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Unformatted text preview: ENDOCRINE CONTROL OF CALCIUM HOMEOSTASIS Calcium ion: -plays a key role in many fundamental biological processes. -essential structural component of the skeleton. -normal blood clotting. -with Na+ and K+ helps maintain transmembrane potential of cells. Calcium is -important in excitability of nervous tissue -contraction of muscles -release of hormones and neurotransmitters. Concentration in cellular and extracellular fluid ~10mg/100ml. -In circulation 50% free, 50% bound to albumin. -About 99 % of the body’s calcium is in bone, and part of this calcium is quite loosely bound. -Bone thus serves as a calcium reservoir - Ca++ is maintained in a tight concentration gradient Hormonal Control -maintenance of plasma calcium is achieved mainly by exchange between bone and plasma under influence of hormones. -Hormones also affect intestinal absorption of calcium and excretion of by kidneys. Important Ca++ factors under hormonal control: 1. uptake 2. urine losses 3. exchange with bone reservoir - bones have both structural functions and function in many fundamental physiological functions - storehouse for Ca++ - calcium generally circulates in the blood loosely bound to albumin (50%) Three hormones in particular are of importance. (1) (2) (3) Parathyroid hormone (PTH): protein and is produced by parathyroid glands -increases circulating levels of Ca++. Calcitonin: protein and is produced by the parafollicular or “C” cells of the thyroid gland -lowers the circulating levels of Ca++. Vitamin D: steroid -increases the circulating levels of Ca++. Calcium Cycle: -obtained in the diet; milk, cheese, eggs, butter etc. -absorbed from the digestive tract primarily in the duodenum and upper jejunum. -Its absorption is increased by vitamin D and PTH (Figure 3.1). -From the plasma -some of the calcium will be deposited in the bone (calcitonin increases calcium deposition in bone) or the cells of other tissues. -some will go through the kidney and excreted in the urine (calcitonin increases this calcium loss). -When plasma concentration is below 10mg/100ml then PTH will stimulate reabsorption of calcium from the kidney and removal of calcium from the bone, a process known as bone resorption. -Stable calcium concentration in blood is achieved mainly by exchange of calcium between bone and plasma under the influence of the above hormones. The Calcium Cycle Figure 3.1 PARATHYROID HORMONE: -Secreted from parathroid chief cells -embedded in surface of thyroid . -In humans 4 parathyroid glands present, located on the back side of the thyroid gland. -Removal of the parathyroid glands results in a drop of plasma calcium levels which causes tetanic convulsions and death. STRUCTURE. -84 amino acid polypeptide.- only Nterminal 34 amino acids important for full activity. -Synthesized as part of a larger protein, preproparathyroid hormone. -undergoes proteolytic cleavage to produce the PTH. Very short half-life – 3-18 minutes depending on species and individual. Figure 3.2 - there are several truncated forms of PTH - all that is needed is the N terminal 34 amino acids which interact with the PTH receptor - very short half life, relatively expensive - speaks to the tight control under which circulating concentrations are Ca++ are controlled FUNCTIONS OF PTH Increase the concentration of plasma calcium : -Bone Resorption: -increases bone demineralization -increases Ca++in body fluids. -Kidney: increase the reabsorption of Ca++ in proximal convoluted tubule. -Vitamin D synthesis: stimulates the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25 D3; biologically active form of vitamin D) -occurs primarily in kidney and in some peripheral organs (e.g. skin). -Gut: PTH (and 1,25 D3, facilitates the absorption of Ca++ from the gut). Control of PTH release: controlled directly by the circulating concentration of calcium. -the 25 hydroxylation of the vitamin D precursor is not constitutive - it is not tightly regulated - this is unlike the 1 hydroxylation which IS tightly regulated and results in the active form of vitamin D - this is regulated by PTH Mechanism of PTH activity: -binds to cognate receptor on target cells exerts -stimulates adenylyl cyclase and increases the production of cyclic AMP. - G protein receptor, works through cAMP Low Calcium High Calcium FIGURE 3.3: CONTROL OF PARATHYROID HORMONE SECRETION PROBLEMS WITH PARATHYROID GLAND FUNCTION (1) Hypofunction -hypoparathyroidism: low levels of PTH in circulation. Symptoms: -low plasma calcium (hypocalcemia). -production of biological active vitamin D is decreased. -Tetany, convulsions more serious clinical problems of hypoparathyroidism. -Ca++ <7mg/100ml -increased neural overexcitability - muscle spasms. -Muscles contract spontaneously and remain contracted. -Spasms of laryngeal muscles may lead to death by asphyxiation. -Treatment: administration of vitamin D and calcium supplements. (2) Hyperfunction -hyperparathyroidism: Often caused by adenoma of parathyroid glands-high levels of PTH in circulation and -high production of 1,25 D3. hormonal form of vitamin D -high PTH stimulates bone resorption and calcium reabsorption from kidney. -1,25 D3 increase calcium absorption from the intestines. -elevated calcium in circulation. hypercalcemia -formation of kidney stones are common symptom. -Severe cases: cardiac arrhythmias, depressed neuromuscular excitability, calcium deposition on walls of blood vessels and cartilaginous regions of bones. Treatment: surgery to remove the parathyroids and replacement therapy of 1,25 D3 and Ca++. benign hyperprolferation of the parathyroid VITAMIN D: -available from limited dietary sources (cod liver oil, fatty fish). -synthesized from a cholesterol metabolite, so strictly speaking, it is not a vitamin. under stimulation from UV light -synthesis involve several tissues e.g skin, liver and kidney SYNTHESIS: 1. UV light + 7-dehydydrocholesterol. 2. 25-hydroxylation in liver followed 3. 1-hydroxylation primarily in kidney - 1,25-dihydroxyvitamin D3. PHYSIOLOGICAL FUNCTION: -increase the calcium absorption from the intestine. REGULATION OF SYNTHESIS: -increased in conditions of low calcium, when PTH is also increased -depressed by high calcium. In northern countries, absence of UV may lead to vitamin D deficiency -deficient bone mineralization (Rickets in growing individuals). More severe in dark-skinned people. -Synthesis may be defective under conditions of renal failure – deficient 1-hydroxylation. -Low vitamin D in adults leads to bone defects known as osteomalacia (soft bone). Hereditary vitamin D-resistant Rickets – dues to inactivating Possible causes for Rickets Mutation in the vitamin D - UV or vitamin D deficient diet Receptor. - deficiency of the enzyme necessary for 1 hydroxylation - 1 hydroxylase deficient - no receptors for vitamin D - hereditary vitamin Dresistant Rickets - also causes baldness (treated by heavy calcium supplement) Figure 3.4 CALCITONIN: in bone and kidney has the opposite function to PTH --> reduction in circulating concentrations of Ca++ -32 amino-acid calcium-lowering peptide hormone (all 32 a.a. necessary) -manufactured in parafollicular or “C” cells of the thyroid gland. -lowers plasma calcium by promoting transfer of Ca++ from blood to bone, and increasing urinary excretion of Ca++. -rise in plasma Ca++ increases release of calcitonin. -decrease in plasma calcium concentration decreases the release of calcitonin. Of lesser importance than PTH and 1,25 D3. Absence of calcitonin does not compromise calcium homeostasis in man, suggesting that its biological importance is limited. ADRENAL GLANDS -located adjacent to upper surface of kidneys. -heavier in the male than in the female. -two distinct types of tissue - cortex and medulla. COMPARISON OF CORTEX and MEDULLA (a) Histologic appearance: Cortex: large-lipid containing epithelial cells. -Medulla: chromaffin cells-fine brown granules when fixed with potassium bichromate. (b) Origin: Cortex: derived from mesoderm; Medulla derived from neural crest. (c) Function: Cortex produces steroid hormones; glucocorticoids (major one being cortisol in human, corticosterone in rodents) and mineralocorticoids (e.g. aldosterone), and progestins. -Medulla produces catecholamines epinephrine and norepinephrine & some peptide hormones (enkephalins, dynorphins and atrial natriuretic peptides). Figure 3.5 Adrenal Cortex: 3 morphologically and functionally different layers: -zona glomerulosa, mostly mineralocorticoids (aldosterone). -zona fasciculata, produces mainly glucocorticoids (cortisol). -zona reticularis, glucocorticoids, progestins, androgens & estrogens. Figure 3.6 different zone have different enzymes necessary for production of different hormones Activity of zona fasciculata and zona reticularis controlled by pituitary hormone adrenocorticotropin (ACTH). Note that 18-hydroxylase (synthesis of mineralocorticoid aldosterone) present only in zona glomerulosa -therefore zona glomerulosa specific for mineralocorticoids Note 17α-hydroxylase is absent in zona glomerulosa -therefore zona glomerulosa does not produce glucocorticoids. injected in injured athletes, reduces inflammation injected as a steroid The adrenal cortex hardly stores its hormones, but releases them into the blood almost as fast as it makes them. Figure 3.7 - hormones are all structurally related Molecular mechanisms of action of steroid hormones: Function to regulate (mostly increase) the transcription of hormone/receptor-specific target genes. -The particular proteins synthesized vary with each target tissue, and relate specifically to those functions regulated by each steroid hormone and the physiological function of the tissue. FIGURE 3.8 Glucocorticoids: Cortisol (humans), corticosterone. (rodents) 1. Salt retention: Some activity but less effective than aldosterone. Can be important under pathological conditions when plasma cortisol remains elevated. when glucocorticoids are in high concentration they can act as weak mineralcorticoids increased glucocorticoids leads to increased glucose in the circulation - stimulate the production of enzymes (and amino acids needed to make them) necessary for the production glucose by glucogenesis (glycolysis in reverse) 2. Effects on protein and carbohydrate metabolism: -Stimulate the synthesis of a number of gluconeogenic enzymes in hepatocytes, and of a number of enzymes that breakdown proteins in muscle and other tissues - released amino acids enter the liver where they are converted to glucose and glycogen (gluconeogenesis). -Decrease glucose uptake by the cells and decrease glycolysis (glucose oxidation) -lead to increased blood glucose levels, and as result increase insulin secretion. Increased blood glucose due to excess of glucocorticoidactivity is known as adrenal diabetes – if prolonged, may lead to destruction of beta-cells of pancreas and true diabetes mellitus. 3. Lipid metabolism: Glucocorticoids maintain or increase the levels of lipolytic enzymes in the adipose tissue cells and augments lipolytic action of other hormones, e.g. epinephrine. Thus, excess of glucocorticoids leads to hyperlipidemia and hypercholesterolemia. 4. Anti-inflammatory actions of glucocorticoids: At higher than physiological concentrations, glucocorticoids inhibit inflammatory and allergic reactions. May result from (a) stabilization of lysosomal membranes which prevents the secretion of enzymes that normally occurs during inflammation and (b) inhibition of infiltration of leucocytes into the injured area. 5. Immunosuppressive actions of glucocorticoids: they are antiinflammatory agents - can cause decreased levels of circulation WBC's and antibody formation Cause atrophy of the lymphatic system (lymph nodes, thymus, spleen) - decreased levels of circulating lymphocytes and antibody formation. Therefore glucocorticoids used in organ transplantation. Glucocorticoids also decrease histamine formation and thus decrease allergic reactions. glucocorticoids cause protein degradation 6. Effects of glucocorticoids on bone: decrease the protein matrix of the bone through their protein catabolic effect. As a result, increased loss of Ca++ from the bone leading to osteoporosis. Control of glucocorticoid secretion. -controlled by pituitary ACTH (adrenocorticotropin), a 39 amino acid polypeptide, synthesized as part of larger protein known as proopiomelanocortin (POMC). -feedback control of cortisol secretion is via hypothalamus and anterior pituitary (fig. 4.3). In human only cortisol exerts this negative feedback for ACTH release. Thus, in cases of enzyme deficiencies, e.g. lack of 11βhydroxylase, cortisol is not produced and ACTH secretion is unchecked and adrenal hyperplasia occurs leading to congenital adrenal hyperplasia. -treatment: administration of cortisol, which (a) corrects the cortisol deficiency and (b) normalizes the ACTH secretion. corticotropin releasing hormone conceptually similar to thyroid deficiency and the formation of a goiter glucocorticoid induced negative feedback Figure 4.3 Mechanism of action of ACTH: -binds to specific ACTH receptor on membranes of zona fasciculata and zona reticularis cells. -stimulation of adenylyl cyclase leading to increased production of cyclic AMP. -activates steroidogenic enzymes leading to increased synthesis and release of steroid hormones. Daily rhythm of plasma cortisol and ACTH: -diurnal rhythm of ACTH and cortisol secretion - minimum at midnight and maximum in the morning. - rhythm may be independent of sleep -abolished by stress and Cushing’s disease. - very tight pattern of circulating ACTH and cortisol during the day Figure 4.4 Glucocorticoids and stress-responses: because of its effect on glucose level it can actually cause adrenal diabetes - a constant release of insulin by the kidneys is necessary for uptake of all the extra glucose produced A variety of stress stimuli, psychological or physical, induce a significant increase in synthesis and release of CRH, ACTH and cortisol. -e.g. pain, fear, exercise, hunger, cold, hemorrhage etc. -Release of cortisol during stress can be advantageous - provides energy and amino acids through the breakdown of tissue proteins, especially under conditions where normal feeding not feasible. -Can also be disadvantageous effects - cortisol inhibits wound healing. -Prolonged stress would maintain constantly high levels of glucocorticoids which could lead to increased blood glucose (true diabetes mellitus), decreased immune responses (individual will become susceptible to infections), loss of bone etc. PATHOPHYSIOLOGY OF ADRENAL CORTEX Addison’s Disease: hypofunction -characterized by failure of the adrenal cortex to produce adrenocortical hormones. lack of function of the adrenal cortex -may involve total destruction of the gland. -mostly due to atrophy of the adrenal glands due to tuberculosis and involves medulla as well as the cortex. -When cause of Addison’s disease not known (idiopathic) usually only the cortex is involved. Remember left hand side: cleavage, liberation of fats Figure 4.5 Cushing’s Disease: hyperfunction -Characterized by hyperplasia of the adrenal cortex due to increased circulating levels of ACTH. can be due to a pituitary misfunction -excessive production of glucocorticoids as well as increased production of mineralocorticoids (ACTH will stimulate aldosterone synthesis to a certain extent by increasing the availability of the substrates for steroidogenesis) Figure 4.6 ...
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