Parathyroid Glands n The parathyroid glands are small

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

Histology of the Parathyroid n 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).

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

In humans, the major calcium storage organ is bone. n Calcium is stored as Ca. PO 4. n n Generally, calcium salts are not very soluble in aqueous solutions such as plasma. Calcium metabolism is virtually inseparable from phosphate metabolism. n The major factors regulating calcium and phosphate metabolism are parathyroid hormone (PHT), calcitonin and calcitrol. n

PTH stimulates the following on these target organs: n Osteoclasts (bone absorbing cells) are stimulated to digest bone and release ionic calcium and phosphates to the blood. n Kidneys are stimulated to reabsorb calcium and excrete phosphate. n Intestines are stimulated to increase calcium absorption. n Vitamin D is required for absorption of calcium from ingested food. n n 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.

Pathology of the parathyroid glands: n 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.

Hyperparathyroidism: n Rare, usually the result of a parathyroid gland tumor. n Results in severe loss of calcium from the bones. n The bones soften and deform as their mineral salts are replaced by fibrous connective tissue. n Results in hypercalcemia n 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.

Hypoparathyroidism: n It is a PTH deficiency, which is a common consequence of parathyroid trauma or removal during thyroid surgery. n 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.

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

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

Cartilage was a good starting material for calcium storage, since calcium is already a component. n Having stronger bones would have facilitated jaw evolution by providing a sufficiently strong substrate. n n n Jaws require strong structural support because they can develop great forces. At the same time, fish were developing more robust dermal plating from protection. n Also from Ca. PO 4 deposits in scales.

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

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

Parathyroid Hormone related Hormone (PTHr. H) PTHr. H is a protein with hypercalcemic activity. n It was first isolated from a malignant tumor. n Has significant sequence overlap with PTH, particularly at the N-terminal. n n 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. n Probably plays a role in Ca 2+ accumulation by the fetus. n

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

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

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

n Amphibians: Very little is known. n Amphibians possess both an ultimobranchial gland parathyroid glands. n Specialized structures, the endolymphatic sacs, are involved in calcium metabolism. n n These sacs are located at the base of the skull and contain large amounts of Ca. PO 4. n 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. n Bovine PTH is effective in amphibians. n

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

n 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.

Adrenal Medulla: n It is made up of chromaffin cells which secrete the catecholamines epinephrine (E) (adrenaline) and norepinephrine (NE) (noradrenaline) into the blood. n 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. n 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). n NE has great effect on peripheral vasoconstriction and blood pressure.

Adrenal Cortex: n n 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.

Hormones of the Adrenal Cortex n n 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. n The primary target organs of aldosterone are kidney tubules where it stimulates reabsorption of sodium ions from urine back to the bloodstream. n Aldosterone also enhances sodium absorption from sweat, saliva, and gastric juice.

n 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. n The reverse conditions inhibit secretion of aldosterone.

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

n 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. n Blood levels of glucocorticoids increase significantly during stress, which helps the body to negotiate the crisis. n 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.

Regulation of glucocorticoid secretion: n It is provided by a typical negative feedback system: n increased (hypothalamus) CRH n increased (adenohypophysis) ACTH n increased (adrenal cortex) cortisol negative

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

Pathology of the adrenal cortex function: function n Hyperadrenalism : n n n It is referred to as Cushing's disease and can be caused by a cortisol-secreting tumour in the adrenal glands, ACTHsecreting 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.

n Hypoadrenalism : n 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.

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

Renin-angiotensin system: Kidney (JGA) secretes renin in response to sympathetic stimulation, hypotension or decreased plasma Na+ and/or increased plasma K+. n Angiotensinogen is converted to AI. n AI is converted to AII by ACE in the lungs. n

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

n Renin-angiotensin system is responsible for long-term regulation of blood volume and electrolyte balance. n n 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.

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

n Chondrichthyean fishes: Have one discreet adrenal gland (probably due to only one kidney). n Secretes a unique type of cortisol. n n 1 -a-hydroxycorticosterone Secreted mainly in response to stress. n No discreet renin-angiotensin system. n n 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. n Have natriuretec peptide in heart. n

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

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

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

The principal circulating corticosteroid is cortisol. n Cortisol has been shown to directly stimulate Na+K+ ATPase in epithelial cells of the gill, gut and kidney. n As earlier discussed, cortisol is very important in freshwater adaptation. n n 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. n In Rainbow trout, long photoperiod stimulates elevated corticosteroid levels. May be associated with increased activity levels. n

n Sarcopterygean fishes: H 2 O deprivation stimulates increased corticosteroid levels. n Increases air-breathing during dry spells. n Interestingly, during the aquatic phase the animals secrete cortisol and during the air phase they secrete corticosterone. n

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

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

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

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

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

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