei
- Released by posterior pituitary
» Osmoreceptors: ECF osmolality
» Baroreceptors: Blood pressure/volume - Functions of ADH
- Acts on renal collecting ducts to increase water reabsorption from urine
» Binds on V2 receptors of principal cells (cAMP pathway)
- Increases vascular resistance
» Binds V1 receptors smooth muscle cells (PIP2 pathway)
Oxytocin where produced, released and functions (where receptors located)
- Peptide hormone (9 aa)
○ Produced in supraoptic and paraventricular nuclei
○ Also acts as a neurotransmitter in brain - Released by posterior pituitary
○ Oxytocin receptors are on smooth muscle cells
§ mammary gland and uterus
○ Oxytocin receptor is a Gαq coupled rhodopsin type (class I) receptor.
What are the 5 main steps in the mechanism of hormonal release from the posterior pituitary
- Large neuron bodies in supraoptic & paraventricular nuclei synthetise Oxytocin (OCT) and Anti-diuretic hormone (ADH)
- Travel down axons via hypothalamohypophyseal tract (Neurophysins serve as low affinity carrier proteins) to the synapse
- Secretion of OCT & ADH from the neurosecretory nerve endings is regulated by action potentials down the neuron
○ Signals are received from brain -> to the particular nucleus -> down the tract to the synapse - Nerve endings in the pituitary contain large numbers of OCT or ADH containing vesicles
- Released by exocytosis when the nerve terminals are depolarised.
What are the 6 hormones released from the anterior pituitary
- Thyroid stimulating hormone (TSH)
- Adrenocorticotropic hormone (ACTH)
- Prolactin (PRL)
- Lutenizing hormone (LH)
- Follicle stimulating hormone (FSH)
- Growth hormone (GH)
What are the 4 main steps in the mechanism of hormone release from anterior pituitary
- Inhibiting and releasing hormones secreted by small bodied neurons in various regions of the hypothalamus
- arcuate, periventricular and preoptic nuclei - Released into the hypothalamohypophyseal portal system to synaptic nob
- Released into primary capillary plexus within pituitary stalk and engages with certain cell types that result in release of anterior pituitary hormones (if interact with somatotrophs get release of growth hormone)
- Hormones move into a secondary capillary plexus within the anterior pituitary into draining veins
Growth hormone what hypothalamic hormones are involved, where secreted, what also called, what is important for half life and the main function
Hypothalamus
- Growth hormone inhibition and releasing hormone
Anterior pituitary
somatotrophs release
Also called somatotrophin
- 50% circulates in complexes with soluble forms of GH receptor
○ GH binding protein (GHBP) -> increases the half-life of the hormone
Main function
- Responsible for postnatal somatic growth
- increasing the number of cells (hyperplasia)
- Increasing the size of cells (hypertrophy)
What are the 3 main functions of growth hormone and how achieve theses
- Acute metabolic effects
- “Anti-insulin like” i.e. Mobilizes fat & conserves glucose
- Lipolysis in adipose tissue - decrease fat content
- Inhibition of glucose uptake by muscle
- Stimulation of gluconeogenesis by hepatocytes - Growth promoting
- GH causes release from liver of Insulin like growth factor (IGF-I)
○ Stimulates differentiation and proliferation of cells. - Growth of long bones
- GH caused bones to grow in length
- Causes proliferation and enlargement of chondrocytes (cartilage cells).
○ Causes the epiphyseal plate to increase in width
○ calcification of the extracellular matrix on the diaphyseal border and old nutrient deprived chondrocytes die and are cleared by osteoclasts then replaced by oestoblasts that deposit bone
What are the 2 main growth hormone disorders, what result from, caused by and lead to
- Pituitary dwarfism
- Hyposecretion of GH during the growth years
- Genetic predisposition, tumours, infarcts & infections
- Causes slow bone growth, and early epiphyseal plates closure - Gigantism
- Hypersecretion of GH (early in life) results in gigantism
○ Possible due to pituitary tumour
- Abnormal increase in the length of long bones
- Larger muscle mass
Feline acromegaly what is it caused by and lead to
Caused by a growth hormone- secreting tumour of the anterior pituitary
- Hypersecretion of GH during adulthood
○ 8-14yr old (more common in males)
- Further lengthening of the long bones cannot occur because the epiphyseal plates are already closed.
- Instead, the bones of the limbs, skull, and jaw thicken.
- Other tissues & organs also grow
○ the eyelids, paws, cheeks, lips, tongue, and nose enlarge, and the skin thickens.
Feline acromegaly what are the 4 main clinical signs
1) Net weight gain of lean body mass in cats with uncontrolled diabetes (polydipsia, polyuria, and polyphagia).
2) Cardiomegaly (radiographic and echocardiographic), systolic murmurs & heart failure
3) Enlargements of extremities
4) Azotemia also develops in 50% cats
Growth hormone secretion levels what occurs daily and throughout life
- Growth hormone secretion occurs as several pulses/day - spikes
○ Last from 10 to 30 min before returning to basal levels.
○ The largest GH peaks occurs about an hour after onset of sleep (diurnal secretion). - The amount and pattern of GH & IGF-I secretion changes throughout life.
○ Basal levels are highest in early life decline throughout adult life.
○ The amplitude and frequency of peaks is greatest during the pubertal growth spurt
Regulation of growth hormone secretion what are the 3 main CNS inputs and list some GH release stimulators and inhibitors
CNS inputs via hypothalamus 1) pulsatile secretion 2) negative feedback 3) diurnal rhythms Stimulators of GH release include (among others) - hypoglycemia, - stress - dietary protein - low fatty acids - Exercise - Ghrelin (stomach hormone). Inhibitors of GH secretion include - high carbohydrate - negative feed back( IGF-I & GH -> result in release of growth hormone inhibiting hormone)
Besides the release of growth hormone inhibiting hormone what is another inhibitory feedback that occurs
○ Somatostatin (GHIH) - has on receptor (inhibitory response)
§ Produce Gsα & Giα proteins regulate cAMP levels and GH secretion - decrease the release
Describe the 3 parts of the adenohypophysis (anterior pituitary)
1) pars distalis the largest part; contains the bulk of the endocrine cells which secrete trophic hormones
2) pars tuberalis - consists of dorsal projections of endocrine cells along the infundibular stalk
- mainly acts as a scaffold for the portal blood vessels coursing from the median eminence to the pars distalis
3) pars intermedia - forms the junction between the pars distalis and the pars nervosa and contains endocrine cells
in all species except the horse, the pars intermedia is separated from the pars distalis by a cleft
what is the anterior and posterior pituitary derived from
- the adenohypophysis (anterior pituitary) is derived from the ectoderm of Rathke’s pouch (craniopharyngeal duct)
- the neurohypophysis (posterior pituitary) is derived from the neuroectodermal downgrowth
What are the potential consequences to the foetus and dam of failure of adequate in utero development of the pituitary or hypothalamus?
- prolongation of gestation, at least in ruminants
○ in ruminants, the signal for normal parturition at term is a rise in the foetal cortisol concentration, which requires an intact foetal hypothalamic-pituitary-adrenocortical axis and sufficient maturation of the adrenal cortices to respond to the foetal ACTH signal - can result in retarded foetal growth and development in late stages of gestation (due to inadequate production of such anabolic hormones as growth hormone, thyroxine and testosterone)
List 3 syndromes where there is inadequate development of the pituitary or hypothalamus, what species and why occur
1) Anencepahly and Prosencephalic Agenesis (absence) -> ruminants
- early embryonic failure of the rostral neural tube
2) Prosenecphalic Hypoplasia (Holoprosencephaly) -> rostral tube closes but some degree of failure of prosencephalon to differentiate
- ewes consumed steriodal alkaloid-containing plant Veratrum californicum between days 9 and 14 of pregnanacy (severe expression is cyclopia)
3) Adenohypohydeal Hypoplasia -> Guernsey, Jersey and Swedish Red and White cattle as an autosomal recessive inherited condition characterised by prolonged gestation
What is the craniopharyngeal duct (Rathke’s pouch) and what lesions can arise from remnants of this structure
dorsal evagination of oropharyngeal ectoderm that forms the anterior pituitary
Pituitary cysts can develop from this remnant as well as craniopharyngioma (a benign tumour derived from epithelial remnants of oropharyngeal ectoderm of the craniopharyngeal duct (Rathke’s pouch))
In which species are developmental pituitary cysts most often diagnosed and What is their clinical significance?
- most often seen in dogs
- small cysts are asymptomatic but larger cysts may provoke clinical signs
- depend on the area it grows may occlude caudal nares -> respiratory distress OR compress pituitary, hypothalamus, optic chiasm etc. OR result in pituitary dwarfism
Pituitary dwarfismwhich species is this condition most commonly seen and how does it manifest clinically?
Dogs - most often in German shepherd dogs but is also reported in Weimaraner, Spitz, toy pinscher and Karelian bear dogs
Clinically
- normal till 2 months then growth slows
- 3-4 months obvious runts never obtain full adult dimensiosn
- most have normal proportions but some chuncky square shape
- puppy coat retained lack of primary guard hairs (appear woolly)
- skin initially normal but becomes hyperpigmented, thin, wrinkled, scaly
List 5 clinical consequences of large space-occupying mass in the pituitary
- compression adenohypophysis (hypothyroidism, hypoadrenocorticism, loss of libido, anoestrus, infertility)
- loss of protein anabolic effects of growth hormone (pituitary cachexia, dull and dry hair coat)
- diabetes insipidus (polyuria, polydipsia)
- cranial nerve deficits -> central blindness
- CND dysfunction -> behavioural, emotional disturbances, thermoregulation
What is the most common type of pituitary neoplasm in dogs and what effect would such a tumour have in the adrenal glands?
Corticotroph (ACTH-secreting) Adenoma of Dogs
- ACTH secretion by the tumour -> bilateral enlargement of the adrenal glands due to hypertrophy and hyperplasia of cells of the zonae fasciculata and reticularis of the adrenal cortices
What is the most common type of pituitary neoplasm in horses, what are the typical clinical signs associated with such tumours and why do these signs develop
Melanotroph Adenoma of the Pars Intermedia of Horses
many of these clinical signs (e.g. polyphagia, PU/PD, sweating and failure to cyclically shed hair) are due to compression and dysfunction of the overlying hypothalamus - NOT AS MUCH DUE TO EXCESS HORMONES
What is the usual cause of acromegaly in cats and dogs
Cats
functional somatotroph adenomas of the pars distalis
Dogs
due to prolonged administration of synthetic progestagens
List 6 clinical signs of acromegaly
1) polyphagia
2) increase in body size and weight
3) enlargement of head, feet, abdomen and viscera
4) rapid claw growth
5) hypertrichosis (increased hairiness)
6) formation of excessive skin folds
What is the usual clinical signs of diabetes insipidus
inability to concentrate the urine -> polyuria secondary polydipsia to prevent dehydration
What is meant by the term central diabetes insipidus and what are some possible causes of this condition?
There is a partial or complete deficiency of ADH
Causes - any condition that damages the hypothalamic supraoptic nucleus, the infundibular stalk or the pars nervosa
1. most idiopathic
2. head trauma
2. congenital in some dogs
What is meant by the term nephrogenic diabetes insipidus and what are some possible causes of this condition?
Blood levels of ADH are normal to high but target cells in the distal renal tubules and collecting ducts are unable to respond
Causes
1) primary - congenital in various dog breeds
2) secondary - primary renal disease (e.g. pyelonephritis) or extrarenal disorders (e.g. pyometra, hypoadrenocorticism, hypercalcaemia, hypokalaemia) impair the renal response to ADH
What is the basic structure of the adrenal galnd
- bilateral structures encased in a connective tissue capsule Consists of 2 layers 1) Cortex (80-90% of adrenal gland) 1. zona glomerulosa 2. zona fasciculta 3. zona reticularis 2) Medulla - chromaffin cells (columnar shape and basophilic with granules) surrounding blood vessles
Describe the 3 layers of the cortex of the adrenal gland
1) Zona glomerulosa
§ The outermost zone and cells here are columnar in shape and are arranged in irregular cords
§ Creates aldosterone
2) Zona fasciculata
§ Middle zone and cells are polyhedral, with foamy appearance (lipid) and are arranged in straight cords radiating towards the medulla
§ Production of glucocorticoids such as cortisol
3) Zona reticularis
§ Cells are arranged in cords that run in many different directions and anastomose with one another
§ Produce Androgen precursors
Within the cortex of the adrenal glands what are the 3 areas and what hormones do they produce
1) Zona glomerulosa produces mineral corticoids such as aldosterone
2) Zona fasciculata produce glucocorticoids such as cortisol
3) Zona reticularis produce androgen precursors such as dehydroepiandrosterone (and some cortisol)
Steroid hormones produce from adrenal gland what is the rate limiting step, what produced where and how
- Cholesterol to pregnenolone rate limiting step is production of an enzyme which is activated by ACTH
- Zona fasiculata and reticularis have 17-alpha-hydroxylase which is necessary for synthesis of 17-hydroxypregnenolone and 17-hydroxyprogesterone so can form cortisol
- Zona reticularis can create dehydroepiandrosterone (DHEA) which is converted to testosterone and oestrogen in peripheral tissues
What is involved in the transport and removal of adrenocortical hormones
TRANSPORT
○ 90% of glucocorticoids in blood are bound to protein and have a relatively long half-life in blood ~ 60-90 min.
○ Cortisol is transported in blood bound to corticosteroid-binding globulin (transcortin), and albumin.
REMOVAL
- inactivated in the liver decreasing their bind to blood protein
- increased excretion in bile and urine
List the 4 steps on how cortisol and aldosterone exert their effects
- Cortisol and aldosterone pass through the cell membrane and bind to a glucocorticoid receptor (GR) or mineralcorticoid receptors (MR) in the cytoplasm.
- This binding of cortisol to its receptor allows the disassociation of heat shock proteins hsp90/70
- Allows a homodimer to form that translocates to the nucleus.
- Inside the nucleus, the receptor complex binds to specific DNA responsive elements to activate gene transcription.
- The mineralocorticoid receptor can binds both aldosterone and cortisol.
What are the 4 broad actions of glucocorticoids
1) within the endocrine system
2) anti-inflammatory
3) bone
4) delayed wound healing
Glucocorticoids what are the 4 main actions within the endocrine system and how achieve
- Raise blood glucose by increasing liver output of glucose
○ Promotes gluconeogenesis by inducing the synthesis of gluconeogenic enzymes (side effect of diabetes)
○ Promotes proteolysis and inhibit protein synthesis thus freeing up amino acids for gluconeogenesis. - Induces mobilization of fat from subcutaneous adipose tissue.
- Prior action of cortisol build-up of glycogen stores in liver and used as a substrate for glucagon and adrenaline
- permissive hormone
○ In adipose tissue it must be present for catacholamines to stimulate hormone sensitive lipase
○ In liver other gluconeogenic hormones are ineffective without the permissive effect of glucocorticoids.
Glucocorticoid anti-inflammatory actions what are the 4 effects
1) Inhibits prostaglandin and leukotriene production by inhibiting phospholipase A2 and formation of arachidonic acid.
2) Decrease release of proinflammatory cytokines IL-1, IL-6 & TNF-a
3) Reduces IL-2 production inhibiting lymphocyte proliferation
4) Reduce expression of cell adhesion molecules important for cell extravasation from the blood
Immunosuppressive - SIDE EFFECT
Glucocorticoid bone and delayed wound healing functions what occurs
Bone - High cortisol --> decreased bone mass - Inhibits formation of calcitriol and calcium absorption - Inhibits collagen synthesis - Synergizes with PTH to break down bone - Inhibits bone formation (reduce osteoblasts activity) ○ Osteoporosis - SIDE EFFECT Delayed wound healing - Inhibits collagen synthesis
