Endocrinology notes

Endocrinology notes - 1 ENDOCRINOLOGY Coordination of...

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Unformatted text preview: 1 ENDOCRINOLOGY Coordination of physiological processes - In a living organism there must be coordination of a number of physiological activities taking place simultaneously such as: movement, respiration, circulation, digestion, excretion and metabolism. -The central nervous system and the endocrine system represent the two major means by which these functions are coordinated. Long Distance Communication -Communication between cells that are not in contact is achieved through a number of chemical substances, which are secreted by releasing cells and interact with specific receptors on distant target cells. -Signaling through these receptors leads to a specific physiological effect. -Endocrine signalling is not limited to long distance communication example: a cell talking to itself Endocrine Signaling -Involves hormone secretion into the blood by an endocrine gland -Hormone transported by blood to distant target site -Hormones don't always come from specialized endocrine glands -Anterior pituitary gland major endocrine gland produces many hormones -LH and FSH travel from pituitary down to the gonads gonads, under the influence of LH and FSH, are induced themselves to act as secondary endocrine organs that produce steroid hormones -Cascades of hormonal systems hormones can induce other hormones Neuroendocrine signalling -Source of hormone is nerves in this case, a ganglion of neurons in the hypothalamus -Nerves can be responsive to hormones, but also under specific conditions they can be sources of hormones -Portal vessel system conduit for hypothalamic hormones to travel to the pituitary In the pituitary, secretion of another hormone (cascade) -Steps: Stimulus causes hypothalamus to secrete Hormone A Hormone A travels via hypothalamopituitary portal vessels to the pituitary Increased plasma levels of Hormone A Presence of Hormone A in the pituitary causes secretion of Hormone B from the pituitary Plasma levels of Hormone B increase and induce a third endocrine gland Hormone C is secreted from this third endocrine gland to the plasma and affects target cells 2 Paracrine and Autocrine Signalling -Signaling does not have to be over long distances -Paracrine: cell that releases a hormonal substance that travels to an adjacent target cell (can be of a different cell type or of the same cell type) -Autocrine: cell talking to itself releases a hormonal substance and also has a receptor for that hormone sets up a feedback loop Paracrine Signaling Autocrine Signaling Communication by Hormones (or neurohormones) usually (but not always) involves 6 steps (1) Synthesis of the hormone by endocrine cells (or neurons in case of neurohormone). Figure 1.3 Figure 1.4 -There are some hormonal substances that we ingest in our diets and therefore are not actually synthesized in the body (2) Release of the hormone by the endocrine cells (or the neurohormones by the neurons) in the classical endocrine pathway (3) Transport of the hormone or neurohormone to the target site by the blood stream. (4) Detection of the hormone or neurohormone by a specific receptor protein on the target cells. -this must happen 100% of the time in endocrine signaling (5) A change in cellular metabolism triggered by the hormone-receptor interactions -this must happen 100% of the time in endocrine signaling -equally as important what happens after the hormone has bound to the receptor as when the hormone is detected (6) Removal of the hormone, which often terminates the cellular response -pathway generally signals its own removal example: vitamin D its presence in the cell increases transcription of the gene that codes for the removal of vitamin D self-limiting process Classical Endocrine Organs -Hypothalamus -Anterior and Posterior Pituitary -anterior and posterior pituitary are anatomically and physiologically different "Classical" produce different hormones Endocrine -Thyroid and Parathyroid Glands Organs -thyroid in the neck thyroid hormone -parathyroid glands two on each lobe of the thyroid physiologically different from the thyroid (structure of hormone different) only named like that because of the location within the body -Heart -Atrial natriuretic peptides (ANP) comes from atrium -natri (sodium) and uretic (urine) -Atrial peptide that stimulates sodium in the urine Figure 1.5. 3 wants the body to urinate sodium to decrease blood pressure -Adrenal Glands -inner adrenal medulla amine hormones -outer adrenal cortex steroid hormones -Pancreas -Beta cells in Islets of Langerhans produce Insulin -Ovaries (female) -Testis (male) Hypothalamic-Pituitary Signaling -Via blood vessels of the pituitary stalk -Hypothalamic-Hypophyseal Portal System - from the hypothalamus to the the adenohypophysis (anterior pituitary). -Hypothalamic neurohormones either activate or inhibit activity of one of the six types of hormone-producing cells in the anterior pituitary. -Called either releasing hormones (releasing factors) or inhibiting hormones (inhibiting factors) -called a releasing hormone if it causes the release of a hormone from the pituitary Hy -via bl stalk. -Hypo System the the pituita -hypot activa the six cells in TABLE 2: CLASSES OF HORMONES BASED ON THEIR STRUCTURE Classes of Hormones Based on Their Structure PEPTIDES AND PROTEINS GLYCOPROTEINS POLYPEPTIDES - Follicle Stimulating Hormone (FSH) -Luteinizing Hormone (LH) - Thyroid Stimulating Hormone (TSH) - Human Chorionic Gonadotropin (HCG) Figure 1.6 STEROIDS AMINES -Epinephrine -Thyroxine (T4) -Triiodothyronine (T3) -Melatonin -called (relea hormo - Adrenocorticotropin - Aldosterone Hormone (ACTH) - Cortisol - Growth Hormone (GH) - Estradiol - Prolactin - Progesterone - B-Lipotropin (B-LPH) - Testosterone - B-Endorphin - Vitamin D - Insulin - Glucagon - Insulin-like growth factors (IGFs) or (Somatomedins) - Parathyroid Hormone (PTH) - Calcitonin - Oxytocin - Vasopressin - Angiotensin (ADH) - Relaxin - Somatostatin - Corticotropin Releasing Hormone (CRH) - Cholecystokinins - and others -Don't memorize except for the steroids -What's important is that almost anything can be hormonal 4 -Glycoproteins proteins that has been post-translationally modified by the addition of oligosaccharide trees -Structure does not give the function of a protein i.e. just because you know a hormone is a glycoprotein does tell anything about what it does -Polypeptide short protein protein hormones are generally quite small -Amines T3 and T4 together are thyroid hormone derivatives of the amino acid tyrosine -Glycoproteins and polypeptides are encoded by genes within the genome -If a hormone is not a protein, than it does not have a gene instead have genes for the production of enzymes that then produce the hormone Synthesis of Protein Hormones -Encoded by genes -Specific physiological signals which control the rate of synthesis -Hormones stored in vesicles its release can be regulated at this stage SYNTHESIS OF PROTEIN HORMONES -Peptides are initially synthesized on the ribosomes of endocrine cells as larger proteins (preprohormones) -They are then cleaved to become prohormones -The prohormone is cleaved to leave the active hormone as it is packaged into secretory vesicles Figure 1.7 Structures of Steroid Hormones Structures of some steroid hormones 5 Figure 1.8 -All have 4-ring structures -Difference between testosterone and estrogen methyl group on testosterone (little `stick') and benzene ring in estrogen if remove methyl group, the ring of testosterone automatically become an aromatic benzene ring like in estrogen STRUCTURES OF THYROID HORMONES Structure of Thyroid Hormones -NH2 group amine part Figure 1.9 -Contains iodine -Thyroid hormone is derived from the amino acid Tyrosine -Thyroid hormone is derived from tyrosine that is attached to a large protein `Lock and Key' Mechanism for Hypothetical Membrane Receptor -Receptor has a complimentary structure to accept the hormone -When a hormone binds a receptor, the receptor goes from an inactive conformation to an active conformation capable of interacting with other proteins that are associated with the signalling "lock and key" mechanism for a hypothetical membrane receptor 6 Properties of Hormone Receptors (a) SPECIFICITY: recognition of single hormone or hormone family. - Almost universally true, except for one type receptor in the liver that recognizes a wide variety of substances (b) AFFINITY: High affinity for the hormone; i.e. binding hormone at its physiological concentration. - Activates receptor at its physiological concentration - i.e. for estradiol, it activates receptor even in nano-molar concentrations (c) SATURABILITY: Should show saturability; i.e. a finite number of receptors. (d) MEASUREABLE BIOLOGICAL EFFECT: A measurable biological response due to interaction of hormone with its receptor - there must be a measurable effect, otherwise there is no point of having the communication Receptor Regulation -Receptors can be upregulated either by increasing their activity in response to hormone or their synthesis. -Often results from a prolonged exposure to a low concentration of hormone 3mechanisms by whichbehormone can exert effects on by decreasing their activity or their synthesis -Receptors can a downregulated either target cells: (1) Direct effects on function at the cell membrane. -Often from exposure to high concentrations of hormone prevents overstimulation (2) Intracellular effects mediated by second messenger systems. (3) Figure 1.10 Mechanisms by which a hormone can exert effects on target cells 1. Direct Effect Direct effects on function at the cell membrane Example: insulin binding to the insulin receptor directly regulates glucose transport (1) Direct effect. Intracellular effects mediated by genomic or nuclear action. Figure 1.11 2. Signaling via an intracellular second messenger Intracellular effects mediated by a second messenger system G-protein coupled receptor Production of cAMP that is a regulator of a kinase (2) Signaling via an intracellular second messenger. Kinase: an enzyme that induces phosphorylation of a substrate 7 Figure 1.12 3. Intracellular genomic signalling Intracellular effects mediated by genomic or nuclear action Steroid hormones are the metabolites of cholesterol cholesterol is found in cell membranes steroid hormones are capable of entering through the cell membrane on their own into to have a nuclear effect (3) Intracellular genomic in the cell is a regulator of gene transcription The hormone receptor signaling. Example: Vitamin D goes directly to the nucleus where it affects gene transcription Feedback control of Hormone Secretion -Hormone secretion is precisely regulated by feedback mechanisms. An excess of hormone, or excess hormonal activity, leads to a diminution of secretion. Similarly, a deficiency of hormone leads to an increase in secretion. -Some instances where you have positive feedback, but generally characterized by negative feedback loops (self-limiting) -Regulation by either hormonal or nonhormonal mechanisms. Mechanism no different between hormonal and non-hormonal Non-hormonal negative feedback -Calcium acts in a hormonal manner but known as non-hormonal Non-hormonal, because calcium is not a hormone but it acts in a hormonal fashion by affecting the parathyroid glands Figure 1.13 diminution of secretion. Similarly, a deficiency of hormone leads to an increase in secretion. -Regulation by either hormonal or nonhormonal mechanisms. 8 Non-hormonal negative feedback Figure 2.1 Hormonal negative feedback -hypothalamus-pituitary-X axis -Corticotropin releasing hormone(CRH) stimulates release of adrenocorticotropic hormone (ACTH) -ACTH leads to release of Cortisol (glucocorticoid) -Elevated levels of cortisol turn off the release of CRH and ACTH Hormonal feedback mechanisms -Hormonal mechanism, because cortisol is a hormone acting on endocrine glands -CRH: corticotopin releasing hormone -ACTH: adrenocorticotropic hormone -cortisol (glucocorticoid) Figure 2.2 Pituitary Gland Anatomy Two distinctly different tissues. (1) adenohypophysis (a.k.a. anterior pituitary, or pars distalis) (2) neurohypophysis (a.k.a. posterior pituitary, or pars nervosa). Histologically, anterior pituitary = endocrine tissue. posterior pituitary = neural tissue. -the posterior pituitary is actually an extension of the neural components of the hypothalamus (1) adenohypophysis (a.k.a. anterior pituitary, or pars distalis) (2) neurohypophysis (a.k.a. posterior pituitary, or pars nervosa). Histologically, the anterior pituitary is endocrine tissue. The posterior pituitary is neural tissue. 9 Figure 2.3 Signalling between the hypothalamus and the pituitary -Hypothalamus and pituitary source of lots of hormones -Most are `releasing hormones' hormone that stimulates release of downstream hormone from the pituitary -FSH Follicle stimulating hormone Signaling between the hypothalamus and the pituitary -LH luteinizing hormone -IGF-1 insulin-like growth factor 1 FSH: follicle stimulating hormone LH: luteinizing hormone IGF-1: insulin-like growth factor 1 Figure 2.4 Hypothalamic Hormones -don't have to memorize structures -derived from proteins means that there is a gene that encodes the hormone -Vasopressin and Oxytocin evolved from gene duplication events (have very similar structures) an error in replication that ended up being advantageous same amino acids except at 2 positions Table 3. Hypothalamic Hormones Hormone Structure Posterior pituitary hormones Arginine vasopressin Oxytocin Hypophyseotropic hormones Thyrotropin-releasing hormone (TRH) Gonadotropin-releasing hormone (GnRH) 10 Somatostatin1 Growth hormone-releasing hormone (GRH) Prolactin-inhibiting hormone (PIH, dopamine) Corticotropin-releasing hormone (CRH) 1In addition to the tetradecapeptide shown here (somatostatin 14), an N-terminally extended molecule (somatostatin 28) and a 12-amino acid form (somatostatin 28 [1-12]) are found in most tissues. Posterior Pituitary Posterior Pituitary Gland (Neurohypophysis) Gland [Neurohypophysis] -Outgrowth of hypothalamus connected by the pituitary stalk. -Outgrowth of hypothalamus connected -The hormones are not actually synthesized in the posteriorby the pituitary stalk. pituitary -Posterior pituitary hypothalamus in small -The hormone travels from thesecretes oxytocin vesicles and vasopressin (a.k.a. antidiuretic where it is secreted from the posterior pituitaryhormone). -Posterior pituitary secretes oxytocin and vasopressin -Oxytocin and vasopressin synthesized (a.k.a. antidiuretic hormone). nuclei (supraoptic in two hypothalamic -Oxytocin and vasopressin synthesized innucleus), nucleus and paraventricular two hypothalamic nuclei (supraoptic nucleus and whose axons run down the pituitary paraventricular nucleus), whose axons run down the pituitarystalk and terminate in in the posterior stalk and terminate the posterior pituitary pituitary close to capillary blood close to capillary blood vessels. vessels. -Nucleus collection of neurons with similar -Prohormones processed in secretory functions -Axons terminate right at the start of capillaries granules during axonal transport. such that substances enter the bloodstream -mature hormones liberated from the right away carrier molecules, neurophysins. -Prohormones processed in secretory granules during -circulating half lives: 1-3 minutes axonal transport. -Mature hormones liberated from carrier molecules Figure 2.5 neurophysins -Circulating half lives: 1-3 minutes 11 -Act over very short time but not all hormones are like this (can last for hours) -Takes lots of energy to make the hormone considering it only acts for a few minutes Oxytocin -Small protein -Induces smooth muscle contraction -Males: no known function, although secreted by posterior pituitary??? -Females: two main functions, both motor. (i) Parturition (birth process); uterus extremely sensitive to oxytocin at end of pregnancy -lots of oxytocin receptors present -dilation of the uterine cervix by fetal head causes reflex release of oxytocin. -causes uterus to contract, which assists the expulsion of fetus and later of placenta. -Injections of oxytocin can be used in difficult deliveries to stimulate uterine contraction (ii) Milk ejection. In lactating mother: response to the stimulus of suckling. -Oxytocin causes milk filled ducts to contract and squeeze milk out. Vasopressin -Acts on smooth muscle cells around blood vessels to cause muscle contraction -Acts within the kidney to decrease water excretion in the urine -Aka anti-diuretic hormone (ADH) Thyroid Gland Anatomy -Colloid: major component is thyroglobulin, a large protein of 700,000kDa -Thyroglobulin base sequence rich in tyrosine mRNA of 20,000 bases very large -Thyroglobulin contains thyroid hormones thyroxine (T4) and triiodothyronine (T3). -T4 and T3 are split off the thyroglobulin, and enter blood where they bind to special plasma proteins. -Synthesis of thyroglobulin under control of TSH of pituitary gland. -Thyroglobulin provides a type of storage for T4 and T3 prior to release. -15 to 20g, varies size with sex, age, diet, reproductive state, etc. Larger in females than males. -Only 3g of healthy thyroid needed to maintain euthyroid state. -Thyroid hormone is made when tyrosines are iodinated and transfer of aromatic rings from one tyrosine to another to make either T3 or T4 coupled to the protein diet, reproductive state, etc. -Larger in females than males. -Only 3g of healthy thyroid needed to maintain euthyroid state. 12 ent is rotein of thyroid 4) and the blood ial plasma ulin under ary gland. s a type of rior to nes Thyroid hormones contain iodine Figure 2.8 -Availability of iodine to terrestrial vertebrates limited -Cellular mechanisms developed for concentration, utilization and conservation of iodine in thyroid gland. -Within the thyroid gland are numerous follicles -each follicle is composed of an enclosed sphere of highly specialized cells surrounding a protein-rich core -the follicular cells participate in almost all phases of thyroid hormone synthesis and secretion -Thyroid follicular cells are able to trap iodide and transport it across the cell against a chemical gradient (active transport). contain iodine -Reverse T3 produced under pathophysiological conditions -marker of Hyperthyroidism inactive not recognized dine to imited ation, ation of . are cell dient Synthesis of thyroid hormones Figure 2.9 -Iodine (I2) used for iodination of tyrosine residues of thyroglobulin (TGB) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). -Oxidative coupling of two DIT forms thyroxine (T4), while oxidative coupling of one MIT with one DIT forms triiodothyronine (T3). -These hormones are stored linked to thyroglobulin. -Rate of all steps of T4 and T3 formation increased TSH. -Thyroid has an active transport mechanism that takes circulating iodine and pumps it against its concentration gradient requires energy - I+ oxidized to I2 to then form the substrate that helps form thyroid hormone Control of thyroid activity 13 of thyroid hormones -Without TSH, thyroid has very low -All of these processes controlled by TSH turnover of thyroid hormones. d for iodination -Synthesis and release of TSH ues of controlled by hypothalamic TGB) to form ne (MIT) and neurohormone thyrotropin releasing DIT). hormone (TRH). When T4 and T3 in ling of two oxine (T4), blood increase they exert a negative coupling of feedback at both hypothalamic and ne DIT forms pituitary levels to decrease release of (T3). s are stored TRH and TSH lobulin. -TSH interacts with specific receptors s of T4 and T3 located on follicular cells, and ased TSH. induces activation of adenylyl cyclase and production of cAMP Figure 2.10 Control of thyroid activity leading to increased has very low and -Without TSH, thyroid synthesis turnover of thyroid hormones. release of T4 and T3. of TSH controlled by hypothalamic neurohormone thyrotropin releasing -Synthesis and release Figure 2.11 hormone (TRH) When T4 and T3 in blood increase they exert a negative feedback at both hypothalamic and pituitary levels to decrease release of TRH and TSH -TSH interacts with specific receptors located on follicular cells, and induces activation of adenylyl cyclase and production of cAMP leading to increased synthesis and release of T4 and T3 -TSH G-protein coupled receptor Iodine deficiency -When the supply of iodide is deficient, synthesis of thyroid hormones decreases and T4 and T3 in circulation decrease. -Release of TSH increases and the thyroid follicular cells are constantly stimulated. -Thyroid enlarges and may form a visible lump, a goiter. -Since the enlarged thyroid is unable to synthesize biological active thyroid hormones due to the iodine deficiency, known as non-toxic goiter. -Synthesis of thyroid hormone reduced no negative feedback loop TSH keeps acting on thyroid thyroid gets larger (goiter) to try and compensate and make more hormone -Compensatory mechanism where the cells in the thyroid start to proliferate Action of Thyroid Hormones -Stimulates calorigenesis in most cells increases basal metabolic rate ** -increase cardiac output -increase rate and strength of cardiac contractions -increase oxygenation of blood -increase rate of breathing -increase number of RBCs in circulation -Effects on carbohydrate metabolism -promotes glycogen formation in the liver -increases glucose uptake into adipose and muscle -Effects on lipid turnover 14 -increase lipid synthesis -increase lipid mobilization -increase lipid oxidation -Effect on protein metabolism -stimulate protein synthesis -promote normal growth **thyroid deficiency in children can have severe lifelong consequences due to effects on growth** -stimulate growth hormone secretion -promote bone growth -promote IGF-1 production by the liver -Promotes development and maturation of the nervous system -Promotes neural branching -Promotes myelination of nerves Effect of thyroid hormones of Basic metabolic rate Increased calorigenesis or basic metabolic rate (BMR): -BMR: the rate at which the organism burns up its stores of fuel to produce energy in the form of heat or calories -Both T4 and T3 increase BMR. Thus, T4 and T3 increase the breakdown of carbohydrates, lipids and proteins. -Increases in metabolic activity increases the need of oxygen. Effect of thyroid hormones on Growth In the absence of T4 and T3, growth hormone cannot act effectively to stimulate growth. T4 and T3 have a permissive effect on growth hormone. Effect of thyroid hormone on CNS -Required for normal development of the brain -In the absence of thyroid hormones there is decreased neuronal development -Since brain development occurs prenatally and immediately after birth only, absence of thyroid hormones at early stages of development lead to irreversible mental retardation - Thyroid hormones stimulate the synthesis of the nerve growth factor (NGF) induces dendritogenesis and regeneration of sympathetic neurons Mechanism of Action of Thyroid Hormone -Analogous to the mechanism of action of steroid hormones. -T3 and T4 enter target cell nucleus, bind to their cognate nuclear receptor. -Alters the transcription of specific genes, and thus levels of encoded proteins. E.G. increased synthesis of the sodium-potassium (Na-K) ATPase, an enzyme involved in the sodium pump and leads to the production of heat. -Effects blocked by protein synthesis inhibitors. -In addition to interactions with nuclear receptors, thyroid hormones may induce some effects by interactions with plasma membrane & mitochondria. A specific receptor for T4/T3 located in inner mitochondrial membrane. T4/T3 interact with this receptor and increase oxygen consumption and production of heat mitochondria. This effect is not blocked by inhibitors of protein synthesis: i.e. de novo gene expression and protein synthesis are not necessary. 15 -In addition T4/T3 act directly at plasma membrane and increase uptake of amino acids. This effect is also independent of protein synthesis. -Primary mechanism through interaction with nuclear receptors regulates transcription of a subset of genes -Thyroid hormone controls transcription and manifested by changes in protein levels FAQs 1. Iodine - nuclear power plants, thyroid cancer etc. Dr. Enrique Silva, Lady Davis Inst., Jewish General Hospital. "1. Yes, excess stable iodine (127I) is used to protect the gland from radioactive iodine isotopes (131, 126, 123, etc). They saturate the iodine transport system diluting (isotopically) the amount of radioactive iodine entering the gland 2. Yes, radioactive iodine is used to treat thyroid cancer. Fortunately, this is quite differentiated most of the time and under appropriate stimulation may take significant amounts of radioactive iodine. " 3. Epinephrine and bee stings (anaphylactic shock). In anaphylaxis there is a nasty combination of bronchial constriction and vasodilation (i.e. you can't breath and your blood pressure goes through the floor) Epinephrine works rapidly as a broncodilator and vasoconstrictor. Abnormalities of Thyroid Function (1) Hypofunction of the thyroid gland known as hypothyroidism characterized by low levels of thyroid hormones (2) Hyperfunction of the thyroid gland known as hyperthyroidism characterized by high levels of thyroid hormones. -Such abnormalities in the activity of thyroid gland may be present at birth, or may occur later in life. Major Physiological Consequences of Hyperthyroidism and Hypothyroidism Hyperthyroidism -elevated T4-T3 levels -elevated BMR** -increased perspiration -rapid pulse -increased body temperature -heat intolerance -warm, moist palms, -nervousness, anxiety, insomnia, weight loss -muscle wasting -increased appetite -menstrual irregularities -exophalmos -goiter Hypothyroidism -decreased or absent T4-T3 levels -low BMR ** -decreased perspiration -slow pulse -lowered body temperature -cold intolerance 16 -coarse, dry skin, subdermal thickening -lethargy, depression, paranoia, tiredness -weight gain -loss of hair -edema of face and eyelids -menstrual irregularities -carotenemia (increased plasma levels of carotenes) -goiter Hypothyrdoidism (A) Primary hypothyroidism (Myxedema): -At level of the thyroid gland; inability of gland to synthesize active thyroid hormones. -More common in women than in man; appears at about 40-60 years of age. -Causes. (1) Atrophy of the thyroid . (2) Autoimmune Thyroiditis: Destruction by antibodies against cellular components of thyroid A.K.A. autoimmune thyroiditis or Hashimoto's disease. More common in women. (3) Goitrous Hypothyroidism or Non-Toxic Goitre: blockage in a step of T4/T3 synthesis. -thyroid gland increases in size and there is goitre formation (non-toxic goitre). (B) Secondary hypothyroidism: -At level of the pituitary; synthesis of little or no thyroid stimulating hormone (TSH). (C) Tertiary hypothyroidism: -At the level of the hypothalamus; synthesis of little or no thyrotropin releasing hormone (TRH) (D) Infantile hypothyroidism: -Absence of thyroid gland or incomplete development of thyroid gland at birth. -At birth infant is normal since the fetus uses mother's T4/T3. However, a few months later, child exhibits decreased physical growth & mental development -Early treatment necessary otherwise both the growth retardation (dwarfism) and the mental retardation associated with cretinism. Treatment: -All types of hypothyroidism are effectively treated by administration of thyroid hormones. Ectopic thyroid -Developmental defect -Thyroid develops on the wrong side of the throat (i.e. it is in the throat) Hyperthyroidism (A) Primary hyperthyroidism: at the level of the thyroid gland. (1). Toxic Diffuse Goiter (Graves Disease): -Autoimmune disease characterized by presence of substance produced by lymphocytes called Long Acting Thyroid Stimulator (LATS), an immunoglobulin that mimics the action of TSH and stimulating release of T3 and T4. -Constant stimulation by LATS increases mass of thyroid leading to the formation of goiter synthesizes biologically active T4/T3; known as toxic goiter. -Toxic goiter because producing large amounts of thyroid hormone turning on the TSH receptor -thyroid is being stimulating all the time, lots of TSH -negative feedback loop is functioning because TSH levels drop, but TSH receptors are still being activated (2) Thyroid adenoma or thyroid cancer: 17 -synthesize of thyroid hormones independent of TSH stimulation. (B) Secondary hyperthyroidism: level of anterior pituitary gland. -No negative feedback from increased levels of T3/T4 and synthesize autonomously thyroid stimulating hormone (TSH) -Often due to the presence of a pituitary tumor. (C) Tertiary Hyperthyroidism: at level of the hypothalamus. -No negative feedback of high T3/T4 to decrease synthesis of thyrotropin releasing hormone (TRH) -Often it is due to the presence of a hypothalamic tumor. Treatment: Depending on the severity of hyperthyroidism: 1. Surgery plus replacement therapy (administration of thyroid hormones). 2. Administration of radioactive Iodide (131I) about 5 mCi. The radioactive iodide concentrates in the cells of the thyroid follicles and destroys them. Replacement therapy may be administered as needed has a short half-life so it doesn't stay around in the body for long (i.e. not dangerous) 3. Administration of antithyroid drugs such as propylthiouracil. These drugs decrease the synthesis of thyroid hormones. Care must be taken not to inhibit the synthesis of thyroid hormones to a great extent and cause hypothyroidism. 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. -important in excitability of nervous tissue -contraction of muscles -vesicle release 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 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 -bone will release its calcium under hormonal signals when the body requires calcium Three hormones in particular are of importance (1) Parathyroid hormone (PTH): protein and is produced by parathyroid glands increases circulating levels of Ca++. (2) Calcitonin: protein and is produced by the parafollicular or "C" cells of the thyroid gland lowers the circulating levels of Ca++ increases Ca++ deposition in bone does the opposite of PTH not as important as PTH and vitamin D (3) Vitamin D: steroid 18 -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 (upper digestive tract) -Its absorption is increased by vitamin D and PTH -From the plasma The Calcium Cycle -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 Parathyroid Hormone Figure 3.1 -Secreted from parathroid chief cells -embedded in surface of thyroid -In humans 4 parathyroid glandspresent, 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 N-terminal 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. chief -Parathyroid hormone is a protein must be injected as a supplement cells - ROID : parathroid face of thyroid . parathyroid glands on the back side of the he parathyroid glands op of plasma calcium ses tetanic convulsions olypeptide.- only No acids important for part of a larger protein, id hormone. olytic cleavage to Figure 3.2 . Functions ife 3-18 minutes ecies and individual. 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. 19 -Vitamin D synthesis: stimulates the conversion of 25-hydroxyvitamin D3 to 1,25dihydroxyvitamin D3 (1,25 D3; biologically active form of vitamin D) -occurs primarily in kidney and in some peripheral organs (e.g. skin). -vitamin D ingested must undergo 2 changes to become its hormonal form hydroxylation in the liver and then hydroxylated in the kidney (process is regulated by PTH) -constitutive on all the time (i.e. not regulated) -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 -low calcium, high release of PTH Mechanism of PTH activity: -Binds to cognate receptor on target cells exerts -Stimulates adenylyl cyclase and increases the production of cyclic AMP. Low Calcium Low Calcium High 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. -high PTH stimulates bone resorption and calcium reabsorption from kidney. -1,25 D3 increase calcium absorption from the intestines. -if too much PTH, too much hormonal vitamin D leads to elevated levels of Ca in the circulation calcium deposition in the heart and other inappropriate places -elevated calcium in circulation. 20 -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++. 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. 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). -if a problem with the vitamin D receptor (due to genetic mutation), then there is no point in giving any supplements of vitamin D because it can't be received Hereditary vitamin D-resistant Rickets dues to inactivating Mutation in the vitamin D Receptor. Calcitonin -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. -opposite effect as PTH -Of lesser importance than PTH and 1,25 D3. Absence of calcitonin does not compromise calcium homeostasis in man, suggesting that its Figure 3.4 21 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 (outer) and Medulla (inner) (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). Adrenal Cortex: Adrenal Cortex 3 morphologically and functionally different layers: -3 morphologically and functionally different layers (i.e. each layer makes different hormones): -zona glomerulosa, mostly mineralocorticoids (aldosterone). -zona glomerulosa, mostly mineralocorticoids (aldosterone). -zona glucocorticoids mainly glucocorticoids (cortisol). -zona fasciculata, produces mainly fasciculata, produces (cortisol). -zona reticularis, glucocorticoids, progestins, androgens & estrogens. -zona reticularis, glucocorticoids, progestins, androgens & estrogens. -Activity Figure 3.5 Figure 3.6 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 17a-hydroxylase is absent in zona glomerulosa therefore zona glomerulosa does not produce glucocorticoids. -The adrenal cortex hardly stores its hormones, but releases them into the blood almost as fast as it makes them. -All of these hormones are derived from cholesterol 22 and zona hormone thesis of esent only ecific for in zona not does tores its the blood hanisms steroid Molecular mechanisms of action of steroid hormones Figure 3.7 -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. e (mostly ription of ecific proteins with each d relate functions h steroid ysiological 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. 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) 23 -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. -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. -cortisone injections reduce swelling 5. Immunosuppressive actions of glucocorticoids: 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. 6. Effects of glucocorticoids on bone: -Decrease the protein matrix of the bone through their protein catabolic effect. -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 11b-hydroxylase, 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. Control of glucocorticoid secretion. controlled by pituitary ACTH adrenocorticotropin), a 39 amino acid olypeptide, synthesized as part of larger rotein known as proopiomelanocortin POMC). eedback control of cortisol secretion is ia hypothalamus and anterior pituitary ig. 4.3). n human only cortisol exerts this negative eedback for ACTH release. Thus, in cases f enzyme deficiencies, e.g. lack of 11ydroxylase, cortisol is not produced and CTH secretion is unchecked and adrenal yperplasia occurs leading to congenital Mechanism of action of ACTH drenal hyperplasia. -Binds to specific cortisol, reatment: administration ofACTH receptor on membranes of zona fasciculata and zona reticularis cells. Figure 4.3 -Stimulation of adenylyl cyclase leading to increased production of cyclic AMP. hich (a) corrects the cortisol deficiency -Activates steroidogenic enzymes leading to increased synthesis and release of steroid hormones. nd (b) normalizes the ACTH secretion. 24 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. on of ACTH: TH receptor on ciculata and zona cyclase leading to clic AMP. nzymes leading to release of steroid ma cortisol and TH and cortisol at midnight and ent of sleep ushing's disease. Figure 4.4 Glucocorticoids and stress-responses -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. -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. HYSIOLOGY OF ADRENAL CORTEX 25 sease: hypofunction failure of the adrenal roduce adrenocortical tal destruction of the atrophy of the adrenal berculosis and involves the cortex. Addison's disease not ) usually only the cortex Cushing's Disease: Figure 4.5 -hyperfunction -Characterized by hyperplasia of the adrenal cortex due to increased circulating levels of ACTH. -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) g's Disease: on ed by hyperplasia of the x due to increased vels of ACTH. oduction of glucocorticoids creased production of ticoids (ACTH will dosterone synthesis to a nt by increasing the of the substrates for sis) The Pancreas -located behind the stomach and has both endocrine and exocrine functions. 99 % of pancreas is exocrine and secretes the digestive enzymes. Figure 4.6 26 -However, scattered between the acini of the exocrine pancreas are small structures, the islets of Langerhans, which are endocrine structures - compact mass of cells with good vascularization. -About 60 % of the cells of the islets of Langerhans are known as beta-cells and synthesize insulin. -About 25 % of the cells of the islets are alpha-cells and synthesize glucagon. -In addition to alpha- and beta- cells there are smaller numbers of other types of cells for example the delta cells, which synthesize somatostatin and others. -insulin and glucagon: small protein hormones and both control of glucose concentration in blood. -insulin is more important than glucagon and insulin deficiency or absence compromises significantly the well being of the individual and if not treated may lead to death. -only 1% of the pancreas has endocrine function -lumen of the pancreas considered `outside the body' exocrine -insulin and glucagon have opposite effects -insulin more important than glucagon Actions of Insulin -Insulin controls blood glucose concentrations - only hormone that acts primarily to decrease blood glucose -glucose always present in the blood (the fasting level is about 80mg/100ml). -However, very little free in tissues. -Glucose does not diffuse very readily into most cells except in brain must be transported. -When it enters it is rapidly esterified with phosphate and (a) in the liver and muscle cells is converted to glycogen, (b) in the adipose tissue is converted to fat and stored for later use and (c) in many cells of the body is oxidized to produce energy. Insulin receptor: ONS OF -membrane receptor, stimulates insertion of glucose transport proteins stored in cytoplasm into plasma INSULIN: membrane increases glucose uptake. glucose that acts se blood (the However, ry readily must be esterified liver and gen, (b) in o fat and ny cells of gy. s insertion stored in increases Insulin deficiency Figure 4.8 -Results when the b-cells are destroyed, will lead to Diabetes Mellitus - most tissues cannot take up glucose efficiently, glucose accumulates in circulation -occurs even if no glucose in diet because of increased gluconeogenesis (e.g. breakdown of nonstructural proteins to amino acids and synthesis of glucose). 27 -Under these conditions free fatty acids (FFA), becomes the principal source of energy increased lipolysis. -However, fat inefficiently used - incomplete oxidation of FFA and increased circulating acetoacetic acid and b-hydroxybutyric acid (metabolic acidosis) and acetone (ketosis - acetone smell in breath of untreated diabetics). Insulin deficiency -leads to decreased blood pH, diabetic coma and death Results when the -cells are destroyed, will unless appropriate treatment is provided. lead to Diabetes Mellitus - most tissues -Type 1 lack of insulin production cannot take up glucose efficiently, glucose accumulates in circulation -Type 2 too much insulin, obesity-induced -Type 1 beta cells are destroyed (autoimmune disorder), -occurs even if no glucose in diet because of increased gluconeogenesis (e.g. breakdown glucose builds up in the bloodstream of non-structural proteins to amino acids and -glucose is in the circulation at high levels, but it's synthesis of glucose). not in the cells -Under these conditions free fatty acids -because the cell doesn't have enough fuel, starts to (FFA), becomes the principal source of burn fatty acids energy increased lipolysis. -However, fat inefficiently used - incomplete oxidation of -end up with a build-up of intermediates FFA and increased circulating acetoacetic (carboxylic acids) in the circulation (acetic acid, acid and -hydroxybutyric acid (metabolic etc...) acidosis) and acetone (ketosis - acetone smell in breath of untreated diabetics). -increase in acid, decreases the pH of blood, Figure 4.9 causing a coma -leads to decreased blood pH, diabetic coma and death unless appropriate treatment is provided. Other Symptoms of Diabetes Mellitus -increase in blood glucose. -At >180mg% glucose spills over into urine, causing glycosurea. -leads to loss of water in urine, causing polyurea - dehydration and increased thirst (polydipsia). As mentioned above, untreated diabetes leads to ketosis, and metabolic acidosis. -administration of insulin is needed to restore individual back to normal. -in diabetic comas, acidosis and associated electrolyte imbalance must be corrected in addition to insulin administration. Causes of Diabetes Mellitus -Diabetes: "running through" used by Greeks 2000 years ago to describe polyurea. -Mellitus: "sweet" distinguishes urine polyurea of produced by persons suffering from antidiuretic hormone deficiency (diabetes insipidus). -In adults, diabetes mellitus may be due to a deficiency of insulin (type 1 insulin-dependent diabetes mellitus) or hyporesponsiveness to insulin (type 2 or insulin-independent diabetes mellitus). Type 1 Insulin-Dependent Diabetes Mellitus (a) Destruction of the b-cells of pancreas - synthesis of insulin does not occur. -treatment: administration of insulin is needed associated with proper diet. (b) Defective insulin release - drugs stimulating insulin release could be administered again associated with proper diet and exercise. -When insulin administered as treatment for diabetes mellitus it is important to control the dose since too much insulin could lead to severe decrease in blood glucose content. -When blood glucose reaches 20-30mg/100ml, the availability of glucose for the brain is not sufficient and the individual may fall into a coma known as insulin shock or hypoglycemic coma - individual must be treated with immediate administration of glucose, otherwise death or permanent brain damage may occur. Type 2 Insulin-Independent Diabetes Mellitus -Insulin levels normal or abnormally high. -problem is hyporesponsiveness of target cells to insulin, a.k.a. insulin resistance. -often due to decreased number of insulin receptors on target cells 28 -associated with obesity. -obesity due to overeating - prolonged high insulin levels decrease number receptors (downregulation). -Treatment: -proper diet and exercise.- decreased caloric intake, decreased insulin, upregulation of receptors. -insulin receptors increased in response to frequent endurance exercise, independent to changes in body weight. Juvenile Diabetes Mellitus MEASUREMENT OF GLUCOSE TOLERANCE Juvenile diabetes mellitus appears in childhood and is insulin Glucose tolerance test: -Glucose tolerance is decreased in diabetes dependent. The b-cells of pancreas do not produce insulin. Treatment (low or absence of insulin) and is increased in hyperinsulinism. requires administration of insulin. -After an overnight fast of 12hrs, patient Measurement of Glucose Tolerance given 0.75 to 1.5g of glucose/kg body weight. Glucose tolerance test: -Blood taken before administration and at 30-60 minutes intervals thereafter for 3-4 -Glucose tolerance is decreased in diabetes (low or absence of insulin) hours and glucose is measured and is increased in hyperinsulinism. -Blood glucose in a normal individual increases in 1 hour from 80mg/100ml to -After an overnight fast of 12hrs, patient given 0.75 to 1.5g of glucose/ Figure 4.10 Glucose tolerance test 130mg/100 ml. After ~2-3 hours, it returns to normal. In a diabetic, increase in blood kg body weight. glucose is greater than normal and returns to normal more slowly. -Blood taken before administration and at 30-60 minutes intervals thereafter for 3-4 hours and glucose is measured -Blood glucose in a normal individual increases in 1 hour from 80mg/100ml to 130mg/100 ml. -After ~2-3 hours, it returns to normal. In a diabetic, increase in blood glucose is greater than normal and returns to normal more slowly. Control of Insulin Secretion -Efficient feedback control of insulin release is essential to avoid hypoglycemia. -Several mechanisms: -most important, beta cells respond to levels blood glucose, secreting little or no insulin when blood glucose low, secreting much more when the blood glucose is high. -Also, release of gastrin (digestive hormone) and vagal impulses to the beta-cells induce insulin release, as a result insulin starts to leave the pancreas even before the blood glucose begins to rise during meals Glucagon - peptide hormone. synthesized and released by a-cells of pancreas. -metabolic functions are opposite of insulin's - resemble those of epinephrine. -raises blood sugar by promoting glycogenolysis (breakdown of glycogen) and gluconeogenesis (synthesis of glucose) in the liver. -In adipose tissue, glucagon increases rate of lipolysis leading to increased concentration of free fatty acids in circulation. -Glucagon interacts with membrane receptor stimulating the activity of adenylyl cyclase, increasing the production of cyclic AMP. -Glucagon release controlled by concentration of glucose in circulation. -Low blood glucose content stimulates a-cells of pancreas to increase the synthesis and release of glucagon, while high blood glucose content would decrease the release and synthesis of glucagon. -Glucagon not as important as insulin, other hormones increase blood glucose content such as epinephrine, nor-epinephrine, cortisol etc. Growth Hormone -produced by anterior lobe of the pituitary. -responsible for growth; a.k.a. Somatotropin (STH). -single chain polypeptide - shows great species specificity Thus only human GH promotes growth in humans. Rat or bovine GH does not. 29 -Increases protein synthesis in many tissues such as bone, muscle, kidney, liver by enhancing amino acid uptake by cells and by accelerating the transcription and translation of mRNA. -Also increases the rate of lipolysis and utilization of free fatty acids as a source of energy. This is a direct effect of GH not mediated by the somatomedins. Somatomedins -Many effects of GH mediated by substances produced by the liver under stimulation of GH Somatomedins -produced downstream of growth hormone -Are structurally similar to insulin and are named insulin-like growth hormone I and II (IGF-I and IGF-II) - somatomedins may bind to insulin receptors and insulin at high concentrations may bind to somatomedin receptors. -increase protein synthesis and stimulate growth. Control of GH Release CONTROL OF GH RELEASE -complex feedback mechanism mediated by two hypothalamic -complex feedback mechanism mediated by neurohormones: two hypothalamic neurohormones: (a) growth hormone releasing hormone (GRH) also known as (a) growth hormone releasing hormone (GRH) also known as somatoliberin, somatoliberin, which stimulates growth hormone release. which stimulates growth hormone release. (b) somatostatin (growth hormone inhibiting hormone), which (b) somatostatin (growth hormone inhibiting hormone), which inhibits growth inhibits growth hormone release. hormone release. -GRH and somatostatin tightly regulated by an integrated system of GRH and somatostatin tightly regulated by an integrated system of neural, neural, metabolic, and hormonal factors. metabolic, and hormonal factors. Figure 4.11 -statin maintaining the given state -somatostatins block the release of GH into the circulation -exercise and sleep somatostatins -stress and low blood sugar + somatostatins Pathophysiology of GH GH Deficiency: -In the young, absence of growth hormone leads to decreased physical growth. Excess of GH: -In young individual leads to gigantism. -Excess of GH in later life (adult) produces the condition of acromegaly, in which many bones (particularly at the cartilaginous regions of the bones) get longer and heavier. Reproduction Overview -primary reproductive organs: the gonads, testes in the male, ovaries in the female. -Accessory reproductive organs include system of ducts through which sperm or eggs are transported, and the glands that empty into them. In the female, breasts are also included in this category. -The gonads serve two functions: 1. Gametogenesis: the production of reproductive cells known as gametes; the spermatozoa in the male, and ova in the female. 2. Secretion of sex hormones (specific steroids); testosterone (androgen) in the male, and estrogen and progesterone in the female. -The differences in reproductive endocrinology in males and females is quantitative and not qualitative. -Androgens not unique to males, and estrogens not unique to females. Testes produce small amounts of estrogen, and androgens can be converted into estrogens by a single enzymatic step in several non 30 gonadal tissues (bone, for example). Androgens produced in small amounts in ovaries and in larger amounts by the adrenals. -Recall that all sex steroids signal by similar underlying mechanisms. Different sex steroid hormones bind to specific receptors, which are members of the nuclear receptor family of regulators of transcription. Control of Reproductive Function -A similar chain of signals function in males and females -Gonadotropin releasing hormone (GnRH), secreted by hypothalamus, travels to anterior pituitary via hypothalmo-pituitary portal vessels - stimulates release of pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). - Note that, while FSH and LH hormones were originally named for their effects in the female, they function in both sexes. -FSH and LH stimulate development of spermatozoa or ova, and secretion of sex steroids. -Sex steroids exert effects in gonads, in other parts of the reproductive system, and body (e.g. estrogen maintains bone density; i.e. prevention of osteoporosis). -gonads also produce a protein hormone known as inhibin, which also feeds back on the anterior reproductive function. pituitary. s. (GnRH), to pituitary g hormone H). rmones fects in exes. ent of of sex ds, in tem, and e density; mone s back on Figure 5.1 Male Reproductive System: Function of the Testes -The principal function of testes is production of mature germ cells (spermatogenesis), and steroid hormones (steroidogenesis). -Unlike females, who at birth has her whole life's supply of ova, the male continually renews his pool of precursor germ cells (spermatogonia) relatively constant supply of germ cells available throughout most of the life of the male mammal. -The process of spermatogenesis takes place within the coiled seminiferous tubules of the testes. -The process of maturation from immature spermatogonia to the mature spermatozoon takes approximately 60 days in humans. -Two cell types play a critical role in the maturation of spermatozoa Leydig cells, which are located outside the seminiferous tubules Sertoli cells, which are located within the seminiferous tubules. -The Leydig cells are responsive to LH 31 -The Sertoli cells are responsive to FSH. -In response to LH, the Leydig cells synthesize androgens. -In response to FSH the sertoli cells synthesize the Androgen Binding Protein (ABP) and inhibin. -The Sertoli cells are intimately involved with the sperm maturation process and microscopic examination reveals that these cells envelop the germ cells throughout their development -Spermatogenesis critically dependent on androgen concentration within seminiferous tubules Must be approximately 10 times higher than the androgen concentration in circulation. The presence of ABP, which is synthesized by the Sertoli cells, ensures that this high concentration of androgens will exist within the seminiferous tubules. If testosterone concentrations are not maintained at high levels within the testis spermatogenesis will cease. higher concentration maintained by local production of androgen by the Leydig cells and the presence of ABP from Sertoli cells paracrine signalling (adjacent cell types communicating to each other) -Androgen synthesis by testis regulated by two negative feedback mechanisms: (a) Hypothlamic-pituitary-leydig cell axis: GnRH stimulates release of LH and FSH - stimulate Leydig cells and Sertoli cells. Leydig cells produce androgen, which inhibit the release of GnRH, LH and FSH. (b) Hypothalamic-pituitary-seminiferous-tubules axis: non steroidal inhibin secreted by the Sertoli cells inhibits testes. Function of theFSH release only. -Contrary to female reproductive system, no (+) feedback control in males. stem: ermatogenesis critically dependent on drogen concentration within seminiferous ones bules ust be approximately 10 times higher than e androgen concentration in circulation. e presence of ABP, which is synthesized sor the Sertoli cells ensures that this high ls is ncentration of androgens will exist within of e seminiferous tubules. testosterone concentrations are not s aintained at high levels within the testis ermatogenesis will cease. Figure 5.3 ndrogen synthesis by testis regulated by re o 0 negative feedback mechanisms: Hypothlamic-pituitary-leydig cell axis: GnRH stimulates release of LH and Figure 5.2 Female Reproductive System: Ovarian Function FSH - stimulate leydig cells and sertoli cells. Leydig cells producehormones, which regulate the reproductive -Principal functions; production of mature eggs, and steroid androgen, which inhibit the release of sexual behavior. FSH. tract and influence GnRH , LH and Hypothalamic-pituitary-seminiferous-tubules axis:ofnon steroidal inhibin (about 2 million), which are its -At birth ovary contains non-proliferating pool germ cells or oocytes secreted by the sertoli cells inhbits FSH release only. whole life supply of ova. At puberty about 400,000 ova left. -The oocytes are surrounded by a single layer of granulosa cells and a basement membrane making up ontrary to the structures called primordial follicles - fundamental control in males. the ovary. female reproductive system, no (+) feedback reproductive units of -Growth of primordial follicles into primary follicles begins by an unknown initiating event (independent of pituitary) 32 Female Reproductive System: Ovarian Function. ovulate or degenerate (atresia). Ovary: -Once initiated, growth controlled by gonadotropins and steroid hormones until the follicles either -Principal functions; production of mature eggs, and steroid hormones, which regulate the reproductive tract and influence sexual behavior. -At birth ovary contains non-proliferating pool of germ cells or oocytes (about 2 million), which are its whole life supply of ova. At puberty about 400,000 ova left. -The oocytes are surrounded by a single layer of granulosa cells and a basement membrane making up the structures called primordial follicles - fundamental reproductive units of the ovary. -Growth of primordial follicles into primary follicles begins by an unknown initiating event (independent of pituitary). Once initiated, growth controlled by Follicular growth: gonadotropins and steroid hormones until Figure 5.4 the follicles either ovulate or degenerate -Initially limited to enlargement and differentiation of the oocyte (atresia). -Oocyte grows & elaborates the zona pellucida (an acellular layer rich in glycoproteins surrounding the oocyte) -Then, granulosa cells divide & increase to 2 or more layers - primary follicles. Influenced by FSH and estrogens. Estrogens important for expression of LH receptors on surface of granulosa cells -positive feedback loop -Under influence of FSH and LH, primary follicle develops into a secondary follicle which expresses receptors for FSH, estrogens and LH. Also, appearance of the follicular antrum which contains secretions from the granulosa cells. -Under the combined influence of FSH and LH the granulosa cells elaborate follicular fluid, which takes up the larger portion of the preovulatory follicle (also known as late secondary follicle or Graafian follicle or mature follicle). -As follicle matures from primary to secondary follicles cells from ovarian stroma surrounding follicle differentiate and become steroid-producing cells known as theca cells (theca interna). -Theca interna and the granulosa cells collaborate for the synthesis of higher amounts of estrogen -positive feedback loop Follicular Atresia: Although many follicles initiate growth and development in each reproductive cycle, in humans usually only one follicle will ovulate in each reproductive cycle - remaining secondary follicles degenerate in a process known as atresia. Ovulation: Mechanism of follicular rupture poorly understood - possible that increase in intrafollicular pressure and proteolysis of ovarian wall of mature graafian follicle lead to ovulation. Luteinization (after ovulation): -Ruptured follicle transformed into Corpus Luteum secretes progesterone. -Both theca and granulosa cells contribute in formation of the corpus luteum, a temporary endocrine structure within the ovary that synthesizes progesterone and estrogens. 33 -Progesterone and estrogens are produced in large amounts by corpus luteum for few days following ovulation but then drop off unless implantation of the fertilized ovum occurs. -Progesterone drives cell differentiation -Estrogen drives cell proliferation -If implantation occurs, corpus luteum transformed into corpus luteum of pregnancy, responsible for synthesis of progesterone and estrogens and creation of proper endocrine environment for maintenance of pregnancy until progesterone and estrogen synthesis by placenta established. tion): Corpus ribute in mporary that ens. duced in ew days unless ccurs. Figure 5.5 Luteolysis: Luteolysis: -In absenceof implantation, lifelife span of corpus luteum limited. In absence of implantation, span of -Luteal luteum limited. Luteal regression prostaglandins which decrease LH binding and thus corpus regression may be induced by steroidogenesis by prostaglandins which may be induced -Decrease of binding and thus decrease LH plasma progesterone and estrogen may be trigger for initiation of next reproductive cycle. -Decrease of plasma progesterone and The menstrual cycle: estrogen may be word for initiation of -From the Latin triggermenses (month). next 1 considered as the -Day reproductive cycle. first day of detectable vaginal bleeding represents a deterioration of the uterine endometrium -Prior to day one endometrium proliferates and becomes thick under the influence of estradiol. -Progesterone induces the appearance of glycogen-secreting glands. -Menses (bleeding) begins when estradiol and progesterone very low in circulation, when the blood vessels supplying the endometrium constrict reducing the blood supply Endometrium deteriorates, flows through the cervix into the vagina Bleeding occurs for about 5 days during -ovaries are endocrinologically rather inactive during this time. -Low estradiol and progesterone leads to increased secretion of FSH by pituitary. Usually, moderate levels of estradiol block FSH release. -Also, decrease in non-steroid ovarian hormones, inhibins, which selectively inhibit secretion of FSH and may in part raise FSH levels during 5-6 days -Under influence of FSH, a cohort of ovarian follicles develop. -FSH stimulates granulosa cells of follicles to proliferate, and induces production of aromatase, converts androgens to estrogen. -Local production of estrogen stimulates granulose cell proliferation. -Day 8, one of the follicles becomes dominant and committed to further development. The remaining follicles begin to degenerate by atresia. In humans, how one follicle becomes dominant still unknown. -Dominant follicle produces increasingly more estradiol, and estradiol becomes important in late stages of cycle - increased estradiol produced by growing follicle causes uterine endometrium proliferation. -By day 13 the endometrium very thick. Under the influence of estradiol, there is an induction of progesterone receptors in the endometrium. steroidogenesis. m egnancy, rone and ocrine gnancy hesis by 34 -Low estradiol and progesterone leads to increased secretion of FSH by pituitary. Usually, moderate levels of estradiol block FSH release. -Also, decrease in non-steroid ovarian hormones, inhibins, which selectively inhibit secretion of FSH and may in part raise FSH levels during 5-6 days -Under influence of FSH, cohort of ovarian follicles develop. FSH stimulates granulosa cells of follicles to proliferate, and induces production of aromatase, converts androgens to estrogen. Local production of estrogen stimulates granulose cell proliferation. -Day 8, one of the follicles becomes dominant and committed to further development. The remaining follicles begin to degenerate by atresia. In humans, how one follicle becomes dominant still unknown. -Dominant follicle produces increasingly more estradiol, and estradiol becomes important in late stages of cycle - increased estradiol produced by growing follicle causes uterine endometrium Estradiol effects on brain and pituitary. Figure 5.7 proliferation. -Rising estradiol - negative feedback on FSH release -By day 13 the endometrium very thick. Under the -Moderate concentrations, estrogen also stimulates synthesis of LH by pituitary and increases influence of estradiol, there is an induction of sensitivity of the pituitary to GnRH, which stimulates synthesis of LH progesterone receptors in the endometrium. -Although moderate estradiol concentrations stimulate LH synthesis, they inhibit LH release. LH accumulates to high levels within pituitary. -Under influence of the developing follicle estrogen concentrations continue to build. -Elevated estrogen concentrations stimulate LH release - LH surge on or about day 14. Small increase in FSH release also occurs. -vesicles of LH building up in the pituitary until high estrogen levels finally release them LH surge -Stimulation of LH synthesis by estradiol and increased sensitivity of the anterior pituitary to GnRH leading to increased LH synthesis by anterior pituitary known as the estrogen (+) feedback control mechanism. -Thus estrogens exert both a negative feedback such as decreased GnRH and LH release and a positive feedback such as increased sensitivity of the anterior pituitary cells to GnRH and increased LH synthesis. -Meanwhile, at the ovarian level the follicle has become huge. The sudden surge of LH causes the follicle to rupture (mechanism unclear) and the ovum is ejected. . sa ium. erates e of Figure 5.6 e of adiol ion, lood ows ay one ing rather Feedback mechanisms of steroid hormones on gonadotropin action Feedback mechanisms of steroid hormones on gonadotropin action. 35 Oral contraceptives. Figure 5.8 Figure 5.9 Pills contain estrogen and progesterone - maintain moderate circulating levels of estrogen and progesterone suppress the release of LH and FSH from the pituitary and prevent ovarian follicles from maturing and being ovulated. 99 % success, provided that the pill is taken daily for 21 consecutive days with seven days of no medication that would induce menstruation. Corpus Luteum. Under the influence of LH the follicle becomes corpus luteum -produces large amounts of estradiol and progesterone induce endometrial growth of the uterus. In addition, under the influence of progesterone the endometrium becomes glandular. The endometrium is now fully prepared to receive and support the development of a growing embryo. Luteal Phase -No fertilization - egg degenerates, corpus luteum degenerates (luteolysis). -Lasts a constant 14 days, known as the luteal phase of cycle since steroids produced by corpus luteum dominate. -After 14 days in absence of implantation corpus luteum degenerates, steroid levels drop, uterine endometrium degenerates, menstruation begins and pituitary starts to increase its secretion of FSH, and we are back to the beginning of the cycle. Menstrual cycles are unique to primates. Non-primate mammals - reproductive cycles referred to as estrous cycles, vary considerably between species. Estrous cycle - no bleeding. However, the relative hormone changes in the estrous cycle are similar to those in menstrual cycle. Fertilization and Implantation -At ovulation, unfertilized egg is taken by the fimbria of the oviduct (or fallopian tube) and is being propelled towards the lumen of the uterus. -If sexual intercourse takes place around this time and the male partner is fertile, some spermatozoa deposited in the vagina will travel as far as the oviduct and one of these spermatozoa will fertilize the egg. 36 -Egg starts dividing to the stage of blastocyst during its transport down the oviduct into the uterine lumen. -The uterine endometrium prepared for implantation of blastocyst by estradiol and progesterone. The blastocyst differentiates into the trophoblast (which eventually will become the placenta) and the inner cell mass (which eventually will form the embryo). -Trophoblast invades uterine mucosa and leads to embedding of developing embryo in endometrium. -At about time of implantation, trophoblast starts to synthesize human chorionic gonadotropin (HCG) which has LH-like properties and stimulates the corpus luteum to continue the secretion of gonadal steroids. -After about 12th week of pregnancy endocrine function of corpus luteum taken over entirely by placenta, which together with developing fetus forms the fetoplacental unit. -Close functional interdependence between the fetal and maternal compartments, and fetal liver acquires an important function in the synthesis of estriol (an estrogen). -Additional well-characterized hormones produced by the placenta are human chorionic somatotropin, progesterone, and relaxin. -HCG implantation. quickly appears in blood and urine where it forms the basis for the biological or immunological pregnancy test. HCG quickly appears in blood and urine where it forms the basis for the biological or immunological pregnancy test. gg is taken t (or propelled rus. place e partner is eposited in as the rmatozoa age of rt down the en. The uterine endometrium prepared for implantation of blastocyst by estradiol and progesterone. The blastocyst differentiates into the trophoblast (which eventually will become the placenta) and the inner cell mass (which eventually will form the embryo). Trophoblast invades uterine mucosa and leads to embedding of developing embryo in endometrium. At about time of implantation, trophoblast starts to synthesize human chorionic gonadotropin (HCG) which has LH-like properties and stimulates the corpus luteum to continue 5.10 Figurethe secretion of gonadal steroids. -After about 12th week of pregnancy endocrine function of corpus luteum taken over -The by placenta, which together with developing fetus forms glands) is termed entirelysecretion of milk by the breast (mammary the fetoplacental unit. Lactation Figure 5.11 Figure 5.12 lactation. Normal mammary -Close functional interdependence between the fetal and maternal compartments, and fetal Mature non-pregnant mammary glands (Ductal): liver acquires an important function in the synthesis of estriol (an estrogen). development required for lactation - under endocrine control. -Additionalof duct growthhormones produced by the placenta are humanlittle development well-characterized and duct branching but relatively chorionic somatotropin, progesterone, and relaxin. growth of alveoli -Progesterone stimulates -With onset of puberty under the action of increasing levels of estrogens, marked enhancement of the alveoli. -However, most breast enlargement due to fat deposition under the glandular tissue. -In addition to estrogens and progesterone, corticoids and growth hormone contribute to growth of mature non-pregnant mammary gland. 37 Pregnant mammary gland (Lobulo-alveolar): During pregnancy under influence of several hormones (estrogen, progesterone, prolactin, human placental lactogen) both ductal and alveoli structures fully develop -Also growth hormone, cortisol and thyroxin are needed for complete growth of mammary glands. -Milk production during pregnancy controlled by prolactin, however high estrogen levels inhibit secretion. breast lactation. ment required ne control. mmary glands Lactating mammary gland: -After parturition, levels of estrogen decrease, while levels of prolactin remain high. -Under the action of prolactin there is milk synthesis the alveoli secrete milk filling the ducts. -During nursing, under action of oxytocin, ducts contract to cause milk ejection - both prolactin release from anterior pituitary and oxytocin release from posterior pituitary are stimulated by afferent fibers (nerves) from nipple. Prolactin sustains milk production, oxytocin causes milk letdown or ejection. -Milk: water, protein, fat and carbohydrate lactose and antibodies important for the newborn. Also, infectious agents such as viruses and drugs may be transmitted from the mother to infant through breast milk. r the action of s, marked and duct e development wth of alveoli gement due to dular tissue. In ogesterone, one contribute gnant Figure 5.14 Pregnant mammary gland (Lobulo-alveolar): Figure 5.12 -During pregnancy under influence of several hormones (estrogen, progesterone, prolactin, human placental lactogen) both ductal and alveoli structures fully develop -Also growth hormone, cortisol and thyroxin are needed for complete growth of mammary glands. -Milk production during pregnancy controlled by prolactin, however high estrogen levels inhibit secretion. Lactating mammary gland: -After parturition, levels of estrogen decrease, while levels of prolactin remain high. -prolactin important in milk production -Under the action of prolactin there is milk synthesis the alveoli secrete milk filling the ducts. -During nursing, under action of oxytocin, ducts contract to cause milk ejection - both prolactin release from anterior pituitary and oxytocin release from posterior pituitary are stimulated by afferent fibers (nerves) from nipple. - Prolactin sustains milk production, oxytocin causes milk letdown or ejection. -Milk: water, protein, fat and carbohydrate lactose and antibodies important for the newborn. ---Also, infectious agents such as viruses and drugs may be transmitted from the mother to infant through breast milk. Lactational amenorrhea -Maintained nursing inhibits the secretion of FSH and LH and blocks the resumption of the reproductive cycle -Actually, nursing used to be a natural method of contraception -However, the intensity and frequency of suckling appears to be an important parameter for the maintenance of the blockade on the reproductive cycle and ovulation -If suckling is not frequent then ovulation, and pregnancy, may occur Menopause -At the end of reproductive period, most ovarian follicles have disappeared by atresia and a few hundred have been ovulated during successive menstrual periods. -Ovarian depletion of follicles results in loss of capacity for steroid (estrogen and progesterone) hormone production by the ovary. -Lack of estrogens often induces number of symptoms such as: -hot flashes, dry vagina, restlessness, bone loss (osteoporosis - long term) etc. 38 -Cessation of ovarian steroid hormone production also leads to rise in the plasma gonadotropins FSH and LH, because their suppression by the negative feedback is no longer possible. -The constantly high levels of plasma FSH is most reliable criterion for onset of menopause. -Symptoms caused by estrogen lack respond readily to estrogen replacement therapy. -However, because follicular depletion is primary cause of menopause, fertility cannot be restored by steroid replacement therapy. Orphan Hormone Receptors With the advent of molecular biology, and our increasing capacity to clone genes encoding specific classes of proteins, researchers started to identify genes encoding proteins that were clearly novel members of specific classes of hormone receptors (i.e. G protein-coupled receptors, cytokine receptors, nuclear receptors, etc), and yet did not bind known classes of hormones. These receptors became known as orphan receptors. -identified receptors by their protein sequence, but had no clue what they were receptors for Human Nuclear Receptor Family -N.B. ligands now identified for many receptors originally isolated as orphans. However, researchers in the field still refer to many of them as orphan receptors. -48 nuclear receptors -vitamin D dietary compound, different from the others -most of the receptors are not receptors for classical endocrine hormones, but for things like dietary fatty acids, bile acids, certain types of drugs, and glucose -there is more inter-cell hormonal communication between these non-classical hormones than the classical endocrine hormones The i.e. the classical hormones are more of the exception than the rule complete human nuclear receptor family Thyroid hormone Vitamin D Estrogen Gluco., Mineralo. Progesto., Andro. N.B. ligands orphan receptors so receptors originally isolated as orphans. Why are now identified for many interesting? However, researchers in the field still refer to many of them as orphan receptors. 1. Hormones (ligands) for classical receptors carry signals that control many fundamental human physiological processes (e.g. sexual development, reproduction, mineral homeostasis, etc). -The possibility that there existed novel signaling molecules that controlled other fundamental processes was tantalizing indeed. 2. Nuclear receptor ligands are ideal candidates for drug development. -For example: the anti-inflammatory agent dexamethasone binds to the glucocorticoid receptor, the French abortion pill RU486 blocks the action of the progesterone receptor (endometrial differentiation), the antiestrogen hydroxytamoxifen binds to the estrogen receptor, and is used to combat breast cancer, anabolic steroids bind to the androgen receptor. 39 -If signaling through orphan receptors controlled fundamental physiological processes then they too would be ideal candidates as drug development. The History of Vitamin D 1600s rickets described for the first time. 1800s prevalence growing as Europe becomes industrialized 1822 Polish physician prescribes sunbathing as a cure for rickets 1827 French physician prescribes cod liver oil. 1892 relationship between rickets and prevalence of sunlight established Early 1900s Casimir Funk coins term vitamine (vital amine) "e" later dropped. 1919 cure for rickets with artificial UV. 1922 term vitamin D coined. 1926 2 Dutch chemists purify first vitamin (Vitamin B1, thiamin) 1929 first Nobel Prize for discovery of essential nutrients. 1920s several researchers independently discover that UV irradiation of food renders it antirachitic. 1931 vitamin D defined as a steroidal compound. 1936 structure defined and 7-dehydrocholesterol precursor identified. 1968 25-hydroxylation in liver discovered 1969-71 1,25-dihydroxy (hormonal) form identified 1975 receptor described as a nuclear protein (radiolabeling experiments) 1950s-1990s extensive physiological actions of vitamin D described 1988-90 receptor cDNA isolated A Brief History of PXR: classical endocrinology in reverse 1986-7 first use of existing nuclear receptor gene sequences to identify (clone) related receptors of unknown function - orphan receptors. 1980s-1990s development of high throughput DNA sequencing technology. 1980s-1990s new biotech companies (e.g. Incyte) start generating proprietary libraries of DNA sequence (ESTs; expressed sequence tags) 1995-6 Glaxo-Wellcome uses a purchased EST data base to identify sequences encoding a novel nuclear receptor (PXR) expressed in mouse. cDNA cloned by RT/PCR. 1997 high throughput ligand screening shows that PXR activity induced by a large number of commercially available drugs. 1997 genes encoding critical hepatic drug metabolizing enzymes (e.g. CYP3A) found to regulated by drug-activated PXR. -special receptor in the liver detector of foreign molecules binds lots of different molecules foreign molecule stimulates its own metabolism and clearance from the cell 2000-1 gene encoding the ATP-driven pump responsible for multi-drug resistance in cancer found to be target of chemotherapeutic agent-activated PXR. PXR Ligands and Drug-Drug Interactions -One of the interesting aspects of studies of PXR was that previous classical pharmacological studies had shown that different classes of drugs differed in their capacity to induce CYP3A activity in mouse and humans. -Strikingly, these differences paralleled exactly the relative capacities of these drugs to stimulate the activity of human and mouse PXRs. 40 -These studies have provided researchers in the pharmacology industry with a very simple screen (i.e. binding to and activation of PXR) to rapidly assess the capacity of small molecule drug candidates to activate their own metabolism and the metabolism of other drugs (i.e. drug-drug interactions). -Candidate compounds that are potent activators of PXRs are eliminated from further drug development. PPARs: Control of lipid metabolism and adipogenesis. PPARs: Control of lipid metabolism and adipogenesis -3 PPAR receptors, ,receptors, a, b, and g. -3 PPAR , and . -Focus on PPAR and - best characterized and most interesting. -Focus on PPAR a and g - best characterized and most interesting. -Unfortunate name PPAR (peroxisomal proliferator-actived receptor) -Unfortunate name PPAR (peroxisomal proliferator-actived receptor) derived from observation that derived from observation that PPARs bind at high concentrations classes of PPARs bind at high concentrations in livers of rats toxic compounds that caused proliferation of peroxisomesclasses of toxic compounds that caused proliferation of (apparently theperoxisomes in livers observed in humans, but the same phenomenon is not of rats (apparently the same phenomenon is not observed in humans, but the compounds arecompounds are toxic anyway). toxic anyway). igure 6.2 PPARa -Most highly expressed in tissues that display high rates of fatty acid metabolism. -Fatty acids regulating their own metabolism -Subsequent to discovery that PPARa bound peroxisomal proliferators, it was discovered that PPARa bound certain types of fatty acids and their metabolites. -More recently, shown that ligand-activated PPARa receptors stimulated expression of several genes controlling fatty acid metabolism. -Thus, some fatty acids can control their own metabolism through PPARa by inducing the expression of genes encoding metabolic enzymes required for fatty acid catabolism. PPARg. -One of the most fascinating of all orphan receptors. -Most highly expressed in adipose tissue intestine and spleen. -First high affinity ligand for PPARg was identified in a large ligand screen at Glaxo-Wellcome, and turned out to be a thiazolidinedione (TZD). -TZDs are fascinating because they were originally developed as antidiabetic drugs, although their molecular targets were not known (this was not uncommon; the molecular target of aspirin was not known for over 100 years). -Once they figured out what the target was, they could make more efficient TZDs -More effective TZDs were rapidly developed, and are widely used in diabetes therapy today. PPARg and Insulin Resistant Diabetes. -Subsequent studies - PPARg function essential for normal adipogenesis. -Given that stimulation of PPARg is adipogenic, and that obesity is correlated with insulin resistance and diabetes, how is it that stimulation of PPARg by TZD combats diabetes? -The antidiabetic action of TZDs arises from the fact that they lower circulating levels of fatty acids. -This leaves less fat in the circulation to be used as fuel, and therefore a higher dependence of glucose as a fuel source. This is particularly true in muscle. -Indeed, recent studies have shown that TZD signaling enhances the capacity of muscles to burn glucose and represses their capacity to burn fat. 41 -As a result, TZDs are very effective in obese people with insulin resistance, where they significantly increase insulin sensitivity, and actually cause slight weight gains. FXR: Control of bile acid metabolism -The term FXR is derived from early observations that FXR could be activated by extremely high concentrations of farnesyl, an intermediate in cholesterol biosynthesis. However, it was subsequently shown that farnesyl does not actually bind to FXR, and therefore, that some metabolite was responsible for the activation observation at extremely high concentrations -Cholesterol metabolism is controlled in two ways: 1. A feed-forward mechanism whereby oxysterols activate expression of CYP7A, the enzyme responsible for their conversion to bile acids. 2. A feed-back mechanism whereby elevated levels of bile acids inhibit further bile acid synthesis. FXR as a bile acid receptor The orphan receptor FXR is most highly expressed in tissues where bile acids function; i.e. the liver and intestines. It was therefore not surprising to find that FXR was activated by the primary bile acid chenodeoxycholic acid. Bile acids -Produced in the liver, secreted into bile ducts and transported to the small intestine. They are not simply cholesterol breakdown products. In fact, they are important for two reasons: -They represent solubilized excretable forms of cholesterol. -Since they are both hydrophobic and hydrophilic in character, bile acids function to facilitate absorption of fats and fat-soluble vitamins in the intestine Evidence that FXR is a bona fide bile acid receptor: 1. Bile acid-bound FXR repressed expression of CYP7A, which encodes the rate-limiting enzyme in cholesterol biosynthesis, thus providing a molecular mechanism for the observed feed-back mechanism by which bile acids regulate cholesterol metabolism. 2. Elevated bile acid levels were known to induce expression of intestinal bile acid binding protein (IBABP). Recent studies showed that bile acid-bound FXR could activate transcription of the IBABP gene in the intestine. Mechanisms of signaling by nuclear and membrane receptors receptors -glucose can act in a hormonal way by binding to a nuclear receptor very new information Small lipophilic molecules: steroid hormones, cholesterol metabolites, bile acids, thyroid hormone, vitamin A metabolites vitamin D3 fatty acids & metabolites numerous xenobiotics & Glucose!!! Peptide hormones Peptide growth factors Small hydrophilic molecules Mechanisms of signaling by nuclear and membrane 42 Nuclear Receptors -Nuclear receptors exert their physiological effects largely by regulating the transcription of a (receptor-specific) subset of genes in the human genome. -Ultimately, this leads to changes in the types and concentrations of proteins present in target cells, thus altering cell function. -Molecular evidence for the existence of nuclear receptors dates from ca. 1960 with the demonstration by Elwood Jensen that radioactive estrogen associated with an apparent receptor in the nucleus. -Evidence that nuclear receptors might regulate gene transcription dates accumulated through the 1970's. -First nuclear receptor genes identified in the mid `80's. -The first nuclear receptors were identified for classical endocrine hormones: Estrogen Progesterone Androgens Steroid hormones Glucocorticoids Mineralocorticoids Thyroid hormone & Vitamin D -Receptor-ligand interactions were characterized by: 1. Lipophilicity of the ligand 2. High ligand-receptor specificity 3. High ligand-receptor affinity (low nM) -It is now known that there are 48 genes in the human genome that encode nuclear receptors. -All of the nuclear receptors identified since the genes for "classical" endocrine receptors were identified bind vitamins, other dietary constituents (e.g. fatty acids) and their metabolites, or "xenobiotics (foreign molecules like toxic compounds and drugs). -Glucose can also regulate the function of a nuclear receptor -Techniques are now available for identifying on a large scale (thousands at a time) genes whose transcription is regulated by nuclear receptors. -This has provided novel and unexpected insights into the physiological processes regulated by nuclear receptors. New insights into vitamin D physiology -critical calcium regulatory hormone but does have other functions 1,25-dihydroxyvitamin D3 Biosynthesis 1,25-dihydroxyvitamin D3 Biosynthesis 24 25 24 25 43 2 3 1 CH3 10 5 6 7 UV-B vitamin D3 Provitamin D3 OH 4 Skin 4 3 5 2 10 1 Vitamin D receptor 24 25 OH Liver (Skin) 25-hydroxylation 24 OH Peripheral Tissues (incl. Skin) 1-hydroxylation 5 2 25 OH 4 3 5 2 10 1 1,25-dihydroxyvitamin D3 OH OH 4 3 10 1 25-hydroxyvitamin D3 OH -vitamin D obtained from two sources food and supplements (fish, cod oil) and UV-B light -UV-B wavelength induces photochemical reaction in the skin -1-hydroxylation can be done in additional tissues other than just the kidney regulation is not under Calcium signalling Vitamin D Winter -as the sun drops in the sky, it has a longer path through the atmosphere to get to the Earth surface -all of the UV-B gets absorbed by the atmosphere if sun is low enough in the sky -tanning beds are not the same as getting real sunlight Vitamin D Winter -vitamin D deficiency very prevalent in Europe Three types of diseases have demonstrated north-south gradients. Tavera-Mendoza and White, Sci. American, Nov 2007. -if there a certain diseases that are benefited by vitamin D in the diet, then they should have NorthSouth gradients 1. Certain types of cancers (e.g. colon, prostate). 2. Autoimmune diseases: e.g. multiple sclerosis, Crohn's disease. 3. Infectious diseases. -tuberculosis sunlight has believed to be beneficial for hundreds of years Colon cancer rates and summer surface UVB levels -blue is low; red is high levels of colon cancer Colon cancer rates and summer surface UVB levels. 44 Colon Cancer rates 1970-94, White males Spectral UVB exposure kJ/m2 July, 1992 Treatment of cells with 1,25-dihydroxyvitamin D3 induces secretion of antibacterial activity -TB prevalence back on the rise think its because vitamin D deficiency is on the rise Treatment of cells with 1,25-dihydroxyvitamin D3 after treatment with vitamin D -experiment detects proteins in bacterial cells before and -48 hour 1,25-dihydroxyvitamin D3 treatment of cells in culture increases levels of antimicrobial induces secretion of antibacterial activity. proteins inside cells 0h Bact. colonies (%) 120 100 80 60 40 20 0 Bact. colonies (%) 120 100 80 60 40 20 0 0 24 48h D3 0 24 48h D3 E. coli 48h P. aerug. 48 hour 1,25dihydroxyvitamin D3 treatment of cells in culture increases levels of antimicrobial proteins inside cells ...
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