Endocrine System PDF

## PART III ENDOCRINE SYSTEM ### Chapter 1. INTRODUCTION Endocrine system cooperates with nervous system and immune system to maintain body homeostasis. Endocrine glands are also named glands with "internal secretion". The notion of internal secretion was introduced by the famous physiologist Clau...

## PART III ENDOCRINE SYSTEM ### Chapter 1. INTRODUCTION Endocrine system cooperates with nervous system and immune system to maintain body homeostasis. Endocrine glands are also named glands with "internal secretion". The notion of internal secretion was introduced by the famous physiologist Claude Bernard to identify the substances which are released in the internal environment (blood, lymph). But, because there are many other substances which are also released into the blood without being hormones (lactic acid, CO2), Bayliss and Starling introduced the term of hormone to designate a stimulatory substance. ### HORMON Today, the term of hormon represents a chemical messengers secreted by specialized cells which can be or not organized in glands. A hormon is released in small quantities, acts on target cells where exhibits physiological, metabolic, behavioral and morphological effects. It is very important to emphasize that hormones regulate fundamental biochemical reactions, but they do not initiate new processes. They do not invent other mechanisms and they are not structural or energetical substances. Many organs have an endocrine secretion: brain and heart release ANP (atrial natriuretic peptide), kidney is involved in calcitriol synthesis, liver synthesize somatomedines, skin produces calciferol and the digestive tube secretes more than 200 hormones (gastin, CCK, secretin etc.). The internal secretion is represented by the endocrine secretion (including endocrine glands, APUD - amine precursors uptake decarboxilation-), paracrine and autocrine secretions and neurosecretion, consisting in the internal secretion of certain neurons, localized or organized in diffuse networks. It is possible that the same substance plays a dual role i.e. CCK: it acts as hormone in the digestive tube, but it is neurotransmitter in the central nervous system (CNS), limbic system. The type of hormonal action can be: - **Autocrine** – when a cell release a substance which regulates itself with a special form, Intracrine control – when a substance located inside the cell regulates structures inside the same cell (the substance is not released out of the cell) - **Paracrine**- when a cell release a substance which regulates the neighbour cells - **Endocrine** - when a cell release a substance into the blood and it is carried by the blood stream to regulate a target cell, at distance. ### CLASSIFICATION OF THE HORMONES 1. Depending on their structure (chemical composition), hormones can be: - **A. Proteic hormones**: Proteic or glycoproteic, Peptidic hormones - **B. Derived from aminoacids**: Phenol or indol ring - **C. Lipidic hormones**: Sterolic ring (steroid hormones) 2. Depending on target organs: - **A. with target organs**: Tirotropin, TSH - **B. with diffuse action**: Growth hormon, GH, insulin ### A. Proteic hormones Are water soluble, circulates in a free form in plasma (unbound by plasma protein), have different sizes of molecule. The great majority are synthesized as precursors: **PRE PRO HORMON → PRO HORMON → HORMON (active form)** The preprohormon is cleaved into prehormon at Golgi apparatus resulting prohormon. Enzymes from the endoplasmic reticulum, transform the prohormon into hormone. The last one is packed in vesicles and released by exocytosis. In some cases, from one precursor, many hormones can result, i.e. Proopiomelanocortin (POMC) derivatives: - POMC (proopiomelanocortin)- 239 aa. - Promelanocortin – 148 aa - BLPH-Lipotropin 91 aa - y lipotropin - Bendor - y MSH - 12 aa - ACTH-39 aa. - B MSH - aendorphin -α MSH - CLIP - corticotropin like intermediat lob peptide - Metenkephalin - Leuenkephalin Following synthesis they are secreted by exocytosis. The proteic and peptidic hormones are macromolecules so they can act as antigens generating in some cases immune reactions. The antibodies against these hormones can be synthesized, producing autoimmune endocrine diseases (i.e antiinsulinic autoantibodies lead to immune diabetes). ### B.Amine derived hormones - Catecholamines and thyroid hormones are derived from tyrosin. They are synthesizes by cromafin cells (cathecolamines) and by follicular cells (tyropid hormones). ### C.Steroid hormones Are derived from cholesterol and include androgenes, estrogenes, progesteron, glucocorticoids, mineralocorticoids. There is a group of modified steroids - secosteroids - D vitamins group also derived from cholesterol. The steroid hormones are fat soluble and they are released by diffusion into the blood flow. ## HORMON RECEPTORS All hormones interact with specific receptors; the receptor is represented by a specific molecule which recognizes hormon, with high affinity for it transduces the information into a cellular response. The number of exposed receptors is variable, depending not only by hormon concentration, but by other factors. The excess of hormon induces down regulation (the reduction of receptors density). In downregulation, the decrease of hormone binding and hormone response depends on hormone concentration and duration of treatment and is reversible. The mechanisms for receptor desensitization or downregulation include: - Internalization or compartmentalization of the receptor - Enhanced receptor degradation - Decreased receptor synthesis - Uncoupling of the receptor from effector system protein - Decrease in activities downstream from effector systems - The lack of hormon induces up regulation ( the increasing of receptors density). The mechanisms for receptor upregulation include: - Activation of protein kinase may - Some hormones act as positive regulators of their own receptors ( prolactin - Hormones act as positive regulators of receptors for other hormones (thyroid hormones upregulate the receptors for cathecolamines). Depending on their location, receptors are: 1. Membrane receptors (for proteic, peptidic hormones, cathecolamins) 2. Cytoplasmic receptors (for steroid hormones, they act as an intracellular transporter) 3. Nuclear receptors (for thyroid and steroid hormones) The fat soluble hormones enter the cell and finally act on nuclear receptors, stimulating the transcription of DNA, synthesis of ARNm, and proteins. Instead, water soluble hormones cannot enter the cell and bind surface receptors. Steroid hormones pass through cell membrane and bind cytoplasmic receptors. The hormone-receptor complex migrate to nucleus where acts on nuclear receptors. In the absence of hormone, steroid receptors are known to exist in heteromeric complexes containing multiple proteins, including heat shock protein (Hsp). The steroid hormone bind receptor, releases Hsp and activates DNA transcription and RNA translation to ribosomes. The final step consists in the synthesis of specific proteins with certain physiological roles. ## SECOND MESSENGERS After the interaction with receptor, a secondary messenger system is activated. - **The cAMP system are**: - ACTH, FSH, LH, TSH, MSH, Ang II, ADH ( acting on V2 receptorors) - **Hormones which activate the calcium – phosphoinositol system ( Ca-PIP) are**: - ADH (acting on V1 receptors ), angiotensin II, catecholamines (alpha-receptors), -gonadotrophin releasing hormone GnRH), growth hormone releasing hormone – GHRH, oxytocin, thyroid-releasing hormone - TRH. - **Hormon which activates enzyme linked receptors**: In this case, receptors function directly as enzymes or are associated with enzymes. For instance, the leptin receptor activates many intracellular kinases: JAK2 (jun activayed kinase), MAPK (mitogen-activated protein kinases) and PI3K (phosphatidylinositol 3-kinase), each of these inducing different, specific responses. - **For other hormones, the mechanism of action was not clarified yet**: insulin, IGF 1,2 (somatomedines), GH. **The adenilat cyclase - CAMP system** The hormon interaction with receptor induces an activator or an inhibitory response. Receptors are coupled with a G protein (GTP-binding proteins). It presents different subdomains Gs /Gi which modify the GTP intracellular concentration. As result of the interaction hormone-receptor, the a subunit of the G-protein binds to GTP and separates from the ẞ subunit. The a subunit-GTP complex activates an specific effector protein, depending on the kind of a subunit. In case the a subunit is Gs, it activates adenylate cyclase, increasing the production of cAMP. If the hormone-receptor complex interacts with a Gaq/11 kind of G protein, then the activated enzyme is phospholipase C as it will be presented. Some hormones are coupled to inhibitory G proteins (Gi proteins), whereas others are coupled to stimulatory G proteins (Gs proteins). A hormone can either increase or decrease the activity of intracellular enzymes, depending on the coupling of a hormone receptor to an inhibitory or stimulatory C protein. The intracellular increasing of the AMPc increases protein synthesis, secretion, modifies the membrane permeability or increases the muscle contraction/relaxation. The AMPC synthesis is inhibited by the phosphodiesterase. **Adenyl cyclase - cyclic AMP system** **The phosphatidyl inositol - system** Phospholipase C catalyzes the hydrolysis of phosphatidyl inositol 4,5 biphosphate that is forming part of the plasma membrane. The action of the enzyme on this substrate produces IP3 (inositol triphosphate) and Ca diacylglycerol. IP3 difuses into the cytosol and binds to its receptor in the sarcoplasmic reticulum and opens a calcium channel. Diacylglycerol remains close to the membrane and, with the participation of Ca2+ released by IP3, activates protein kinase C, that phosphorylates other proteins, modifying its function. Ca²+ binds to calmodulin, troponin C and other Ca2+ binding proteins generating activation of some enzymes, actin myosine interaction, promotes exocytosis, synthesis of NO, and other effects. **The PIP2 - Ca 2+ system** **TRANSPORT OF HORMONES** The transport of the hormones to the target tissues is done by the blood stream, less by lymph; there are two forms of hormon: the main fraction is bound with specific transport proteins (albumins, TBG-thyroid binding globulin, CBG-cortisol binding globulin, etc.) and the free form, which is less representative as quantity but exerts the active roles of the hormones. The free form originates from the bound one and presents some advantages: is more active and has a rapid acces to target tissues. Bound form represents a physiological storage with adapted releasing to body neccesities. It provides a gradual distribution of hormones. A dynamic equilibrium between the free and the bound form exists. | CHARACTERISTICS | PEPTIDIC HORMONES | STEROID HORMONES | AMINE HORMONES | TYROID HORMONES | | -------- | -------- | -------- | -------- | -------- | | SOLUBILITY | Water soluble | Fat soluble | Water soluble | Fat soluble | | PLASMA PROTEIN BOUNDING | Low | High | Low | High | | T1/2 | Minutes | Hours | Seconds | Days | | RECEPTORS | Membrane | Nucleus | Membrane | Nucleus | | MECHANISM ACTION | ↑AMPC | ARNm | ↑AMPC | ARNm | ## METABOLIZATION AND ELIMINATION OF HORMONES Peptidic hormones are inactivated intracellular by phagocytosis of extracellular enzyme hydrolysis. The aminoacid derived hormones (cathecolamines) are metabolized by oxidation, using monoaminoxidase (MAO), and cathecol -O-methyl transferase (COMT). Steroid hormones are inactivated by dehydrogenation and conjugation. Elimination of hormones takes place by metabolic processes such as the inactiviation of peptide hormones by proteolytic enzymes, or the transformation of hormones in the liver. Hormones are also eliminated by excretion in the urine or bile. In the liver hormones are coupled to glucuronic acid or sulphate, and are reabsorbed in the entero-hepatic-circuit ## MECHANISMS OF HORMON SECRETION REGULATION 1. Chronotropic control 2. Nervous control 3. Feed back mechanism 4. Receptor regulation 5. Activation/inactivation regulation **1. Chronotropic control** Biorhythms - rhythmical modulation of a biological activity may be exogenous (circadian rhythm) or endogenous, controled by a biological "clock". The endocrine secretion is influenced both by endogenous neuronal rhythmicity and diurnal rhythms, circadian rhythms (growth hormone and cortisol), sleep-wake cycle and seasonal rhythm. The most important episode of release occur with a frequency of about one hour - referred to as circhoral. An episode of release longer than an hour, but less than 24 hours, the rhythm is referred to as ultradian. If the periodicity is approximately 24 hours, the rhythm is referred to as circadian usually referred to as diurnal because the increase in secretory activity happens at a defined period of the day. It is controlled by the suprachiasmatic nucleus (SCN) which acts as a biological clock (diurnal clock). SCN neurons are spontaneously active circadian oscillator even when deprived of the afferent signals. These neurons work in conjunction with the pineal gland, a midline brain structure near the third ventricle, which secretes melatonin and assists in the synchronization of diurnal rhythms with a 24-hour day/night cycle. The ablation of the SCN results in a loss of rest-activity rhythm, and disturbances of the estrus cycle and reproductive capacity. Secretory episodes occur with different periodicity and in some cases, in pulses. There are different patterns of pulsatile secretion: at each 1hour for GnRH or at each 5hours for GH-RH. The importance of pulsation was demonstrated by GnRH infusion for fertility treatment: if given once hourly, gonadotropin secretion and gonadal function are maintained normally. A slower frequency cannot mantain gonad function. A faster or continuous infusion inhibits gonadotropin secretion and blocks gonadal steroid production. Long-acting GnRH analogs have been applied to the treatment of precocious puberty, to manipulate reproductive cycles (used for in vitro fertilization), for the treatment of endometriosis, etc. Daily biorhythm influences cortisol/ACTH axis – the maximal secretion occurs early in the morning. The complying to biorhythms is useful for drug/hormones administration, efficacy establishing, and reducing of the number and intensity of the adverse events. **2. Nervous control** The magno- and parvocellular cell groups producing the hypothalamic hormones receive a variety of stimuli from different parts of the brain, primarily within the hypothalamus, but also from extrahypothalamic areas including the amygdaloid body, hippocampus and various brainstem areas. Neural input to hypothalamus (parvicellular and magnocellular neurosecretory cells) stimulates synthesis and secretion of releasing factors which stimulate pituitary hormone production and release. This control is also exerted by monoaminergic neurons with cell bodies in the mesencephalon and lower brainstem that secrete biogenic amines. Norepinephrine, dopamine, and serotonin control the secretion of hormones from the parvicellular neurons. Acetylcholine (Ach) stimulates while norepinephrine inhibits the release of hormones from the magncellular neurosecretory neurons. The subject of neuroendocrine control mechanism is complicated further by the fact that many neurons in the nervous system, including the hypothalamic magnocellular and parvocellular neurosecretory neurons, contain two or many neuroactive substances. **3. Feedback control** The history of this notion begins in 1927, when H.S. Black described a cybernetic term to design a system which maintain constant a parameter. Norbert Wiener introduced the term in biology in 1946 (Wiener, N., Cybernetics: or Control and Communication in the Animal and the Machine, Cambridge: MIT Press, 1948). An endocrine feedback system is a system whereby the first hormone controls the secretion and liberation of the second (fig. III.1.5). The second hormone acts by feedback to modulate the secretion of the first. Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion. Negative feedback is regulatory mechanism, is self limiting and has the role ro mantain the concentration of a given hormon between some limits. Instead, the positive feedback is rare, is an exception in human body acts as an amplification, a self reinforcing spiral leading to a continuously increase of a hormon concentration. When this concentration reaches a peak corresponding with a point of no return, a biological phenomenon takes place (ovulation due to LH estrogens relation, birth initiation and continuation due to oxytocin ). Non hormonal feedback or substrate -hormone control explain the relation between a plasma compound (Ca, glucose) and the secretion of a certain hormon **4. Hormonal receptor regulation** When plasma concentration of a hormon raises, the number of exposed receptor on target cell surface decreases. This relation is named down regulation. For example, a large concentration of insulin causes the recipient cells to be fully stimulated. Consequently, they down-regulate their insulin receptor population to bring the response into the normal range. The reducing the total number of receptors reduces the number of occupied receptors and the amplitude of hormonal response. When plasma concentration of a hormon decreases, target cell exposes more many receptors to keep constant the amount of hormon which acts on that cell. This is up regulation. The magnitude of hormon effect mainly depends on the number of receptor molecules, the hormone concentration, the affinity of the receptor for the hormone, duration of exposure, intracellular conditions (second messenger systems), synergistic or antagonistic modulators. The biochemical responsiveness of a cell to a hormone (or a drug, or a neurotransmitter) depends on the number of occupied receptors on the responsive cell. ## METHODS OF INVESTIGATION IN ENDOCRINOLOGY A. The imagistic evaluation includes X ray plains, computerised tomography ans MRI. B. The functional tests includes hormones dossage at rest or during different stimulatory or inhibitory tests. The functional tests are useful ussually in hypofunctions (GH, gonadotropins, ACTH, TSH dossage) or in hyperfunction syndromes (acromegaly, Basedow Graces disease, Cushing's syndrome). Radioimmunoassay RIA was first used to detect hepatitis virus in plasma and then was adopted by endocrinology. New techniques such as immunometric assays and chromatography/mass spectroscopy can now detect molecules with very low concentrations; there were developed new, sensitive radioimmunoassays of high specificity for most peptides, thyroid and steroid hormones. These techniques had equally importance on endocrine research and clinical, applied endocrinology. ## FOCUS ON PHYSIOLOGY Cloning of the genes that express peptide hormones create the possibility to obtain hormones by recombinant DNA technique, an extremely important laboratory technology. Using this techniques, large amounts of hormones can be provided for those diseases which neccesit long term hormonal treatment (it is impossible to extract enough human growth hormone from pituitaries to supply clinical neccessities). Many hormones are now being produced by this technology. New hormones (leptin, orexin) have been identified by positional and/or functional gene cloning of the genes that encode peptide hormones made it possible to produce hormones by recombinant DNA technology. ## CLINICAL APPLICATIONS OF THE The last century consisted of great achievments for medical practice which dramatically improved the quality of human life. Important steps in this clinical evolution are represented by: - 1889 - Brown-Séquard reported that self-administration of aqueous extracts of animal testes had enhanced his physical strength, improved his intellectual capacity, and increased his sexual potency. - 1891 - Murray administered thyroid extract to a woman with myxoedema. - 1894 - Oliver and Schäfer described epinephrine in extracts of the adrenal medulla. - 1903- Bayliss and Starling discovered secretin, and Starling chose the term hormone to describe all chemical messengers. - 1910-Bouin and Ancel deduced the role of the Leydig cells in development of the male phenotype; - 1915 - MacCallum and Voetlin discovered the link between the parathyroid glands and calcium metabolism; - 1918 - Farmi and von den Velden treated diabetes insipidus with posterior pituitary extracts; - 1920 - Evans and Long described growth hormone; - 1922 – Paulescu, followed by Banting and Best discovered insulin. These important changes in the field are due to the large application of advances from other fields: neuroscience, immunology, cell and molecular biology, physics, chemistry, genetics, and cybernetics. Hormones are now discovered, synthesized, measured and investigated in new ways. Two of the very important therapeutic advances are scientifically designed therapies for diabetes- insulin treatment and birth control methods, using oral contraceptives. **References** 1. Parker P, Pawson T. Cell Signalling. 1996. Plainview, NY, USA: Cold Spring Harbor Laboratory Press. 2. Argetsinger LS, Carter-Su C. Mechanism of signaling by growth hormone receptor. Physiol Rev. 1996;76:1089-1107 3. Barrington EJW Hormones and Evolution. London, 1964. UK: English Universities Press. 4. Brivanlou AH, Darnell JE Jr Signal transduction and the control of gene expression. Science 2002. 295: 813-818 5. Evans R. A transcriptional basis for physiology. 2004. Nat Med 10: 1022-1026 6. Dimitrov S, Lange T, Fehm HL, Born J. A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines. Brain Behav Immun. 2004;18:368-374