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endocrinology The study of hormones overview Comparison of n.s. & endocrine as control/signaling systems Nervous system Fast response Detects external events (mostly), but also internal events Controls muscle effectors that operate on external environment (mostly), but also directly controls internal functions (heart rate, breathing, exocrine gland secretion) Controls endocrine system! Endocrine system Slower response (mostly) & longer term action Detects internal events (external if include pheromones!) Controls organ function Supervises growth & development Controls nervous system! Nervous system control of endocrine system: Hypothalamic brain neurons release synaptic vesicles containing “neuro-hormones”1 Endocrine control of nervous system: At different times in the organism’s life, certain neurons make receptors for hormones. NH’s travel “synaptically” or via blood to endocrine target tissue in Neuron binding of a hormone the brain (ant. or post. pituitary). can change growth, development of neuron, and Target tissue stimulated to release activity level of neuron. its own set of hormones. Some neurons have The latter travel via blood to many permanent hormone receptors tissues/organs. (e.g. those that respond to (also called releasing hormones or releasing factors) epinephrine) 1 Two broad functional grouping of hormones: 1. Steroids & thyroid hormones & prostaglandins are lipid soluble - travel through cell membranes. Bind to cytosol receptors. Typically the receptor-hormone complex then moves through the nuclear membrane & acts as transcription regulator. 2. Amino acid derivatives & peptides bind to transmembrane chemoreceptor proteins. The binding activates intracellular 2nd messenger systems (G-proteins, various phosphorylation events). Can also lead to transcription regulation. Chemical (not functional!) classes of hormones NOT Lipid soluble Lipid soluble In all cases, there is an internal messenger system to activate intracellular processes. Internal messenger system for lipid soluble steroid hormone… Internal messenger system for non-lipid soluble hormones. Example: Epinephrine (an amino acid derivative) To activate the target cell it must bind to a membrane receptor protein. Cells may have receptors for more than one type of hormone. Two different hormones activate liver cells. Glucagon Epinephrine (adrenalin) They bind to different receptors. Liver cell Both hormones cause liver cells to break down glycogen & release glucose to blood… but effects are not additive. Glucagon Epinephrine (adrenalin) Liver cell If saturate with glycogen, can’t get further increase with epinephrine same internal 2nd messenger (non-additive). So why does liver cell make receptors for 2 different hormones that do the same thing? Diagram modified from Hadley, Endocrinology Epinephrine: Stress hormone. Causes increased blood flow to muscles, increased respiration, etc AND breakdown of glycogen (fight/flight response) Glucagon: Regulator of blood sugar; monitoring of hypoglycemia under non-stress conditions. So: Two different physiological control mechanisms need to activate the same cellular process. As earlier, hormone binding mechanism depends on the type of chemical. So does the hormone release mechanism: Thyroid hormones: Diffuse out of lysosome, through cell membrane, into blood. Steroid hormones & prostaglandins: Diffuse out of cytoplasm, through cell membrane, into blood. All other hormones: Packaged into secretory vesicles. Held in cell until vesicle release triggered. Previous slides How hormones get into cells How hormones get out of cells But how do hormones get to cells? endocrine To blood – classic definition of hormone. Neuroendocrine Neuron releases hormone to blood. paracrine Diffusion to nearby cells neurocrine autocrine Hormone released at synaptic cleft. Diffusion to same cell. Diagram modified from Hadley, Endocrinology These are all broadcast chemical communication systems. What is or is not part of the “endocrine” system gets fuzzy. Note: Not all chemical signaling systems involve hormones! Non-hormonal chemical signals: 1. Pheromones – transmission of specific chemical signal through medium outside of organism. 2. Synaptic Transmission – almost the same thing as “neurocrine”. Pheromones. Specific molecules released by one individual typically to attract a conspecific. Extreme sensitivity – in some cases a behavioral response to detection of a single molecule. Serious pheromone detector – can detect a single molecule of pheromone Another serious pheromone detector Released by elephant Synaptic transmission is short distance, short duration, private chemical communication but endocrine signals are broadcast. … but the fact that synaptic chemical signals are not broadcast and endocrine signals are broadcast -- is not a sufficient criterion. Other broadcast chemicals may still not be endocrine. The original experiments showing the presence of chemical communication systems within organisms. Easy read for U. … so we will skip in lecture. Steroid Hormones Types of steroid hormones Glucocorticoids Example: cortisol Mineralocorticoids Example: aldosterone Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone Steroid hormones… … are not packaged, but synthesized and immediately released. … are all derived from Cholesterol. … are produced by enzymes in mitochondria and smooth ER. … (as mentioned already) are lipid soluble, freely permeable to membranes, so not stored in cells. Consequence of lipid solubility…. NOT water soluble!!! So steroids are carried in the blood complexed to specific binding globulins. Examples: • Corticosteroid binding globulin carries cortisol. • Sex steroid binding globulin carries testosterone and estradiol. Steroids vs Peptides Peptide hormones encoded by specific genes (steroid hormones are synthesized from the enzymatic modification of cholesterol) SO… There is no gene which encodes aldosterone, for example! SO … • Far fewer different types of steroid hormones re peptide hormones. • Steroid structures are the same across taxa. • Regulation of steroid production (Steroidogenesis) involves control of the enzymes which modify cholesterol into the particular steroid hormone. Overview of human endocrine system Part of the brain The pituitary is two completely separate glands (anterior & posterior) that grow together during development Skin of most mammals can synthesize vitamin D (really a hormone) Coming up next: Revisit stress hormone response as an example system of how hormones work in general. 1. Epinephrine (= Adrenalin). Gets body ready for fast muscle action. Expect changes in heart rate, blood pressure, making glucose available. Experiment to document one of the expected effects: to mobilize glucose. Inject saline control or 3 different chemicals into volunteers. Can show that epinephrine is necessary and sufficient to cause expected change in blood glucose concentration. Note use of two negative controls: saline and phenyephrine. Epi & Nor-epi have effect on blood glucose, negative controls do not. Other experiments show epi & nor-epi do affect pulse rate, blood pressure and O2 consumption by brain. So… the perfect task for the endocrine system - multiple processes (4 of them) controlled at the same time: 1 2 3 Mobilize glucose 0.4 mEq 1.1 mEq 4 Release epinephrine (adrenaline) – the appropriate target tissues will respond to it. The specificity of the response is a function of which tissues are “tuned in” to the signal. … but what causes release of epinephrine Epi produced by the adrenal medulla… How do the post-ganglionic fibers control adrenal medulla cells? The epinephrine release example shows how the nervous system can control the endocrine system We have to specify an adrenal gland chromaffin cell, because often endocrine tissue contains multiple cell types that release different sorts of hormones. The chromaffin cell is controlled by a neuron, but it could just as well have been controlled by a hormone from some other endocrine tissue. The half-life of a hormone is set by degradative processes. Epinephrine controls 3 different processes. How does it do that? Ans: The target tissues have specific receptors for epinephrine, and the receptors can be tuned to produce just the right response. 4. Skeletal muscle B2 receptors bind E vasodilation Increase blood flow Overall, epinephrine release increases blood pressure. Which is why “ß-blockers” treat hypertension (ßadrenergic receptor antagonists) Next: Simple examples of how negative feedback regulation works using two different example hormone systems… Negative feedback Set-point /comparator element regulation Tissue sensor: pancreatic islet cell monitors glucose level (Not) Too much glucose bound to receptors? Incr. insulin secretion Less blood glucose Insulin binds to receptors on most cells Increase transport of glucose from blood to cells Neural sensor: brain neuron osmosensor (Not) Osmotic concentration too high? (implies dehydration) Neuro-secretion ADH release Water retention, thirst … drinking Example of feedback regulation with an adjustable set-point: Cortisol levels…. Cortisol long-term stress-related hormone. Less acute than EPI. Also circadian control. A class of steroid hormones that binds to the glucocorticoid receptor (GCR). Cortisol levels sensed by anterior pituitary Hypothalamus is set point adjuster: (1) Last 3 months pregnancy, or (2) extreme athletes – set point moved higher. Plasma Cortisol concentration Circadian effect: Time of Day Immune system cells (but not just) have glucocorticoid receptors, so taking hydrocortisone, prednesone (say for arthritis) antiinflammatory… But too much for too long -- or if have set-point problem: Cushing’s disease High blood pressure & blood glucose, anxiety, thirst & other problems. In many endocrine systems there is also negative feedback control based on receptor abundance Long-term adaptive change (change in transcription) Down-regulate receptors Anterior pituitary cell Anterior pituitary cell Genetic control (+/- individual variation) of the number of cortisol receptors Up-regulate receptors Anterior pituitary cell Genetic control occurs relative to transcription levels for the production of hormones… and also for the production of hormone receptors! How can you tell which is happening? Figure 47.09 diabetic and obese mice Here is how it works (I’ve changed the nomenclature a bit, and split experiment into two parts…. OB gene Normal: OB-L (lean) Mutant 1: OB-F (fat) Wild-type OB-L/OB-L Normal weight (lean) Heterozygote OB-L/OB-F Normal weight Homozygous OB-F/OB-F Lethargic; eats way too much Consider heterozygote result. This implies lean is dominant. In other words, there must be a ‘lean’ gene product. If you don’t have it, you are fat. If there is a gene product that determines ‘lean’, is it a hormone? Make parabiotic mice: OB-L/OB-L OB-F/OB-F Implies the OB-L mouse of the pair Less food Normal makes something intake than food that moves in expected for intake blood to OB-F the fat mouse and phenotype reduces food intake… …and moreover, that OB-F mice have the necessary receptor. OB gene OB-L/OB-L Stops eating & dies of starvation Normal: OB-L Mutant 2: OB-D (diabetic) OB-D/OB-D Eats normally OB-F/OB-F Stops eating & dies of starvation Diabetic mouse causes wt or fat mouse to stop eating OB-D/OB-D Eats normally Interpretation: Both the wt and fat mice have the receptor for the lean gene product, but the diabetic mice don’t. The diabetic mice do make the gene product, but not the receptor for it! The diabetic mouse keeps eating (no lean receptor), but does not gain weight: diabetes => cells don’t take up glucose. Despite high blood sugar levels cells are still malnourished. The ever-eating diabetic mouse makes more and more lean hormone, but does not know it. The parabiotic fat or wt mice do have the receptor, and get the high levels of the gene product from the OB-D parabiotic buddy. This shuts down appetite in the OB-F or OB-L mouse. The previous examples (Epi, ACTH) showed a hormone system that responded to an external variable: acute or chronic stress detected by the nervous system. The n.s. then controlled the endocrine system. Internal variables are also detected and controlled by the endocrine system: the previous example of pancreatic islet cells. Here is another example of internal variable control… Endocrine cells of the thyroid & parathyroid are both signal detectors and set point comparators. Parathyroids parathormone (PTH), a peptide. osteoblast cells in bone marrow cytokines osteoclast cells resorb/demineralize bone incr. blood Ca2+. Cells of distal renal tubule incr. absorption of Ca2+ from gut incr. blood Ca2+. Other effects on phosphate metabolism, biosynthesis of “vitamin” D incr. gut absorption of Ca2+. Thyroid gland produces thyroxine… but embedded in thyroid are “C” for clear cells or parafollicular cells. C cells produce calcitonin (CT), a peptide hormone. So thyroid is two glands in one! Calcitonin satiety signal. Stop eating… too much calcium in blood. Vitamin D3 = cholecalciferol. A steroid-like hormone. U.V. light ------ skin -----7-dehydrocholesterol ------ skin -----Vitamin D3 Cholecalciferol-Binding protein blood 25-hydroxyvitamin D3 liver Absence of sunlight (e.g. Forks, WA) No absorption of calcium from gut Bone demineralization (Too much 25-OH-D3: Ca2+ feedback via PTH conversion to 25-(OH)2-D3 (inactive)) Hormones that control hormones The anterior and posterior pituitary each produce a number of hormones that stimulate other endocrine tissues. The release mechanism is slightly different for the two glands. Note that these neurons have long axons that project all the way to the posterior pituitary. More on oxytocin later. Here a portal blood system is used instead of long axons. Like cortisol Hypothalamic hormones are all “releasing hormones” All are peptides, and released in spurts. (Replacement therapy also has to be in spurts!) 4 major releasing hormones, cause anterior pituitary to secrete 6 “controlling” hormones… 4 1. Thyrotropin releasing hormone (TRH) (tripeptide: Glu-His-Pro) Thyroid stimulating hormone (TSH) prolactin: mammary growth, lactation (there may be a role in males) 2. Gonadotropin releasing hormone (GnRH) (10 aa) Follicle stimulating hormone (FSH) Luteinizing hormone (LH) Release starts at the onset of puberty, and for the rest of life in spurts every 1-2 hours. Secreted in both males and females. GnRH agonists used to treat prostate cancer: High persistent level of agonist reduction in GnRH receptors in pituitary reduced FSH, LH reduced testosterone less stim of prostate. 3. Growth Hormone Releasing Hormone (GHRH) (mixture of 2 similar 40 amino acid peptides) growth hormone 4. Corticotropin Releasing Hormone (CRH) (41 amino acid peptide) adrenocorticotropic hormone (ACTH) (ACTH adrenal cortex cortisol) Interesting: dramatic circadian rhythm in ACTH production. … but only in individuals with regular sleep habits! • Sharp increase 3-5 hours after sleep • Increase reaches max 1 hour after awakening • Minimum level 3 hours before sleep This cycle cannot be synchronized by external light. Oxytocin Widespread neuropeptide, found in all vertebrates -- modulation of neuro-endocrine reflexes -- affects social/bonding behaviors, care of offspring -- species differences in use Steroid regulation of oxytocin Human Oxytocin Receptor G-protein coupled receptor (GPCR) phospholipase C … Oxytocin (OT) uterine contractions Progesterone uterine quiescence Progesterone may bind directly to the OT receptor, but good evidence that it also blocks intracellular signaling of OT GPCR. So 2 hormones balance physiological processes. At end of pregnancy, uterus up-regulates OT receptor mRNA. So no increase in OT production, but increase in sensitivity to OT. OT release in the CNS is independent of OT release in the general circulation because OT does not cross the bloodbrain barrier. Brain release behavior changes In rats – lordosis (female), penile erection (males) is facilitated by brain neuron release of OT. In general, parental care, pair bonding, mate guarding & territorial aggression have been linked to OT. Studied extensively in Prairie Voles. (see article by Gimpl & Fahrenholz pg 665-666 for more info) Humans – mixed CNS/peripheral effects post-partum: After birth, suckling tactile receptors spinal cord oxytocinergic neurons of the hypothalamus. Hypothalamic OT neurons: 3-4 second bursts of APs Huge OT release to blood contraction of myoepithelial cells in the walls of lactiferous ducts… “let-down” response occurs ½ - 1 min after tactile stimulation. Acoustic stimuli (crying baby sounds!) also activate hypothalamic neurons. Hormones used by the meat and dairy industries Six steroids approved by FDA: estradiol, progesterone, testosterone, zeranol, trenbolone acetate, and melengestrol acetate. Zeranol, trenbolone acetate and melengesterol acetate are synthetic growth promoters (hormone-like chemicals that can make animals grow faster). Currently, federal regulations allow these hormones to be used on growing cattle and sheep, but not on poultry. (They are not so effective on birds) The synthetic hormone rbGH used to increase milk production in dairy cattle; not used on beef cattle. Some key points from this chapter • Animals use at least six major types of chemical signals. Hormones are chemical signals that are present in tiny concentrations and travel throughout the body to affect target cells. • The information in hormonal signals helps animals respond to environmental change, develop as embryos, undergo sexual maturation, and achieve homeostasis. • The information in hormonal signals helps animals respond to environmental change, develop as embryos, undergo sexual maturation, and achieve homeostasis. • The production of a hormone is tightly regulated by input from the nervous system and by other hormones.