Endocrinology Lecture 17 PDF

Overview of endocrinology What do we want from a hormone system A simple control system- Calcium control The neuroendocrine system- The hypothalamus and pituitary Posterior pituitary hormones Anterior pituitary hormones Complex control loops  Learning Outcomes Thi...

Overview of endocrinology What do we want from a hormone system A simple control system- Calcium control The neuroendocrine system- The hypothalamus and pituitary Posterior pituitary hormones Anterior pituitary hormones Complex control loops  Learning Outcomes This Lecture Requirements of an endocrine system Main forms of hormones Measuring hormone activity and how it is controlled Examples of simple feedback systems Single hormones and Paired hormones Endocrine System John Romulus Brinkley “Hormone- Greek to excite” Signalling molecule released into blood (or lymph) to be carried to its target(s) often far removed Active at very low concentrations  Endocrine System The endocrine system along with the parasympathetic and sympathetic nervous systems are the main regulators for homeostasis Manipulating the endocrine system (or intracellular signalling pathways it regulates) is one of the main routes of pharmacological intervention.  Angiotensin II Receptor Inhibitors ACE Inhibitors Reduces blood pressure ALDOSTERONE INHIBITORS RENIN INHIBITORS Reduced Blood Pressure ADH INHIBITORS  Endocrine System What do we want from a hormonal system? Specificity of receptor for the hormone Receptors expressed only on defined (reacting) cells Very high affinity of the hormone for its receptor (Kds – 1x10-12 M) - hormone concentrations as low as pg/ml Integrated amplification system Protected transfer system (many hormones transferred bound to a carrier proteins eg albumin especially if hydrophobic) H-CPrH+CPr (only free hormone binds to its receptor- CPr= carrier protein) OVERALL EFFECIVENESS DEPENDS ON CONCENTRATION OF FREE HORMONE NUMBER OF RECPTORS PRESENT ON CELL AFFINITY OF HORMONE FOR RECEPTOR EFFICIENCY OF AMPLIFICATION STOPPING SIGNALLING  Three main hormone families Amine-derived hormones from tyrosine and tryptophan. Eg, thyroxine and catecholamines. Peptide hormones Small peptide hormones (TRH and ADH/vasopressin). Protein hormones (insulin and growth hormone). Glycoprotein hormones. (Luteinizing hormone, thyroid-stimulating hormone). Lipid and phospholipid hormones, Eicosanoids (prostaglandins , prostacyclines , thromboxanes or leuktreins) Steroid hormones derived from cholesterol (eg testosterone and cortisol). Calcitriol (Vit D) is a sterol derived hormone. A tissue becomes a target for a hormone by expressing a specific receptor for it. Hormones circulate in the blood stream but only cells with receptors for it are targets for its action. H R HR Hormone--receptor interaction is in part defined by the Kd, or dissociation constant. H R HR Most hormone- receptor reactions are 1:1 reactions If it is 1:1 we can measure this ratio 𝐻 𝑅 [𝐻𝑅] The stronger the interaction ie the more in the HR state, the smaller the ratio of free to bound receptors bound What is the Kd Scatchard Plot hormone 50% Hormone hormone 𝐻 𝑅 Kd is the concentration of hormone such than 𝐾𝑑 = [𝐻𝑅] half of all receptors are bound [R]=[HR] The interaction of receptor and hormone is reversible, and the ease of separation Kd is a measure of its affinity. Hormone receptor interactions are very specific and the Kd ranges from 10-9 to 10-12 Molar (ie high affinity cf Integrin – Fibronectin binding Kd 10-6M) Maximal biological response is achieved at concentrations of hormone far lower than required to occupy all the receptors on the cell (Bmax) or even 50% (the Kd) due to amplification of signal occurs within responding cells Eg. Insulin maximum effect in adipocytes with only 2-3% of receptors bound LH maximum effect in Leydig cells (testosterone production) with 1% of receptors bound The concentration of hormone needed for maximal response indicates of the sensitivity of the system. the limiting step is hormone binding as the amplification steps are very efficient: (driven by second messengers or phosphorylation cascades) Second messenger systems include: Adenylate cyclase /cyclic AMP; Guanylate cyclase /cyclic GMP; Calcium and calmodulin; Phospholipase C catalyzing phosphoinositide turnover; Phosphorylation cascades NO The concentration of hormone seen by target cells is determined by three factors: 1. Rate of release: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Controlled by positive and negative feedback loops. 2. Rate of delivery: the blood flow from the endocrine organs to a target organ or group of target cells - high blood flow delivers more hormone than low. Carriers? 3. Rate of degradation and elimination: Hormones, have characteristic rates of decay, (metabolized and excreted). Shutting off secretion of a hormone with a short half-life causes circulating hormone concentrations to drop rapidly, but if a hormone's biological half-life is long, effective concentrations persist after secretion ceases. Carriers? Finally - remember a hormones effect is longer lasting than merely hormone receptor interaction time, how is the signalling terminated  How can we measure levels of Hormones Radio-Immune Assay ELISA Here the hormone is the antigen Here the hormone is the target protein Competition Amount radioactivity precipitated reduces relative to Competitor Eg hormone Sensitivities to 1x10-12M Radioactivity Sensitivities to 1x10-14M Increasing Concentration of added hormone (antigen) 10−1 d Deci 10−2 C Centi 10−3 m Milli 10−6 µ Micro 10−9 n Nano 10−12 P Pico 10−15 F Femto 10−18 a Atto 10−21 Z Zepto 10−24 yv Yocto 0.000000000000001M !  Endocrine System- Questions to ask- CHECK CHARLIE’S SLIDE 1/ Where are the receptors for hormones sitting on the cell? Hydrophilic hormones Cell surface transmembrane receptors Ion Channel linked receptors* Enzyme receptors Must have Tyrosine kinases Secondary G protein-linked receptors messengers Hydrophobic hormones Cytoplasmic receptors Don’t need secondary messengers NB these are mainly paracrine/synaptic not endocrine*eg Nicotinic acetyl choline receptor  Questions to ask- Endocrine System- 2/ where secreted from? Primary endocrine organs: main function is to secrete hormone(s) Secondary endocrine organs: secrete hormones as a secondary function Muscle - Musclin Adipocytes – Leptin Thymus- Thymosine Bone-Osteocalcin Islets in Endocrine Secretions From- Classically endocrine (ductless) glands derived from epithelia But also from neurones (neurohormones) and isolated cells (diffuse endocrine cells- intestine) Cells with other primary roles not always epithelial in origin (muscle, fat, bone) (immune cells –cytokines not considered hormones) Endocrine System- Questions to ask- 3/ How is secretion controlled Gland monitors and responds to concentration of A (2) Substance A changes Concentration (1) Typical simple Hormone released (3) feedback Ty loop Controlling “A” Target cells have receptor and respond and releasing or absorbing A (4)  Endocrine System Control pathways for Hormones Many are in very simple reflex pathways- ie cells monitor A, when A drops (rises) these cells release a hormone which signals to cells elsewhere to modify the production or uptake (or loss or breakdown) of A. Eg Intestinal hormones Secretin, Gastrin, CCK Slightly more complex paired hormones pathways Insulin and glucagon regulate blood sugar. Generally, for more important controls Insulin, Glucagon α/ß CELLS MONITOR GLUCOSE LEVELS ß cells Insulin α cells Muscle and liver(fat) cells glucagon take up glucose (lipids)from blood  Regulation of blood Ca2+ levels Parathyroid and Calcitonin act antagonistically Linked negative feedback cycles give fine control Normal Ca2+ levels Adults-2.25–2.75 mmol/L Correct extracellular Ca2+ are important C cells Parathyroid cells Endocrine System- Questions to ask 4- Which cells have the receptors Endocrine System Low plasma Ca2+ Some of the loops are a bit more complex - Increased plasma Ca2+ http://arthritis-research.com/content/figures/ar2110-1.jpg Parathyroid Cells $ Bones- activates osteocytes (fast) osteoclasts (slow) Parathyroid Hormone Kidney- increases Ca2+ uptake in late distal tubule Reduces secretion of Ca2+ Skin (light) Liver Kidney in intestine 2+ Vit D3 --> 25-OH cholecalciferol --> 1,25-DiOH cholecalciferol --> Increases Ca absorption in kidney and gut Increase parathyroid hormone’s effects on osteoclasts Endocrine System- Questions to ask 5- What happens if too much / little hormone present http://upload.wikimedia.org/wikipedia/commons/thumb/1/17/Parathyroid_adenoma_low_mag.jpg/230px-Parathyroid_adenoma_low_mag.jpg Hyperparathyroidism Hypoparathyroidism Primary- tumour of parathyroid (gives high serum Ca2+) Autoimmune disease Moans Iatrogenic Stones (Low serum Ca2+) Groans Bones Secondary- Caused by Renal failure ->loss of Ca 2+ kidney, low serum Ca causes increased parathyroid activity  So why is regulating serum Calcium so important…. Hypocalcaemia– loss of Ca2+ions in the milk due to the high lactation is so great that the blood plasma levels of Ca2+ drops – the parathyroid is unable to meet the metabolic demand IV Calcium Drip……  Questions to ask about any hormone Where is it formed? What is it’s structure? How is it’s release regulated? Where are it’s receptors – cell type and in cell? What pathways does it induce? What is its effect? What happens if there is more or less of the hormone –and why these may occur?