Endocrinology

• 1. STUDY OF THE ENDOCRINE SYSTEM

2. It is one of the bodys two (2) major communication systems. A system in which a group of secretor cells (a gland) secretes a potent chemical transmitter substance which is known as a hormone, into the BLOOD. The transmitter is then carried by the blood to the target cells where a response is elicited Differs from the other systems. The activity of the endocrine system complements that of the nervous system -the nervous system involves rapid short lived communication between Individual cells -the endocrine system involves slower prolonged communication between large numbers of cells. The endocrine system is essential for maintenance of homeostasis. 3. Some organs in the endocrine systems are involved in and have numerous functions in other systems A single gland may secrete multiple hormones, reflecting different types of endocrine cells in the same gland. In a few cases a single cell may secrete more than one hormone (E.g. Anterior Pituitary follicle stimulating hormone and luteinizing hormone). A particular hormone may be produced by numerous endocrine glands 4. A chemical messenger secreted by an endocrine gland cell is often also secreted by other types of cells and serves in these locations as a -neurotransmitter - paracrine -autocrine 5. The endocrine system is contains 6 major glands including many others. 6. A hormone is chemical message transmitted in the BLOOD that is secreted by an endocrine gland. Hormones can be classified into three(3) categories -Amines -Peptides and Proteins -Steroids. 7. Proteins that act as hormones. Size of the polypeptide varies from 3 to 200 amino acid residues. Cannot pass through cell membranes due to their size and water soluble nature. Protein hormones are the most numerous types. Secreted by many glands 8. Polypeptide hormones synthesized in the same manner as any other protein. DNA in the nucleus is transcribed to mRNA and translated into the protein by ribosomes Protein is then processed by the golgi apparatus and stored in the secretory granules. Many hormones undergo changes in the golgi apparatus/secretory granules -Cleavage reactions -Addition of carbohydrate groups. 9. Secretory Granules released by exocytosis. This occurs when the membrane of the granule fuses with the membrane of the cell causing the contents to be ejected. The process is triggered by calcium entering the cell. Polypetide hormone release is controlled mainly by regulating secretion rather than synthesis. 10. Small and fat soluble Can pass through cell membranes but they must circulate bound to plasma proteins since they Are insoluble in blood. Secreted by certain glands. 11. Derived from cholesterol. Cholesterol is acquired from the diet or synthesized within cells All steroids have the have the same basic structure formed by four(4) rings of carbon. Individual steroid hormones differ primarily . 12. Cholesterol Pregnenolone Progesterone Testosterone Oestrogens eg.oestradiol Androgens Cortisol Glucocorticoids Aldosterone. Mineralcorticoids 13. Released immediately so the rate of release is determined by the rate of synthesis, especially the synthesis of pregnenolone. 14. Formed by altering the structures of amino acids. Secreted by the -Thyroid gland -Adrenal medulla -Hypothalamus -Pineal gland 15. Synthesized from two(2) amino acids. Tyrosine cateholamines(noradrenaline and adrenaline). Tryptophan precursor of melatonin 16. Granules are released by exocytosis. Rate of release is regulated mainly by secretion. 17. All hormones secreted from endocrine glands are transported in the blood. Steroid Hormones: Steroid hormones and thyroid hormones are lipid soluble and require a carrier protein to be transported in the blood in order to reach their target cell. 18. Non Steroid Hormones: Non steroid hormones tend to be water soluble and as such they dissolve in the blood plasma where they are transported to their target cell. 19. Mechanism involved in steroid and thyroid hormone action: Endocrine gland secretes a steroid hormone for example Hormone enters target cell by diffusing through the cell membrane and enters the nucleus. 20. The hormone then bind to the receptor molecule. The hormone-protein complex then binds to DNA and promotes the synthesis of mRNA mRNA leaves the nucleus and enters the cytoplasm where it is translated to proteins molecules. 21. Mechanism involved in non- steroid hormones action Endocrine gland secretes a non- steroid hormone like insulin for example. The hormone is carried to its target cell by the blood plasma The hormone then binds to its receptor site on the membrane of its target cell 22. The hormone receptor binding activates adenylate cyclase via a G-protein. Adenylate cyclase then causes ATP molecules to be converted into cyclic AMP (cAMP) molecules. 23. cAMP then activates various protein kinases which phosphorylates various protein substrates. The activated protein substrates induce changes in metabolic processes. Cellular changes are recognized as the hormone response. 24. Baker, M, 2002. Albumin, steroid hormones and the origin of vertebrates. Journal of Endocrinology 175:121-127. Hole, John. Human Anatomy and Physiology. Oxford, England. 1993 25. Metabolism is the process of converting fuel from foods into energy for the body to function. Hormones concentration in the plasma depends on; 1. Its rate of secretion by the endocrine gland. 2. Its rate of removal from the blood, either by; Excretion Metabolic Transformation The liver or kidneys are the major organs that excrete or metabolize hormones. However they are not the only routes for eliminating hormones. Sometimes the hormones is metabolized by the cells upon which it acts. 26. In the case of peptide hormones, endocytosis of hormone- receptor complexes on plasma membranes enables cells to remove the hormones rapidly from their surface and catabolize them intracellularly. The receptors are then often recycled to the plasma membrane. Metabolism of Peptide Hormones 27. Catecholamine and peptide hormones are excreted rapidly or attacked by enzymes in the blood and tissues thus tend to remain in the bloodstream for only brief periods. In contrast, because protein- bound hormones are less vulnerable to excretion or metabolism by enzymes, removal of the circulating steroid and thyroid hormones generally takes longer. Rate of Metabolism/Excretion of the different types of Hormones 28. Categories of Hormones 29. In some cases metabolism of the hormone after its secretion activates rather than inactivates it. In other words, the secreted hormone may be relatively or completely unable to act upon a target cell until metabolism transforms it into a substance that can act. An Example is provided by Testosterone: Metabolism of Hormones 30. The thyroid gland directly affects metabolism as it is the portion of the endocrine system responsible for secreting hormones that control the rate at which the bodys cells burn fuel for energy. How does the Endocrine System control Metabolism? 31. Finally, there is another kind of activation that applies to a few hormones. Instead of the hormone itself being activated after secretion it acts enzymatically on a completely different plasma protein to split off a peptide that functions as the active hormone. 32. Summary of the processes Metabolism and Excretion of Hormones 33. Endocrine Cell (alters the rate of hormone secretion) Ions or Nutrients Neurotransmitter s Hormones 34. Plasma concentration of specific mineral ions or organic nutrients directly control multiple hormone secretions. Major function is to regulate through negative feedback: oCa2+ homeostasis oGlucose 35. The Autonomic nervous system influences endocrine glands. oParasympathetic & Sympathetic inputs to glands may occur, some of which are inhibitory and others stimulatory. 36. Tropic Hormone: o Stimulates secretion of another hormone o Stimulates the growth of the gland Some hormones in a multihormone sequence inhibit the secretion of other hormones. 37. Hormone Location of Secretion Effect Anti-diuretic Hormone (ADH) Pituitary gland in the brain. Water balance in the kidney. Thyroid Stimulating Hormone (TSH) Pituitary gland in the brain. Stimulates thyroid gland to produce hormone Thyroxine. 38. Disorder Definition Hyposecretion 1. Primary hyposecretion: too little hormone secretion by endocrine gland. 2. Secondary hyposecretion: endocrine gland receiving too little of its tropic hormones. Hypersecretion 1. Primary hypersecretion: too much hormone being secreted by gland on its own. 2. Secondary hypersecretion: gland is excessively stimulated by its tropic hormones. Hyporesponsiveness Target cells do not respond normally to hormone. Hyperresponsiveness Excessive gland response to hormone. 39. The pituitary gland lies in a pocket of the sphenoid bone at the base of the brain , just below the brain area which is known as the hypothalamus. The pituitary is connected to the hypothalamus by the infundibulum. The Pituitary gland has two adjacent lobes : the anterior and posterior pituitary 40. The axons of two clusters of hypothalamus neurons passes down the infundibulum and ends within the posterior pituitary There is no important neural connections between the hypothalamus and anterior pituitary. The capillaries at the base of the hypothalamus recombine to form the hypothalamo-pituitary portal vessels 41. The hypothalamo-pituitary portal vessels passes down the stalk which connects the hypothalamus and pituitary. This now enters the anterior pituitary where they drain into a second capillary bed, the anterior pituitary capillaries. This allows for a rapid response and limits the amount of hormone that must be synthesized to reach an effective blood concentration. 42. There are two posterior pituitary hormones : 1)Oxytocin > Stimulates contraction of smooth muscle cells in breasts > Stimulates contraction of uterine smooth muscle during labour 2)Vasopressin > Acts on smooth muscle cells around blood vessels to cause muscle contraction > Acts within the kidneys to decrease water excretion in the urine > Known as an antidiuretic hormone (ADH) 43. The hormone moves down the axons to accumulate at the axon terminals in the posterior pituitary Neurotransmitters generate action potentials in the neurons These now propagate to the axon terminals and trigger the release of the stored hormone The hormones enter the posterior pituitary and is carried away by blood to the heart 44. Hypophysiotropic Hormones - these are the hypothalamic hormones that regulate anterior pituitary function Each of the hypophysiotropic hormones is the first in a three-hormone sequence: (1)A hypophysiotropic hormone controls the secretion of (2)an anterior pituitary hormone, which controls the secretion of (3) a hormone from some other endocrine gland The last hormone then acts on its target cells 45. Similar to that of the Anterior Pituitary hormones with two differences : 1) The axons of the hypothalamic neurons that secrete the hypophysiotropic hormones remain in the hypothalamus, ending in its median eminence. 2) the hypophysiotropic hormones enter capillaries in the median eminence of the hypothalamus that do not directly join the main bloodstream, but empty into the hypothalamo-pituitaryportal vessels, which carry them to the anterior pituitary 46. Hormone Function CRH Stimulates the release of ACTH TRH Stimulates the release of TSH GRH Stimulates the release of GH GHIH Inhibits the release of GH GnRH Stimulates the release of FSH & LH PIH (Dopamine) Inhibits the release of Prolactin 47. SYNTHESIS, ACTIONS OF THYROID HORMONES & CONTROL OF THYROID FUNCTION 48. What are thyroid hormones? Basically hormones that are produced by the thyroid gland, which have diverse effects throughout the human body. The thyroid gland produces two iodine- containing molecules of physiological importance: 1) thyroxine (T4) 2) triiodothyronine (T3) 49. Thyroxine (T4) is generally converted to triiodothyronine(T3) by enzymes known as deionases in target cells. T4 is the major secretory product of the thyroid and the total T4 concentrations are higher in the blood. However T3 is the major thyroid hormone. 50. The thyroid gland is a bi-lobed structure that sits within the neck, straddling the trachea. 51. The thyroid gland is composed of numerous follicles each made up of an enclosed sphere of highly specialized cells surrounding a core containing a protein rich material called colloid. 52. Step 1: Synthesis begins when circulating iodide is cotransported with sodium ions across the follicular cell plasma membrane. N.B. Iodine cannot diffuse back into the interstitial fluid once it is in the cell. This is called iodide trapping. 53. Step 2: The trapped, negatively charged iodide ions diffuse down their electrical and concentrated gradients to the lumenal border of the follicular cells Step 3: The colloid of the follicles contains large amounts of protein called thyroglobulin(TG). The iodine that diffuses to the colloid is rapidly oxidized at the hormonal surface of the follicular cells to the iodine free radicals. The free radicals are then attached to the phenolic rings of the tyrosine molecules within the amino acid structure of TG. 54. Thyroid peroxidase- The enzyme responsible for oxidizing iodides and attaching them to tyrosines and thyroglobulin in the colloid. N.B. Thyroglobulin and thyroid peroxidase are synthesized by follicular cells. Iodines can be added either of two positions on a given tyrosine within a thyroglobulin. Monoiodotyrosine (MIT) a tyrosine with one iodide attached . Diiodotyrosine (DIT) a tyrosine with two iodines attached. 55. Step 4: The phenolic ring of either a molecule of DIT or MIT are removed from the remainder of its tyrosine and is coupled with another DIT on the thyroglobulin molecule(reaction mediated by thyroid peroxidase) N.B. If two DIT molecules are coupled the result in tyrosine (T4 ). If one DIT and one MIT are coupled the result is T3. 56. Step 5: When thyroid hormone is needed in the blood, extensions of the colloid-facing membranes of the follicular cells engulf proportions of the colloid(with the iodonated thyroglobulin) by endocytosis. Step 6: The thyroglobulin with its coupled MITs and DITs is brought into contact with lysosomes in the cell interior. 57. Step 7: Proteolysis of thyroglobulin releases T3 and T4, which then diffuses out of the follicular cell into the interstitial fluid and from ther back into the blood. 58. Essentially all of the actions of the follicular cells are stimulated by thyroid stimulating hormone, (TSH) which is stimulated but thyrotropin- releasing hormone, (TRH) The basic control mechanism of TSH production is the negative feedback action of TH on the anterior pituary, and to the lesser extent the hypothalamus. 59. TSH not only stimulates T3 and T4 production but it also: Increases protein synthesis in follicular cells. Increases DNA replication and cell division Increases the amount of rough endoplasmic reticulum and other cellular machinery required by follicular cells for protein synthesis. N.B. When TSH levels exceed normalcy in the thyroid cell it undergoes hypertrophy. This causes the cell to increase in size. Enlarged thyroid glands from any cause is called a goiter. 60. Thyroid hormone receptors are present in the nuclei of most cells of the body, unlike receptors for many other hormones, whose distribution is more limited. Thus the actions of T3 and T4 are wide spread and may affect many organs and tissues. 61. They are three main actions of thyroid hormones: 1) Metabolic Action 2) Permissive Action 3) Growth and Development 62. Thyroid hormones(TH) have several effects on carbohydrates and lipid metabolism, although not to the extent of other hormones e.g insulin. However, TH stimulates carbohydrate absorption from the small intestine and increases fatty acid release from adipocytes. These actions provide energy to maintain metabolic rate at a high level, and are consistent with one of the major actions of TH, which is to stimulate the activity of Na+/K+ -ATPases throughout the body. 63. ATP is consumed by Na+/K+ -ATPases at a high rate due to TH activation, the cellular stores of ATP must be maintained by increased metabolism of fuels. The calorigenic action of TH represents a significant fraction of the total heat produced each day in a typical human. 64. Many of the actions of TH are attributable to its permissive effects on catecholamines. TH up-regulates beta-adrenergic receptors in many tissues: Heart Nervous system Increased levels of TH potentiates the actions of the catecholamines even though the catecholamines are within normal levels. 65. TH is needed for normal production of growth hormone. Therefore, in the absence of TH, growth in children is decreased. TH is one of the most important developmental hormones for the nervous system. Absence of TH during fetal life results in poorly developed nervous system and a form of mental retardation called cretinism. 66. 1) PHYSIOLOGICAL FUNCTIONS OF CORTISOL 2) FUNCTIONS OF CORTISOL IN STRESS 67. Cortisol is a steroid hormone. It is produced when there isn't enough cortisol in the blood (to maintain homeostasis in the body) or to deal with stress. 68. It is produced by the adrenal glands. When the body needs cortisol, a message is sent to the hypothalamus via the sympathetic nervous system to produce the hormone CRF. The CRF activates the pitutary gland which then produces the hormone ACTH. This in turn alerts the adrenal gland which stimulates the adrenal cortex to produce cortisol. 69. STRESS RESPONSE ANIMATION 70. Basal cortisol levels help maintain normal blood pressure. Cortisol exerts influence on the reactivity to epinephrine and norepinephrine of muscle cells that surround blood vessels. Basal levels of cortisol are also essential in maintaining cellular concentrations of certain enzymes involved in metabolic homeostasis. 71. Cortisol also serves as an anti- inflammatory agent and also has anti- immune functions Anti-inflammatory: 1) Cortisol inhibits the production of both leukotrienes and prostaglandins. Leukotrienes and prostaglandins are both involved in inflammation. 2) Cortisol also stabilizes lysosomal membranes in damaged cells (preventing the release of their proteolytic contents). 72. 3) Cortisol reduces capillary permeability in injured areas (thus reducing fluid leakage to the interstitium). Anti-Immune: Cortisol suppresses the growth and function of key immune cells. The importance of this is that if cortisol was absent, the body would over react to minor infections and auto-immune diseases can result. It, in essence, acts as a "brake" on the immune system. 73. Cortisol is also important during fetal and neonatal life. It serves to allow for proper differentiation of numerous tissues and glands including various parts of the brain, the adrenal medulla, the intestine and most notably the lungs (cortisol produces surfactant which reduces surface tension in the lungs). 74. 1) Effects on Organic Metabolism : - Stimulation of protein catabolism in bone, lymph, muscle and elsewhere. - Stimulation of liver uptake of amino acids and their conversion to glucose (gluconeogenesis). - Maintenance of plasma glucose levels. - Stimulation of triglyceride catabolism in adipose tissue, with release of glycerol and fatty acids in the blood. 75. 2) Inhibition of inflammation and specific immune responses. 76. 3) Inhibition of nonessential functions (so that all resources can be put towards dealing with the stressful situation). 77. 4) Enhanced vascular reactivity (increased ability to maintain vasoconstriction in response to norepinephrine and other stimuli so that the body can engage in fight or flight). 78. Adrenal insufficiency- Addisons Disease Cushings syndrome Diabetes Mellitus Growth disorders Thyroid Disorders 79. What is adrenal insufficiency? Adrenal insufficiency is an endocrine or hormonal disorder that occurs when the adrenal glands do not produce enough of certain hormones. It refers to any situation in which the levels of cortisol are chronically lowers than normal. 80. Primary Adrenal Insufficiency Secondary Adrenal Insufficiency 81. Also referred to as ADDISONS DISEASE Occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and often the hormone aldosterone. 82. The most common cause is due to the autoimmune attack in which immune system mistakenly recognizes some component of a persons own adrenal cells as foreign. It is due to loss of adrenal cortical function which may occur for example, when an infectious disease such as tuberculosis, HIV, or fungal infections, infiltrate the adrenal gland and destroy them. Tumours 83. Imbalance of sodium, potassium and water in the blood Hypotension (low blood pressure) Chronic diarrhoea Darkening of the skin-patchy skin colour Paleness Extreme weakness Fatigue Loss of appetite Mouth lesions on the inside of a cheek (buccal mucosa) 84. Nausea and vomiting Slow, sluggish movement Unintentional weight loss Salt craving 85. The diagnosis is made by measuring plasma concentrations of cortisol. Tests may also show increased potassium level, low blood pressure, low serum sodium. However, sex hormones will be at normal levels. Addisons disease may be misdiagnosed as chronic fatigue syndrome or even as a psychological disorder because some patients may exhibit anxiety or emotional problems. 86. This disease requires daily oral administration of glucocorticoids and mineralocorticoids. Also, the patient must carefully monitor his or her diet to ensure adequate consumption of carbohydrates and controlled potassium and sodium intake. 87. Secondary Adrenal Insufficiency can be traced to a lack of ADENOCOTICOTROPIC HORMON (ACTH) Aldosterone production is usually not affected. 88. ACTH is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland and is produced in response to biological stress. Its principle effects are increased production and release of corticosteroids and, as the name suggests, cortisol from the adrenal cortex. 89. A temporary form of this disease may occur in person who has been taking a synthetic glucocorticoid hormone for a long time and then stops, either abruptly or gradually. (Glucocorticoid block the release of both ACTH and CRH). Another cause is the surgical removal of the noncancerous ACTH producing tumours of the pituitary glands that cause Cushings disease. 90. Adrenal Insufficiency is a disorder that occurs when the adrenal glands do not produce enough of the hormone cortisol. Primary Adrenal Insufficiency, also called Addisons disease, occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and often the hormone aldosterone. Secondary Adrenal Insufficiency occurs when the pituitary gland fails to produce enough ACTH, a hormone that stimulates the adrenals to produce cortisol. If ACTH output is too low, cortisol production drops. 91. Cushings Syndrome is a hormonal disorder caused by prolonged exposure of the bodys tissues to high levels of the hormone cortisol in the blood, even in a non-stressed individual. 92. Due to primary effect e.g. A cortisol secreting tumour on the adrenal gland. Due to secondary effect, usually due to ACTH secreting tumour of the pituitary gland. It may caused because people take glucocorticoid hormones. May be caused due to overproduction of cortisol in the body. 93. The increased catabolism may produce such a large quantity of precursors for hepatic gluconeogenesis that the blood sugar levels increase as observed in diabetes. The increased blood levels of cortisol tend to promote uncontrolled catabolism of bone, muscle, skin and other organs. The bone strength diminishes and can lead to osteoporosis, muscle weakens and skin become thinned and easily bruised. There is a possibility of immunosuppression which is brought about by the anti-immune actions of cortisol. 94. It is associated with the loss of fat mass from the extremities and with the redistribution of fat in the trunk, face and back of the neck. Obesity can occur. A possibility of developing hypertension due to the pharmacological effects of cortisol, including cortisols ability to potentiate the effects of epinephrine and norepinehrine on the heart and blood vessels. 95. Most people have severe fatigue, weak muscles, high blood pressure and high blood sugar. Women usually have excess hair growth on their faces, necks, chests, abdomens, and thighs. Their menstrual periods may become irregular or stop. Men have decreased fertility with diminished or absent desire for sex. 96. Treatment depends on the specific reason for cortisol excess and may include surgery, radiation, chemotherapy or the use of cortisol inhibiting drugs. 97. Often referred to as Diabetes, is a group of metabolic diseases in which a person has high blood sugar levels, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. There are 3 main types: TYPE I DIABETES TYPE II DIABETES GESTATIONAL DIABETES 98. Insulin is the principle hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells) Insulin is produced by special cells, called beta cells, in the pancreas. (pancreas is found behind your stomach) Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus. Insulin is also the principle control signal for conversion of glucose to glycogen storage in the liver and muscle cells. 99. Type I diabetes melitus is characterized by the loss of insulin-producing beta cells of the Islets of Lagerhans in the pancreas leading to insulin deficiency. This type of diabetes ca be further classifies as immune-mediated or idiopathic, where beta cell loss is a T-cell mediated autoimmune attack. Beta cells produce little or no insulin and as a result glucose builds up in the bloodstream instead of going into the cells. 100. Type II diabetes mellitus is characterized by insulin resistance which may be combined with relatively reduced insulin secretion. The insulin receptors are believed to be the defective responsiveness of body tissues to insulin. Due to the insulin resistance which means that the fat, liver and muscle cells do not respond correctly to insulin, the blood sugar does not get into these cells to be stored for energy. When the sugar cannot enter cells, there are high levels of sugar build up in the blood. This refers to HYPERGLYCEMIA. 101. In the early stage of type II diabetes, the most predominantly abnormality is reduced insulin sensitivity. Hence, at this stage hyperglycaemia can be reversed by a variety of measures and medications that can improve insulin sensitivity or reduce glucose production by the liver. Type II diabetes usually occurs slowly over time and most people with this disease are overweight. (increased fat makes it harder for your body to use insulin the correct way) 102. This type of diabetes only occurs in some women during pregnancy. For moms-to-be the body need additional insulin, therefore the pancreas dutifully secretes more of it. However, if the pancreas cant keep up with the increased insulin level, the blood glucose levels rise too high. Between 2 and 10 percent of expectant mothers develop this condition, making it one of the most common health problems in pregnancy. Most women dont remain with gestational diabetes after pregnancy. 103. Once someone has had gestational diabetes, she is at a higher risk for getting aging during future pregnancy and for developing diabetes later in life. If untreated, gestational diabetes can damage the health of the foetus and such risks include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. 104. Symptoms may develop rapidly (weeks or months) in type I diabetes, while in type II diabetes they usually develop much more slowly and may be subtle or absent. Classic symptoms are polyuria (frequent urination), polydipsia (increased thirst) and polphagia (increased hunger). Changes in the shape of the lenses in the eyes, resulting in vision changes. People may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone. 105. A rapid, deep breathing known as Kussmaul breathing. Nausea Vomiting Abdominal pain Altered states of consciousness 106. Comparison of type 1 and 2 diabetes Feature Type 1 diabetes Type 2 diabetes Onset Sudden Gradual Age at onset Any age (mostly young) Mostly in adults Body habitus Thin or normal Often obese Ketoacidosis Common Rare Autoantibodies Usually present Absent Endogenous insulin Low or absent Normal, decreased or increased Concordance in identical twins 50% 90% Prevalence Less prevalent More prevalent - 90 to 95% of U.S. diabetics 107. When you're stressed, your blood sugar levels rise. Stress hormones like epinephrine and cortisol kick in since one of their major functions is to raise blood sugar to help boost energy when it's needed most. Think of the fight-or-flight response. You can't fight danger when your blood sugar is low, so it rises to help meet the challenge. Both physical and emotional stress can prompt an increase in these hormones, resulting in an increase in blood sugars. 108. People who aren't diabetic have compensatory mechanisms to keep blood sugar from swinging out of control. But in people with diabetes, those mechanisms are either lacking or blunted, so they can't keep a lid on blood sugar. When blood sugar levels aren't controlled well through diet and/or medication, you're at higher risk for many health complications, including blindness, kidney problems, and nerve damage leading to foot numbness, which can lead to serious injury and hard-to-heal infections. Prolonged elevated blood sugar is also a predecessor to cardiovascular disease, which increase the risk of heart attacks and strokes 109. Anything upsetting like going through a breakup or being laid off is certainly emotionally draining. Being down with the flu or suffering from a urinary tract infection places physical stress on the body. It's generally these longer-term stressors that tax your system and have much more effect on blood sugar levels. 110. Bone is a special connective tissue made up of several cell types surrounded by a collagen matrix, called osteoid, upon which are deposited minerals, particularly the crystals of calcium and phosphate known as hydroxyapatite. A growing long bone is divided into the ends, or epiphyses, and the remainder, the shaft. The portion of each epiphysis that is in contact with the shaft is a plate of actively proliferating cartilage, known as the epiphyseal growth plate. 111. epiphyses shaft epiphyses Epiphyseal growth plate Marrow cavity Diagram Showing Simple Structure of the Bone. 112. There are three types of bone cells:- 1) osteoblasts 2) osteocytes 3) osteoclasts 113. oesteobla sts osteoclasts osteocyte Calcified matrix 114. Osteoblasts are the bone-forming cells. They secrete collagen to form a surrounding matrix, which then becomes calcified. Once surrounded by calcified matrix, the osteoblasts are called osteocytes. The osteocytes have long cytoplasmic processes that extend throughout the bone and form tight junctions with other osteocytes. Osteoclasts are large multinucleated cells that break down (resorb) previously formed bone by secreting hydrogen ions, which dissolve the crystals, and hydrolytic enzymes, which digest the osteoid. 115. At the shaft edge of the epiphyseal growth plate, the osteoblasts convert the cartilaginous tissue at this edge to bone, while new cartilage is simultaneously being laid down in the interior of the plate by cells called chondrocytes. The epiphyseal growth plate remains intact, actually it usually widens and is gradually pushed away from the centre of the bony shaft as the latter lengthens. 116. Epiphyseal growth plate Area where new cartiliage is being laid down by Chrondrocytes Shaft edge where osteoblasts convert cartilaginous tissue to bone. epiphyse s shaft 117. As long as the epiphyseal growth plate exists, linear growth of the shaft can take place. However, it ceases when the plates are themselves converted to bone as a result of hormonal infuences at puberty. This is known as epiphyseal closure and occurs at different times in different bones. Therefore, a persons bone age can be determined by x-raying the bones and determining which ones have undergone epiphyseal closure. 118. An important factor here is that bone is constantly being remodeled by the osteoblasts and osteoclasts working together. The purpose of remodeling is to regulate calcium homeostasis, repair micro-damaged bones (from everyday stress) but also to shape and sculpture the skeleton during growth. Osteoclasts resorb old bone, and then osteoblasts move into the area and lay down new matrix, which becomes calcified. 119. This process is dependent, in part, on the stresses imposed on the bones by gravity and muscle tension, both of which stimulate osteoblastic activity. When osteoblasts are stimulated there is an increase in the bone mass through increased secretion of osteoid and by inhibiting the ability of osteoclasts to break down osseous tissue. Bone building through increased secretion of osteoid is stimulated by the secretion of growth hormone by the pituitary, thyroid hormone and the sex hormones (estrogen and androgens) It is also influenced by many other hormones, as summarized in the table below. 120. Hormones that favor bone formation and increased bone mass Insulin Growth hormone Insulin-like growth factor I (IGF-I) Estrogen Testosterone 1,25-dihydroxyvitamin D3 (influences only mineralization, not matrix) Calcitonin Hormones that favor increased bone resorption and decreased bone mass Parathyroid hormone Cortisol Thyroid hormones (T4 and T3) 121. GROWTH HORMONE (GH) GH causes growth of the epiphyseal regions of the long bones. Growth of the long bone can be monitored by measuring the incorporation of sulphur (35S) into the epiphyseal cartilage. It is said that GH acts indirectly on bones by way of the production of a sulfation factor. This sulfation factor is known to consist of several peptides referred to as somatomedins. Injected radiolabeled GH rapidly localized to the liver rather than to the epiphyses of the long bones. 122. Somatomedin is generally used to refer to those growth factors found in the plasma that are under the control of GH, have insulin like properties, and promote the incorporation of sulfate into cartilage ( the somatomedin hypothesis). Insulin-like growth factors I and II (IGF-I and IGF-II) are two substances isolated from the plasma in pure or rather pure form fulfill these criteria. The peptides bear some sort of structural relationship to proinsulin and therefore, exhibit some affinity for insulin receptors. 123. GH does not have a direct effect on cartilage but rather stimulates chondrogenesis and subsequent growth indirectly by way of somatomedins, according to the somatomedin hypothesis. The number of IGF-I immunoreactive cells in the proliferative zone is increased. IGF-I is produced in the proliferative chondrocytes in the growth plate in response to GH. GH can induce local IGF-I production in the epiphyseal plate at the level of both mRNA and protein. 124. GH, but not IGF-I, stimulates the multiplication of the slowly cycling (label-retaining) cells in the germinal layer of the epiphyseal plate. Fact is locally infused IGF-I is able to increase epiphyseal width as well as longitudinal bone growth. 125. Children manifest two periods of rapid increase in height; 1) during the first two years of life, and 2) during puberty Note that increase in height is not necessarily correlated with the rates of growth of specific organs. The pubertal growth spurt lasts several years in both sexes, but growth during this period is greater in boys. This, plus the fact that boys grow more before puberty because they begin puberty approximately two years later than girls, accounts for the differences in average height between men and 126. Graph below shows the relative growth in the brain, total body height and reproductive organs. 127. The primary factors influencing growth are: 1)The adequacy of nutrient supply 2) Freedom of diseases Lack of sufficient amounts of any of the essential amino acids, essential fatty acids, vitamins, or minerals interferes with growth. Total protein and sufficient nutrients needed to provide energy must also be adequate. The growth-inhibiting effects of malnutrition can be seen at any time of development but are most profound when they occur very early in life. Thus, maternal malnutrition may cause growth retardation in the fetus. 128. Since low birth weight is strongly associated with increased infant mortality, prenatal malnutrition causes increased numbers of prenatal and early postnatal deaths. Moreover, irreversible stunting of brain development may be caused by prenatal malnutrition. During infancy and childhood, too, malnutrition can interfere with both intellectual development and total body growth. Following a temporary period of stunted growth due to malnutrition or illness, and given proper nutrition and recovery from illness, a child manifests a remarkable growth spurt (catch-up growth) that brings the child up to the normal height expected for his or her age. The mechanism that accounts for this accelerated growth is however, unknown. 129. Human growth requires hormones. A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affects particular cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. 130. The most important hormones to human growth are:- Growth hormone Insulin-like growth factors I and II Thyroid hormones Testosterone Estrogens 131. There is also a large group of peptide growth factors which includes the insulin-like growth factors and most of these growth factors act as paracrine and autocrine agents. Paracrine- chemical signals that diffuse into the area and interact with receptors on nearby cells. The release of neurotransmitter at synapses in the nervous system. Autocrine - the cell signals itself through a chemical that it synthesizes and then responds to. Autocrine signaling can occur solely within the cytoplasm of the cell or by a secreted chemical interacting with receptors on the surface of the same cell agents. 132. This type of hormone stimulate differentiation and or sometimes cell division of specific cells. Generally the term used for a chemical which that stimulates cell division is called a mitogen. Growth is also modulated by peptide growth inhibiting factors which inhibit cell division in specific tissues of the body. 133. Growth hormone exerts its cell division stimulating effect not directly on cells but rather indirectly through the mediation of a mitogen whose synthesis and release are induced by growth hormone. This mitogen is called insulin-like growth factor I (IGF-I) Under the influence of growth hormone, IGF-I is secreted by the liver, enters the blood and functions as a hormone. 134. The importance of IGF-I in mediating the major growth-promoting effect of growth hormone is shown by the fact that dwarfism cannot be due only to decreased secretion of growth hormone but also to decreased production of IGF-I or even failure of the tissues to respond to IGF-I. IGF-I is required for normal fetal total-body growth and, specifically, for normal maturation of the fetal nervous system. The stimulus for IGF-I secretion during prenatal life is however unknown at this time. 135. Finally, it should be noted that there is another messengerinsulin-like growth factor II (IGF- II)that is closely related to IGF-I. IGF-II, the secretion of which is independent of growth hormone, is also a crucial mitogen during the prenatal period. It continues to be secreted throughout life, but its postnatal function is unknown. 136. The growth hormone is secreted by the anterior pituitary gland. It has little or no effect on fetal growth however it is the most important hormone for post natal growth. Main growth promoting effect is the stimulation of cell division in many particular tissue regions. 137. Growth hormone promotes bone lengthening by stimulating maturation and cell division of the chondrocytes in the epiphyseal plates and thereby continuously widens the plates and providing more cartilage for formation of bone. *Chondrocytes are cells found in the cartilage. They produce and maintain the cartilaginous matrix which consists mainly of collagen and proteoglycan. 138. The Thyroid hormones (TH) includes:- Thyroxine ( T4) which is secreted by the follicular cells of the thyroid gland. Tri-iodothyronine (T3) is released from the pituitary gland. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature and heart rate. 139. Both are essential for normal growth because they are required for both the synthesis of growth hormone and the growth promoting effects of that hormone. Infants and children who are deficient in Thyroid production usually show signs of retarded growth due to the slow formation of bone growth. This deficiency is termed hypothyroidism. 140. Thyroid hormones are also essential for normal development of the central nervous system during fetal life. Inadequate production of maternal and fetal thyroid hormones due to severe iodine deficiency during pregnancy is one of the most occur able instances yet still the most common preventable causes of mental retardation. This is termed Endemic Cretinism. 141. This effect on the brains development must be distinguished from other effects TH exerts on the nervous system throughout the human life and not just during infancy. Therefore a hypothyroid (under secretion of TH) person will exhibit sluggish reactions and poor mental functions, however these effects are completely reversible at times with administration of Thyroid hormones. So too a person with hyperthyroidism (excess secretion of TH) shows signs of being jittery and hyperactive. 142. Insulin is a hormone central to regulating carbohydrates and fat metabolism in the body. It causes cells in the liver, muscle and fat tissues to take up glucose from the blood and store it as glycogen in the liver and muscles. Therefore it is obvious that an adequate amount of insulin is necessary for normal growth since Insulin can be referred to as an anabolic hormone. 143. Human insulin is a peptide hormone and is produced in the Islets of Langerhans in the pancreas. Its inhibiting effect on protein degradation is particularly important when it comes to growth. Insulin exerts direct and specific growth promoting effects on cell differentiation and cell division during fetal life. Insulin is also required for the normal production of Insulin Growth Factor I. 144. Sex hormones include both Testosterone and Estrogen. Secretion of these hormones begins at around ages 8- 10 and gradually increases to reach a certain concentration over the years. Growth of the long bones and vertebrae requires an increased production of sex hormones. 145. The major growth promoting effect of the sex hormones is to stimulate the secretion of growth hormone and insulin growth factor I. The sex hormones does not only stimulate bone growth but also stops it by inducing epiphyseal closure. This double effect of the sex hormones reiterates the pattern of growth development in teenagers. 146. Testosterone is an anabolic steroid hormone. It is the main, male sex hormone . Testosterone is primarily secreted in the testes of males and the ovaries of females. However small amounts are also secreted by the adrenal gland. In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass and the growth of bodily hair 147. In addition, testosterone is essential for health and well-being as well as the prevention of Osteoporosis. Testosterone exerts a direct anabolic effect on protein synthesis in many non reproductive organs and tissues of the body. This is what accounts for the increased muscle mass of men, as compared with that of women. 148. Estrogen is a hormone that comprises a group of compounds, including estrone, estroidol and estroil. It is the main sex hormone in women and is essential to the menstrual cycle. Estrogen is manufactured mostly in the ovaries, by developing egg follicles. In addition, estrogen is produced by the corpus luteum in the ovary, as well as by the placenta. Although estrogen exists in men as well as women, it is found in higher amounts in women, especially those capable of reproducing. Estrogen contributes to the development of secondary sex characteristics, which are the defining differences between men and women that dont relate to the reproductive system. 149. In women, these characteristics include breasts, a widened pelvis, and increased amounts of body fat in the buttock, thigh and hip region. Estrogen also contributes to the fact that women have less facial hair and smoother skin then men. Estrogen is an essential part of a womans reproductive process. It regulates the menstrual cycle and prepares the uterus for pregnancy by enriching and thickening the endometrium. Two hormones, the luteinizing hormone (LH) and the follicle stimulating hormone (FSH), help to control how the body produces estrogen in women who ovulate. 150. Effector sites for Ca 2+ Homeostasis 19 7 151. Why hormones are important in calcium homeostasis? Extracellular Ca 2+ concentration normally remains within a narrow range i.e. approx. 1 mM, or 10,000 times the basal concentration of free calcium within cells. Large deviations in any direction from this range would be catastrophic. 19 8 152. For e.x. a low plasma calcium concentration increases the excitability of nerve and muscle plasma membranes. Conversely, a high plasma concentration causes cardiac arrhythmias (a.k.a irregular heart beat) as well as depressed neuromuscular excitability via its effects on membrane potential. 19 9 153. 20 0 154. 20 1 155. Calcium homeostasis depends on the interplay among bone, the kidneys and gastrointestinal tract. 20 2 156. The activities of the gastrointestinal tract and kidneys determine the net intake and output of Ca 2+ for the entire body. However, interchanges of Ca 2+ between extracellular fluid and bone do not alter total-body balance, but change the distribution of Ca 2+ within the body. 20 3 157. Bone Approx 99% of total-body Ca 2+ is contained in the bone. Therefore, flux of Ca 2+ into and out of the bone in controlling plasma Ca 2+ concentration is very important! Bone is a special connective tissue consist of: Collagen matrix called the osteoid a.k.a hydroxapatite because of Ca2+ and P04 deposits 20 4 158. In some cases, bones have central marrow cavities where blood cells form Approx. 1/3 of a bone by weight is osteoid and 2/3 is mineral Three types of bone cells involved in bone formation: 1. Osteobasts 2. Osteocytes 3. Osteoclasts 20 5 159. 20 6 160. Osteoblasts are the bone-forming cells. They secrete collagen to form a surrounding matrix which becomes calcified (mineralization) Once surrounded by the calcified matrix, the osteoblasts are called osteocytes Osteoclasts are large, multinucleated cells 20 7 161. W.r.t to Ca 2+ homeostasis, many hormones and a variety of autocrine/paracrine growth factors produced locally in the bone, play an important role Only the parathyroid hormone is primarily controlled by plasma calcium concentration 20 8 162. Kidneys They eliminate soluble waste via blood filtration How? This process involves cells in the tubules that are the functional units of kidneys. They recapture most of the necessary solutes that got filtered to minimize loss of vital minerals in urine (i.e. calcium) 20 9 163. Therefore, urinary excretion of Ca 2+ is the difference between the amount filtered and amount re-absorbed The control of Ca 2+ excretion is mainly via re-absorption. Re-absorption decreases when plasma [Ca 2+ ] increases and when plasma [Ca ]2+ decreases re-absorption increases 21 0 164. Gastrointestinal Tract Normally absorbs solutes such as Na+, K+ , but a considerable amount of ingested Ca2+ leaves the body via the G.I tract along with feces. Hormonal control of this absorptive process is the main means for regulating total-body calcium balance, which will be discussed next 21 1 165. Take home message Hormones regulate the levels of calcium in the body via effector sites ( These are?) Bone :- By constant remodeling via interaction between osteoblasts and osteoclass which determines bones mass and provides a means of raising or lowering Ca2+ concentration which is under hormonal control. Kidney:- By regulating the amount of Ca2+ excreted in urine is the difference between amount filtered and amount re-absorbed, in which the latter is under hormonal control. Andrew Grant 21 2 166. Metabolic bone disease refers to abnormalities of bones caused by a broad spectrum of disorders. These disorders are to be differentiated from a larger group of genetic bone disorders whereas in this case there is a defect in a specific signaling system(the endocrine system)or cell type that causes the bone disorder. 167. PTH is the most important hormone in calcium homeostasis. Released in response to low blood calcium levels. Disorders of this system are grouped according to their effect on PTH There are two(2) groups. -Hyperparathyroidism(excess of PTH) -Hypoparathyroidism(deficiency of PTH) 168. Hypercalcemia refers to a condition in which there is to much calcium in the blood. 169. Primary hyperparathyroidism 170. It is the excessive release of PTH. All actions of PTH raise calcium levels Main causes are -Parathyroid gland adenoma -Diffuse Parathyroid gland hyperplasia Symptoms include unexpected bone weakness etc. There are three (3) treatmeant options. 171. Secondary Hyperparathyroidism 172. Many conditions can cause hypocalcaemia. Osteomalacia is a feature of secondary hyperparathyroidism. Hypocalcaemia and excess PTH cause the following symptoms eg. mood changes, etc. Causes of secondary hyperparathyroidism -chronic renal failure -vitamin D deficiency 173. Hypoparathyroidism 174. Deficiency of PTH. Causes the usual symptoms of hypocalcaemia without the osteomalacia. Main causes are -Complications of thyroid or parathyroid surgery. -Idiopathic hypoparathyroidism an autoimmune disorder. -Pseudohypoparathyroidism 175. Osteoporosis 176. Caused by reduced osteoblast activity. New bone is not formed and microfractures cannot be repaired so the bones become thin and brittle. Caused by a deficiency of oestrogen or testosterone. Main treatments are dietary calcium, vitamin D supplements and hormone replacement therapy.