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ENDOCRINOLOGY GENERAL PHYSIOLOGY OF HORMONES HORMONAL FEEDBACK REGULATION OF HORMONE SECRETION Jana Jurcovicova ORGANIZATION OF THE ENDOCRINE SYSTEM Evolution of multicellular organisms demanded coordinating systems to regulate and integrate the function of the different cells. Three basic regulatory systems developed: 1 – THE NERVOUS SYSTEM (elctrochemical signals) 2 – THE ENDOCRINE SYSTEM (chemical agents, affect target organs) 3 – THE IMMUNE SYSTEM (interleukins regulating host defense) These 3 systems are closely interrelated: 1 – 2 NEURO-ENDOCRINE REGULATION (hypothalamo-pituitary reg.) 2 – 3 IMMUNO-ENDOCRINE REGULATION 1 – 2 – 3 IMUNO-NEURO-ENDOCRINE REGULATION HORMON - TO STIMMULATE TO THE ACTION classical definition of hormone by Baylis and Stariling (1902) Hormone is produced by an organ in small amounts, released into the blood stream, and transported to a distal organ to exert action. Nowadays this definition does not apply to all hormones: Paracrine - action on contiguous cells Autocrine – action on the same cell OUT-OF-DATE FACTS OF CLASSICAL ENDOCRINOLOGY not true (paracrine, Hormones act distally autocrine actions Hormones are produced only in specialized glands not true (fat tissue, immune cells etc.) One hormone – one function not true (leptin, estrogens, prolactin cortisol, etc. FUNCTION OF HORMONES Regardless of their chemical nature hormones are present in the blood stream in very low concentration 10-7 – 10-12 M They bind to a very specific, high-affinity cellular receptors located at CELL MEMBRANES or in the NUCLEUS. Single hormone – various effects ( e.g. estradiol promotes granulosa cells prolif., stimulates mammary gland, promotes growth of linear bones and closure of epiphyseal plates. Various hormone – single function (e.g. growth hormone, glucocorticoids stimulate lipolysis Hormones exert their functions in four broad physiological areas: REPRODUCTION GROWTH AND DEVELOPMENT MAINTAINANCE OF INTERNAL ENVIRONMENT REGUPATION OF ENERGY BALANCE CLASSICAL ENDOCRINE GLANDS AND HORMONES The endocrine glands are located in different areas of the body that produce hormones with different functions. Major morphological feature - they are ductless, they release hormones directly into the blood stream, and not into the duct system. They are richly vascularized – efficient delivery of the secretory product into the blood circulation. Classical view of endocrine glands -small glands (weighing tens of grams) whose function is regulation, coordination of physiological processes such as reproduction, growth, metabolism, energy homeostasis CLASSICAL ENDOCRINE GLANDS AND THEIR HORMONES NON-CLASSICAL ENDOCRINE GLANDS AND HORMONES • Heart (atrial natriuretic hormone) • Gastrointestinal tract (cholecystokinin, gastrin, secretin, vasoactive intestinal peptide, somatostatin, incretins) • Stomach (ghrelin) • adipocytes (leptin, adiponectin, visfatin, resistin, angiotensin, interleukins, cortisol, catecholamins) • Kidney (erytropoetin) • Immune cells (interleukins, visfatin, prolactin, growth hormone, neuropeptides, opioids) • Tissues (growth factors) • Endotelial cells (endotelins) • Placenta (placental lactogen, growth factors) • Limbic system (neuropeptides interleukins) FAT TISSUE AS A NON-CLASSICAL ENDOCRINE ORGAN angiotensin dfdf dfdf Adipocytokines implicated in energy homeostasis, insulin sensitivity (IS),insulin resistance (IR) and atherothrombosis. Excessive production of interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), acylation-stimulating protein (ASP) deteriorates insulin action in muscle and/or in liver, whereas increased angiotensin (AGE) favours hypertension,endothelial dysfunction and thrombosis. The role of resistin on insulin resistanceis still not clear. Leptin regulates energy balance and exerts an insulin sensitizing effect. Adiponectin increases insulin action in muscle and liver an exerts an anti atherogenic effect. CHEMICAL NATURE OF HORMONES Steroid, the precursor is cholesterol: estranes, androstanes, pregnanes On the basis of tyrosine: thyroxine, triiodothyronine noradrenaline, adrenaline On the basis of tryptophane: melatonine Polypeptides and proteins: insulin, growth hormone, peptides - releasing hormones, other regulatory peptides TRANSPORT OF HORMONES Water soluble proteohormones and peptides are transported in blood in free form (short half life time - minutes) Lipophilic steroid hormones and hormones of the thyroid gland require specific transport proteins (TBG – Thyroxine Binding Globulin, - half life time 5 days, CBG – Corticosteroid BG – half life time = 90 minutes, SHBG Sex Hormone BG) MECHANISMS OF HORMONE ACTION Nuclear receptors : steroid hormones and thyreoid hormones Membrane receptors: Proteins, peptides, catecholamines Hormone - receptor binding - first messenger Intracellular signal - second messenger BIOSYNTHESIS OF STEROIDS cholesterol estranes pregnanes 18 atoms of C 21atoms of C androstanes 19 atoms of C three main groups of steroidal structures derived from cyclopentanoperhydrofenantren skeleton MECHANISM OF STEROID HORMONE SIGNALLING BIOSYNTHESIS OF THYROID HORMONES Guyton and Hall, 2006 MECHANISM OF THYROID HORMONE SIGNALLING 5´-DI 3,5,3´-T3 (deiodinase) T4 T4 RXR DNA mRNA N C SYNTHESIS OF PROTEO-HORMONES AND PEPTIDES BIOSYNTHESIS OF CATECHOLAMINES DOPAMINE ADRENALINE NORADRENALINE 3 HORMONE SECRETION – EXOCYTOSIS three stages of exocytosis Docking – Vesicles move to plasma membrane.This process requires the presence of actin filaments and ATP. Priming – ATP dependent process the granules move to space, modification of SNARE proteins. the subplasmatic Fusing – attachment of granule membrane to cell plasma membrane with the help of SNARE proteins Easom, 2000 HORMONE SECRETION – EXOCYTOSIS Three phases: 1-docking, 2-priming, 3-fusion docking priming SNARE (soluble N-etalmaleimide-sensitive factor attachment protein receptors) SNAP-25 (synaptosomal-associated protein 25) VAMP (vesicle-associated mebrane protein) NSF (N-etalmaleimide sensitive factor) α-SNAP adaptor protein PLASMA MEMBRANE PROTEINS OF HORMON-SENSITIVE ADENYLYL CYCLASE G-PROTEIN COUPPLED HORMONE RECEPTOR ACTIVATION ADENYLYL CYCLASE RECEPTOR SIGNALING Guyton and Hall, 2006 PHPSPHOLIPASE C RECEPTOR SIGNALING Guyton and Hall, 2006 UPREGULATION OF RECEPTORS time DOWNREGULATION OF RECEPTORS PATTERN OF HORMONE SECRETION The basal secretion of hormones is not continuous process, it has pulsatile character (minutes) When the hormone release is induced by a secretagogue, it has episodic nature Secretory episodes may appear with different periodicities ULTRADIAN - <1 hour< 24 hours CIRCADIAN – episode lasts about a day DIURNAL – episodes occur at defined periods of the day e.g ACTH CIRCANNUAL – SEASONAL – episodes occur in relation to the seasonal phases of the year DIURNAL CHANGES OF ACTH AND CORTISOL IN PLASMA ACTH in plasma cortisol in plasma [ cortisol ACTH 08 12 16 20 24 04 08 time of day HORMONE LEVELS - 8:00 a.m. , 8:00 p.m. morning evening . GH Cortisol ENDOCRINE GLANDS hypothalamus (TRH, GnRH, GHRH, SRIH, CRH, PrlIH-dopamine) pineal melatonin pituitary anterior lobe: TSH, GH, ACTH, FSH, LH, prolactin posterior lobe : oxytocin, AVP parathyreoid: PTH thyroid gland:T3 a T4, calcitonin) adrenal glands: aldosterone, cortisol, androgens adrenaline, noradrenaline, dopamine pancreas Insulin, glucagon, somatostatin ovaries estrogens, progesterone testis testosterone REGULATION OF HORMONE SECRETION Feedback regulation- closed loop system that is an essential feature of endocrine regulation Hypothalamo – adenopituitary- peripheral gland regulation TRH - TSH – thyroid gland CRH – ACTH – adrenal cortex GnRH – LH/FSH – ovaries/testes GHRH/Srif – GH - tissues PRH/PIF – PRL – tissue Paracrine / autocrine regulation CORTISOL FEEDBACK REGULATION Hypothal. CRH adenopit ACTH adrenal gland cortisol Peripheral tissue FEMALE SEX HORMONE FEEDBACK MECHANISMS ASSESSMENT OF ENDOCRINE FUNCTION First step - measurement of hormone levels In vivo – bioassay: Plasma extracts were injected to animals and biological response was quantified Radioimmunoassay- in the 70-ties of the last century Nobel prize for in vitro measurement hormone –andibody binding. IMMUNE – ENDOCRINE INTERACTIONS IN NORMAL AND PATHOLOGICAL STATE CORTISOL physiological suppressor of immune functions GROWTH HORONE , PROLACTIN – physiological activators of immune functions ENDOCRINE DISRUPTORS POLYCHLORINATED BIPHENYLS – PCB, toxic poluants of environment with long dissapearance rate (decades) – accumulate in nature, oceans, animals, soil Use in industry – production of plastics, transformers, capacitors, fillings of fire extinguishers, thinners of dyes They affect endocrine functions - gonads, thyroid gland Since early 90-ties they are named DISRUPTORS OF ENDOCRINE FUNCTIONS – ED Definition: Exogenous substances interfering with production, release, bindning, transport, metabolism, action, and elimination of natural hormones (Kavlock et al., 1996). About 90 % are accumulated in soil and recycle into food. They are lipophilic and are stored in fat tissue and are released into milk. CHEMICAL STRUCTURE OF SELECTED DISRUPTORS THYROXINE DIOXINES FURANES ACTIONS OF ENDOCRINE DISRUPTORS Reversible binding to specific molecules (receptors, transport proteins, enzymes) Irreversible binding to target molecules (DNA, proteins) Accumulation in fat tissue ACTIONS OF ENDOCRINE DISRUPTORS Carcinogenic effects In women a correlation between mammary carcinoma and amount of PCB in fat tissue was found Functions of sex organs PCB negatively affects growth and development and functions of sex organs in men and women. In young boys living near waste incinerator a correlation between decrease of sperm count and amount of PCB in blood was found. Function of thyroid gland In workers in PCB factory a correlation between enlarged thyroid gland and the amount of PCB in blood was found. NEGATIVE CORRELATION OF TESTOSTERONE IN BLOD AND CONCENTRATION OF HEXACHLORBENZENE IN LIPID FRACTION OF BLOOD IN YOUNG MEN TESTOSTERONE TESTOSTERONE TESTO STERÓ N (ng/ml) 16 14 12 10 8 6 4 2 0 0 1000 2000 3000 4000 5000 HCB IN BLOOD (ng/g lipidov) lipids) HCB V SÉRE (ng/g Langer et al, 2011 TRANSGENERATION TRANSFER OF PCB 5000 10000 4000 3000 2000 1000 0 0 MOTHERS 20 00 40 00 MOTHERS MOTHERS MATKY (ng/g) 60 00 ng/g ng/g CORRELATION OF PCB IN LIPID FRACTION OF BLOOD IN MOTHERS AND UMBILICAL CORD IN NEWBORNS 16 MES. DETI (ng/g) 16 mo infants 12000 PUPOČNÍK (ng/g) umbilical cord 6000 8000 6000 4000 2000 0 0 400 0 800 0 120 00 MOTHERS MATKY (ng/g) CORRELTION OF PCB IN LIPID FRACTION OF BLOOD IN MOTHERS AND BLOOD OF BREST FED INFANTS Langer et al, 2011