Parathyroid%20Glands:

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Parathyroid Glands

• The parathyroid glands are small in size and are
  found on the posterior aspect of the thyroid
  gland.
• Typically, there are four of them but the actual
  number may vary.

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Histology of the Parathyroid

• The endocrine cells within these glands are
  arranged in thick, branching cords containing
  oxyphil cells of unclear function and most
  importantly large numbers of chief cells that
  secrete parathyroid hormone (PTH).

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PTH

• Small protein
• Single most important hormone controlling calcium
  homeostasis. Its release is triggered by falling
  blood calcium levels and inhibited by
  hypercalcemia (high blood calcium).
• There are three target organs for PTH
• skeleton
• kidneys
• intestine

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• In humans, the major calcium storage organ is
  bone.
• Calcium is stored as CaPO4.
• Generally, calcium salts are not very soluble in
  aqueous solutions such as plasma.
• Calcium metabolism is virtually inseparable from
  phosphate metabolism.
• The major factors regulating calcium and
  phosphate metabolism are parathyroid hormone
  (PHT), calcitonin and calcitrol.

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PTH stimulates the following on these target
organs

• Osteoclasts (bone absorbing cells) are stimulated
  to digest bone and release ionic calcium and
  phosphates to the blood.
• Kidneys are stimulated to reabsorb calcium and
  excrete phosphate.
• Intestines are stimulated to increase calcium
  absorption.
• Vitamin D is required for absorption of calcium
  from ingested food.
• For vitamin D to exert this effect, it must first
  be converted by the kidneys to its active form
• It is this conversion that is directly stimulated
  by PTH.

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Pathology of the parathyroid glands

• Because calcium is essential for so many
  functions, including transmission of action
  potentials, muscle contraction, pacemaker
  activity in the heart, and blood clotting,
  precise control of ionic calcium levels in body
  fluids is absolutely critical. As a result both
  hyper- and hypoparathyroidism can have severe
  consequences.

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Hyperparathyroidism

• Rare, usually the result of a parathyroid gland
  tumor.
• Results in severe loss of calcium from the bones.
  
• The bones soften and deform as their mineral
  salts are replaced by fibrous connective tissue.
• Results in hypercalcemia
• Leads to, depression of the nervous system
  leading to abnormal reflexes and weakness of the
  skeletal muscles, and formation of kidney stones
  as excess calcium salts are deposited in kidney
  tubules.

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Hypoparathyroidism

• It is a PTH deficiency, which is a common
  consequence of parathyroid trauma or removal
  during thyroid surgery.
• The resulting hypocalcemia increases excitability
  of neurons and may lead to tetany resulting in
  uncontrollable muscle twitches and convulsions,
  which if untreated may progress to spasms of the
  larynx, respiratory paralysis and death.

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Calcitonin in non-mammalian vertebrates

• In most non-mammalian vertebrates, calcitonin is
  secreted from a specific gland called the
  ultimobranchial gland.
• In mammals, this tissue has been incorporated
  into the thyroid gland (C- or parafollicular
  cells).

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• Bone probably evolved as a calcium storage organ
  first, then became structural.
• Calcium availability is not an issue for marine
  organisms.
• However, when fish started moving into fresh
  water, calcium was in short supply.
• These fish needed to start storing calcium.
• This may explain the emergence of the jawed
  fishes.
• Believed to have evolved in fresh water.
• Had bonier skeletons than marine fish.

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• Cartilage was a good starting material for
  calcium storage, since calcium is already a
  component.
• Having stronger bones would have facilitated jaw
  evolution by providing a sufficiently strong
  substrate.
• Jaws require strong structural support because
  they can develop great forces.
• At the same time, fish were developing more
  robust dermal plating from protection.
• Also from CaPO4 deposits in scales.

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Calcium regulation in non-mammalian vertebrates

• Fishes in general
• Unlike other vertebrates, fish do not have
  parathyroid tissue. However, immunoreactive PTH
  has been demonstrated in trout and goldfish.
• Many fish lack true bone.
• In most teleosts, bone is acellular (no
  osteoclasts or osteoblasts).
• Scales may play a major role as calcium storage
  organs.

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• In fish, unlike other vertebrates, the principal
  calcium regulators are calcitonin and
  stanniocalcin.
• Stanniocalcin is secreted in response to elevated
  plasma calcium (similar to PTH in other
  vertebrates).
• Stanniocalcin is secreted by the Corpuscles of
  Stannius.
• Parathyroid hormone related hormone (PTHrH) has
  been isolated from plasma.

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Parathyroid Hormone related Hormone (PTHrH)

• PTHrH is a protein with hypercalcemic activity.
• It was first isolated from a malignant tumor.
• Has significant sequence overlap with PTH,
  particularly at the N-terminal.
• Thought to have evolved from PTH gene.
• Has been identified in over 20 different tissues
  in humans (including lactating mammary, uterus,
  and the amnion and fetal parathyroid glands.
• Probably plays a role in Ca2 accumulation by the
  fetus.

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• Agnathan fishes
• These do not appear to have specific mechanisms
  for regulating calcium and phosphate.
• However, mammalian calcitonin will decrease
  urinary flow and urinary electrolyte
  concentration.
• Chondrichthyean fishes
• Calcium is stored in cartilage, since these fish
  lack true bone.
• Ultimobranchial glands contain a potent
  hypocalcemic factor (for mammals)
• Other fish calcitonins are ineffective in sharks
  and rays.

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• Teleost fishes
• CT lowers calcium influx across the gill.
• Salmon CT is very potent at lowering plasma
  calcium in mammals and birds.
• This may be due to its long half-life (compared
  to mammalian CT).
• Calcitrol (1,25 dihydroxycholecalciferol)
  although not absolutely required, will increase
  calcium uptake across the gut.
• Calcitrol has been shown to increase plasma
  calcium in freshwater catfish.
• Estrogens also increase plasma calcium.

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• Sarcopterygean fishes
• Lungfish appear to be insensitive to mammalian CT
  and PTH from other fish or from mammls.
• There is some evidence that CT and PTH are
  diuretic and antidiuretic, respectively.

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• Amphibians
• Very little is known.
• Amphibians possess both an ultimobranchial gland
  and parathyroid glands.
• Specialized structures, the endolymphatic sacs,
  are involved in calcium metabolism.
• These sacs are located at the base of the skull
  and contain large amounts of CaPO4.
• May also be involved in plasma buffering.
• Frogs have cellular bone and the effects of CT
  and PTH are similar to that seen in mammals.
• Bovine PTH is effective in amphibians.

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ADRENAL GLANDS

• The two adrenal glands are pyramid-shaped organs
  found atop the kidneys.
• Each gland is structurally and functionally two
  endocrine glands in one.

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• The inner adrenal medulla is made up of nervous
  tissue and acts as part of the sympathetic
  nervous system. The outer adrenal cortex forms
  the bulk (about 80) of the gland. Each of these
  regions produces its own set of hormones.

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Adrenal Medulla

• It is made up of chromaffin cells which secrete
  the catecholamines epinephrine (E) (adrenaline)
  and norepinephrine (NE) (noradrenaline) into the
  blood.
• During the fight-or-flight responses, the
  sympathetic nervous system is activated,
  including the chromaffin tissue and large amounts
  of catecholamines (80 of which is E) are
  released.
• In most cases the two hormones have very similar
  effects on their target organs. However, E is the
  more potent stimulator of the heart rate and
  strength of contraction, and metabolic
  activities, such as breakdown of glycogen and
  release of glucose).
• NE has great effect on peripheral
  vasoconstriction and blood pressure.

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Adrenal Cortex

• The cells of the adrenal cortex are arranged in
  three distinct zones, each zone producing
  corticosteroids.
• The Zona glomerulosa is the outer-most layer of
  cells and it produces mineralocorticoids, that
  help control the balance of minerals and water in
  the blood.
• The zona fasciculata is composed of cells that
  secrete glucocorticoids.
• The zona reticularis produce small amounts of
  adrenal sex steroids.

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Hormones of the Adrenal Cortex

• Mineralocorticoids
• Although there are several mineralocorticoids,
  aldosterone is by far the most potent and
  accounts for more than 95 of production. Its
  main function is to maintain sodium balance by
  reducing excretion of this ion from the body.
• The primary target organs of aldosterone are
  kidney tubules where it stimulates reabsorption
  of sodium ions from urine back to the
  bloodstream.
• Aldosterone also enhances sodium absorption from
  sweat, saliva, and gastric juice.

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• Secretion of aldosterone is induced by a number
  of factors such as high blood levels of
  potassium, low blood levels of sodium, and
  decreasing blood volume and pressure.
• The reverse conditions inhibit secretion of
  aldosterone.

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• Glucocorticoids
• Glucocorticoids influence metabolism of most body
  cells, help us resist stress, and are considered
  to be absolutely essential to life.
• The most important glucocorticoid in humans is
  cortisol, but small amounts of cortisone and
  corticosterone are also produced.
• The main effect of cortisol is to promote
  gluconeogenesis or formation of glucose from
  noncarbohydrate molecules, especially fats and
  proteins.

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• Cortisol also breaks down adipose (fat) tissue,
  released fatty acids can be then used by many
  tissues as a source of energy and "saving"
  glucose for the brain.
• Blood levels of glucocorticoids increase
  significantly during stress, which helps the body
  to negotiate the crisis.
• Interestingly, chronic excess of cortisol has
  significant anti-inflammatory and anti-immune
  effects and glucocorticoid drugs are often used
  to control symptoms of many chronic inflammatory
  disorders, such as rheumatoid arthritis or
  allergic responses.

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Regulation of glucocorticoid secretion

• It is provided by a typical negative feedback
  system
• increased (hypothalamus) CRH negative
• increased (adenohypophysis) ACTH
• increased (adrenal cortex) cortisol

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• Gonadocorticoids (Sex Hormones)
• The amount of sex steroids produced by zona
  reticularis is insignificant compared to the
  amounts secreted by the gonads.
• These hormones may contribute to the onset of
  puberty and the appearance of axillary and pubic
  hair in both males and females.
• In adult women adrenal androgens (male sex
  hormones, especially testosterone) may be, at
  least partially, responsible for the sex drive.

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Pathology of the adrenal cortex function

• Hyperadrenalism
• It is referred to as Cushing's disease and can be
  caused by a cortisol-secreting tumour in the
  adrenal glands, ACTH-secreting tumour of the
  pituitary, or ACTH secreted by abdominal
  carcinoma.
• However, it most often results from the clinical
  administration of pharmacological (very high)
  doses of glucocorticoid drugs.
• The symptoms include a persistent hyperglycaemia,
  dramatic loss of muscle and bone proteins, and
  water and salt retention, leading to hypertension
  and edema - one of its signs is a swollen "moon"
  face. The only treatment is a surgical removal of
  tumour or discontinuation of the drug.

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• Hypoadrenalism
• It is referred to as Addison's disease and
  involves significant reduction in plasma glucose
  and sodium, very high levels of potassium and
  loss of weight. The usual treatment is
  corticosteroid replacement therapy.

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Comparative aspects of adrenal function

• Anatomy of adrenal tissue
• In mammals, both cortical tissue and chromafin
  tissue are incorporated into two glands
  (bilateral).
• In lower vertebrates, these two tissues are not
  always associated with each other.
• In amniotes, we see the more traditional adrenal
  gland structure, with the gland at the apical
  pole of the kidney.
• In all vertebrates these two tissues are always
  associated with the kidney.

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Renin-angiotensin system

• Kidney (JGA) secretes renin in response to
  sympathetic stimulation, hypotension or decreased
  plasma Na and/or increased plasma K.
• Angiotensinogen is converted to AI.
• AI is converted to AII by ACE in the lungs.

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• AII has a number of direct effects
• Vasoconstriction
• Cardiac and vascular hypertrophy
• Stimulates thirst
• Stimulates ADH secretion
• Stimulates adrenal cortex to release aldosterone.
• Aldosterone has direct effects on the kidney
• Stimulation of Na recovery.

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• Renin-angiotensin system is responsible for
  long-term regulation of blood volume and
  electrolyte balance.
• Normal response to decreased blood volume or
  increased blood osmolarity.
• If blood volume is to high, then the atrial wall
  releases Atrial Natriuretic Factor (ANF) which
  will inhibit renin secretion by kidney.

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• Agnathan fishes
• No discreet JGA.
• No identifiable renin-angiotensin system.
• However, they do have natriuretic peptides which
  are secreted by the gills.
• Sea lampreys have detectable elevated
  corticosteroid levels when in freshwater.
• Blood is isosmotic to seawater, yet there are
  specific differences in ion concentrations.
• Injections of aldosterone alter blood electrolyte
  composition (mainly sodium). Cortisol has no
  effect.

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• Chondrichthyean fishes
• Have one discreet adrenal gland (probably due to
  only one kidney).
• Secretes a unique type of cortisol.
• 1-a-hydroxycorticosterone
• Secreted mainly in response to stress.
• No discreet renin-angiotensin system.
• However, they do have a a JGA-like structure and
  the cells have secretory granual that are
  immunoreactive for renin antibodies.
• Also have an ACE-like enzyme in the gills.
• Have natriuretec peptide in heart.

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• These fish have hyperosmotic plasma.
• Not due to electrolytes, but to high circulating
  levels of urea and trimethylamine oxide.
• No clearly defined role for corticosteroids.
• 1-a-hydroxycorticosterone does bind to gills,
  rectal gland and kidney nephrons.
• 1-a-hydroxycorticosterone can stimulate salt
  secretion across rectal gland, but this effect is
  minor.

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• May stimulate elevated expression of CFTR in
  gills and rectal gland.
• These fish osmoregulate differently than most
  fishes.
• aHCT affects Na retention in the kidney.
• Natriuretic peptides stimulate aHCT secretion.

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• Teleost fishes
• Respond to ACTH and stress with increased
  corticosterone levels.
• Renin-angiotensis activity has been demonstrated
  in all groups.
• Well developed JGA.
• The renin-angiotensin system appears to be
  involved in in both osmotic and ionic regulation.
• Corticosteroids may play a major role in
  regulating metabolic rate in in migratory and
  spawning fish.

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• The principal circulating corticosteroid is
  cortisol.
• Cortisol has been shown to directly stimulate
  Na-K ATPase in epithelial cells of the gill,
  gut and kidney.
• As earlier discussed, cortisol is very important
  in freshwater adaptation.
• Directly stimulates CFTR insertion into the
  apical membranes of ion transporting cells of
  gills.
• There is secretion of extra-adrenal
  corticosteroid secretion (from ovary) in at least
  one species.
• In Rainbow trout, long photoperiod stimulates
  elevated corticosteroid levels. May be
  associated with increased activity levels.

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• Sarcopterygean fishes
• H2O deprivation stimulates increased
  corticosteroid levels.
• Increases air-breathing during dry spells.
• Interestingly, during the aquatic phase the
  animals secrete cortisol and during the air phase
  they secrete corticosterone.

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• Amphibians
• Adrenal tissue is rather diffusely distributed in
  kidney.
• Larval (aquatic) form secretes cortisol, but
  after metamorphosis the animals secrete
  corticosterone.
• Aldosterone is the principal electrolyte
  regulator (like in amniotes), not cortisol (like
  in fish).
• Well developed renin-angiotensin system.
• The JGA does not contain a macula densa, except
  in one species of toad (convergent evolution).

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• Exposure of ranid frogs to seawater causes
  atrophy of adrenocortical tissue.
• Adrenalectomy causes a decrease in plasma sodium
  and increases plasma potassium.
• Aldosterone seems to be the major salt-regulating
  hormone.
• Acts on skin and urinary bladder to increase salt
  transport into the blood (uptake and recovery,
  respectively).

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• Salt depleted frogs exhibit elevated renin
  levels.
• ACTH elevates aldosterone in at least one ranid
  frog, Rana esculenta.
• AII has been shown to stimulate aldosterone and
  corticosterone synthesis in vitro in
  adrenocortical tissue from Rana ridibunda.
• These results suggest a fair amount of cross-talk
  between the mineralcorticoid and the
  glucocorticoid systems (in ranid frogs at least).
• Aldosterone stimulates increased plasma sodium in
  tiger salamanders.

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• Reptiles
• Discreet adrenal glands associated with kidney.
• Lack of zonation in the adrenal cortex.
• Well developed renin-antiotensin system.
• AII stimulates the secretion of aldosterone as
  well as corticosterone in most reptiles.
• In turtles, AII stimulates only aldosterone
  secretion.
• There is a well-developed atrial natriuretic
  system.
• Secretory cells are diffusely distributed
  throughout the heart.
• No macula densa in the JGA.

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• Few studies on sodium regulation have been done.
• As with the fish and amphibians, there is no
  clear distinction between the effects of
  mineralcorticoids and glucocorticoids in the
  regulation of plasma electrolytes.
• Plasma salt loading depresses plasma aldosterone
  levels in a number of lizard species looked at.
• AII stimulates both aldosterone and
  corticosterone secretion in lizards, but only
  stimulates corticosterone secretion in turtles.

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• Birds
• Structure of adrenal glands is very similar to
  reptiles.
• Lack of zonation.
• Corticosterone is the principal corticosteroid.
• There is a well developed renin-angiotensin
  system, which functions the same as in mammals.
• Like mammals, there is a distinct macula densa in
  the JGA.
• In marine birds containing a nasal gland, the
  gland is sensitive to aldosterone.
• Stimulates expression of the basolateral Na-K
  ATPase.
• Stress stimulates glucocorticoid secretion in ALL
  vertebrate groups