Hormones Overview (LSII 1 week 1 topic)

HORMONES INTRODUCTION Biomedical Importance The term „hormone“ is derived from Greek hormon, the present particle of impel, or set in motion, just it is characterization of these potent molecules. “Endocrine” is also derived from the Greek: endo- for internal or within and krinein meaning separat...

HORMONES INTRODUCTION Biomedical Importance The term „hormone“ is derived from Greek hormon, the present particle of impel, or set in motion, just it is characterization of these potent molecules. “Endocrine” is also derived from the Greek: endo- for internal or within and krinein meaning separate. This term conveys the distance of the site of secretion from the site of action that characterized the systems, such as the pancreas, the thyroid, and the reproductive glands that were studied in the early days of endocrinology. Diseases of endocrine system, which are due to the excessive or deficient production of hormones (horomone imbalance) are examples of the application of basic principles to clinical medicine for effective therapy. Biomedical Importance For the body to function properly, its various parts and organs must communicate with each other to ensure that a constant internal environment (i.e., homeostasis) is maintained. Two systems help ensure communication: the nervous system and the hormonal (i.e., neuroendocrine) system. The nervous system generally allows rapid transmission of information between different body regions. Conversely, hormonal communication, which relies on the production and release of hormones from various glands and on the transport of those hormones via the bloodstream, is better suited for situations that require more widespread and longer lasting regulatory actions. Thus, the two communication systems complement each other. Timeline of Events The study of endocrinology over the past century has been dependent upon the scientific methodologies available to probe the various endocrine systems. Thus, in the interval 1900–1960, endocrinology was largely pursued at the physiological level. This resulted in the discovery of approximately 25 hormones. For example, the complete structure of thyroxine (molecular weight 770) was defined in 1926, while the sequence and structure of the small protein hormone insulin was not obtained until 1953 (amino acid sequence) and 1969 (three-dimensional structure). The availability of radioactive isotopes of carbon (14C), hydrogen (3H), phosphorus (32P), among others, coupled with advances in chemical methodology (chromatography, mass spectrometry, nuclear magnetic resonance spectroscopy (NMR), and X-ray crystallography)  Cell Structure and Hormone Interplay In eukaryotes, the nucleus, containing the chromatin, and the cytoplasm are separated, except during interphase of mitosis. The nuclear envelope, consisting of two membranes separated by a small space, is perforated by nuclear pores through which transport of macromolecules, proteins, and RNA, between the two major compartments of the cell, takes place. For example, messenger and transfer RNA as well as ribosomal subunits must move from the nucleus to the cytoplasm and proteins that participate in the synthesis, repair, and transcription of DNA must move into the nucleus from the cytoplasm. The latter include the steroid hormone receptors and other proteins that regulate gene transcription. Cell Structure and Hormone Interplay Many different types of proteins are found in or associated with the plasma membrane. Complex oligosaccharides may appear on the outer surface as derivatives of sphingosine or other lipids (glycolipids). Proteins may have complex polysaccharides attached to them. These carbohydrate moieties may play important recognition functions or in the case of membrane receptors for hormones, may influence the accessibility of receptors for their ligands. Cell Structure and Hormone Interplay Some of the other intracellular organelles make or respond to hormones. For example, the synthesis and secretion of protein and peptide hormones depend on the rough endoplasmic reticulum and Golgi apparatus and the specific processing enzymes therein. Lysosomes play an important role in the secretion of thyroid hormones and both the mitochondria and the smooth endoplasmic reticulum are the sites of steroid hormone synthesis in the adrenal gland, gonads, and placenta. Hormones and Their Communication Systems The initial step in the action of a hormone, the interaction with its receptor, depends to some extent on its chemical nature. Hormones are heterogeneous in their molecular size, chemical properties, and pathways of synthesis. Nitric oxide is at one extreme of the size range; the pituitary gonadotropins consisting of two subunits are among the largest of the protein hormones with high molecular weight. Peptide or protein hormones range from three amino acids (TRH) to over 100 per subunit. Thyroid hormone and epinephrine are derived from the amino acid tyrosine. thyroid hormone has an intracellular receptor similar to those for the steroid hormones and epinephrine interacts with its membrane receptor. Steroid hormones and vitamin D and its metabolites are derived from cholesterol or 7-dehydrocholesterol, respectively. The actions of these hormones are propagated by interaction of the receptor with nuclear proteins and DNA. Types of Hormonal Communication Systems Hormones are chemical messengers that send a signal within a physiological system from point A (secretion) to point B (biological action). The hormone is biosynthesized within specific cells associated with an anatomically defined endocrine gland. e.g. Insulin action. In some portions of some endocrine systems the hormone-secreting cell releases its product not into the general circulation but into a closed system, such as the hypothalamic-pituitary portal system. In this case the hypothalamic-releasing hormones are released into and diluted by a limited volume, ensuring that most of the hormone molecules will be delivered to the anterior pituitary, which contains their target cells. There is a type of hormonal communication system that does not involve the circulatory system at all. In paracrine systems, hormones secreted from the signaling cell interact with specific high-affinity receptors in neighboring cells which are reached by diffusion.  Biosynthesis of peptide and protein hormones Protein and peptide hormones are biosynthesized in specific cells, through the well-known processes of transcription of a specific message encoded in the DNA of the gene for the protein and the translation of the RNA message (mRNA) into a protein. As with other proteins, variations in modifications to the initially produced mRNA and/or protein leads to deviation from the original “one gene, one protein” concept. The biosynthesis of peptide and protein hormones yields many examples of such deviations.  Biosynthesis of peptide and protein hormones Proteolytic processing of the pro-opiomelanocortin (POMC) precursor. The initial gene product of the POMC genei s a long polypeptide that undergoes cleavage by a series of specific proteases, so produce ACTH, β - and γ-lipotropin, α, β - and γ-MSH (melanocyte-stimulathing hormone or melanocortin , CL IP (corticotropin-like intermediary peptide), β-endorphin and Metenkephalin. The point of cleavage are paired basic residues Arg-Lys, Lys-Arg, or Lys-Lys. Biosynthesis of peptide and protein hormones It is now quite well recognized that one gene does not lead to a single RNA and then to single protein; that is, two or more RNA transcripts can arise through alternative processing of a single RNA primary transcript. The production of either calcitonin (CT) or calcitonin-gene-related peptide (CGRP) was one of the first examples of alternative splicing to be elucidated. Another version of variability in the final product of a gene is the post- translational processing of the initial protein product; the addition of sugar or lipid moieties to the protein backbone; proteolytic cleavage, yielding smaller protein or peptide products. These cleavages are catalyzed by serine endoproteases at cleavage sites in the precursor protein that are designated by two basic amino acids (Lys-Lys, Arg- Arg, or Lys-Arg). The reactions take place largely in the rough endoplasmic reticulum and in the Golgi apparatus. Alternative splicing and cleavage What Are Hormones? Several classes of hormones exist, including steroids, amino acid derivatives, polypeptides and proteins. Those hormone classes differ in their general molecular structures (e.g., size and chemical properties). As a result of the structural differences, their mechanisms of action also differ. They can enter their target cells and modulate the activity of those cells or bind the receptor on the membrane. Like steroids, amino acid derivatives can enter the cell, where they interact with receptor proteins that are already associated with specific DNA regions. The interaction modifies the activity of the affected genes.  Types of Hormones Hormones are heterogeneous in their molecular size, chemical properties, and pathways of synthesis. NO is smallest; Peptide or Protein hormones range from three amino acids to over 100 per subunit. Steroid hormones and vitamin D and its metabolites are derived from cholesterol. Peptide and protein hormones have receptors that are membrane- spanning proteins and can deliver its message on the outside where it will be conveyed to the interior of the cell by structural changes in the receptor protein. Steroid hormones, considered to be soluble in the phospholipid bilayer, can enter the cell so that the receptors for these hormones are located either in the cytoplasm or the nucleus of the cell. The actions of these hormones are propagated by interaction of the receptor with nuclear proteins and DNA. The amino acid-derived hormones differ from one another: thyroid hormone has an intracellular receptor similar to those for the steroid hormones and epinephrine interacts with its membrane receptor. What Are Hormones? Polypeptide and protein hormones are chains of amino acids of various lengths. These hormones are found primarily in the hypothalamus, pituitary gland, and pancreas. In some instances, they are derived from inactive precursors, or pro-hormones, which can be cleaved into one or more active hormones. Because of their chemical structure, the polypeptide and protein hormones cannot enter cells. Instead, they interact with receptors on the cell surface. The interaction initiates biochemical changes in either the cell’s membrane or interior, eventually modifying the cell’s activity or function. Hormone Functions Hormones control: Growth; Development; Metabolism of the body, energy balance; Electrolyte composition of bodily fluids; Reproduction; What Are Hormones? Hormones are molecules that are produced by endocrine glands, including the hypothalamus, pituitary gland, adrenal glands, gonads, (i.e., testes and ovaries), thyroid gland, parathyroid glands, and pancreas. The term “endocrine” implies that in response to specific stimuli, the products of those glands are released into the bloodstream. The hormones then are carried via the blood to their target cells. Some hormones have only a few specific target cells, whereas other hormones affect numerous cell types throughout the body. The target cells for each hormone are characterized by the presence of certain docking molecules (i.e., receptors) for the hormone that are located either on the cell surface or inside the cell. The interaction between the hormone and its receptor triggers a cascade of biochemical reactions in the target cell that eventually modify the cell’s function or activity. Hormones Functions: A single Hormone can exert various effects in different tissues, conversely, several hormones can regulate a single function Single hormone acting on different tissues: Estradiol amplifies the versatility of these hormones. It is produced by the ovary and can act; On the ovarian follicles to promote granulose cell differentiation; On the uterus stimulates its growth and maintain cyclic changes of the uterine mucose; On bone promotes linear growth and closure of the epiphyseal plates; On hypothalamic-pituitary system to regulate secretion of gonadotropins and prolactin; On general metabolic processes to affect adipose tissue distribution; Hormones Functions: Single function regulated by more than one hormone: Example is lipolysis process from adipose tissue stores. A veriety of hormones including catecholamines, glucagon, secretin, prolactine stimulate lipolysis within minutes by acting, via cAMP on hormone sensitive lipase. Hormones such as insulin, IGFs, oxytocin and gastric inhibitory lipopeptide inhibit lipolysis.  Regulation of hormone synthesis, secretion and serum levels The production and/or secretion of most hormones is related to the requirement for the biological response(s). Once this requirement has been met, the secretion of the hormone is restricted/stoped to prevent an overresponse. Thus, a characteristic feature of most endocrine systems is the existence of a feedback loop that limits or regulates the secretion of the hormonal messenger. Two general categories of endocrine feedback systems exist: In one case serum Ca2+ triggers biological response that causes increase of its action and at the same time Ca2+ can be an agent that exerts negative feedback inhibition on the gland producing the hormone. In another case hormone itself is an inhibitor.  Endocrine feedback systems Directly feeds back upon Involving CNS and the endocrine gland Hypothalamus  Regulation of Hormone Synthesis, secretion and serum levels There are many other possible regulatory points varying with the type of hormone. For example the steroid hormones (including vit. D) are regulated primarily at the first step in their synthesis and are released as synthesized, not stored in the gland. Thyroid hormone, on the other hand, is stored in large quantities within the thyroid gland. The short-term regulation of its secretion is on the secretory process, while the synthetic process takes place over a longer time frame. Peptide hormones, such as insulin, PTH, and the trophic hormones of the pituitary, are stored in varying amounts in the glands, so the relative roles of synthesis and secretion in the regulatory processes also vary among these hormones.  Regulation of Hormone Synthesis, secretion and serum levels Two other contributors to the biological availability of hormones deserve mention here: One is the conversion of a relative inactive hormone to an active one in its target glands as occurs with thyroid hormone and, in some cases, testosterone. Secondly, removal of active hormone from the blood must occur as part of the attenuation of its effect (in addition to shutting off the flow of new hormone into the blood). Thus, the half-life of an active hormone in the blood, which can vary from seconds to days, is important in understanding its regulatory dynamics.  Binding proteins, PTP Most steroid hormones have limited solubility in plasma due to their intrinsic hydrophobic character; accordingly, steroid hormones are largely (99%) bound to specific Plasma Transport Proteins (PTP), which are synthesized in the liver. Each transport protein has a specific ligand- binding domain for its cognate hormone. For some endocrine systems, the concentration of the plasma transport proteins can be subject to physiological regulation; the concentration of PTP can be either increased or decreased. Thus, changes in the amount of PTP can alter the amount of free hormone in the blood, as well as affect the total amount of hormone in the blood. This role of the binding proteins in the availability of steroid and thyroid hormones can be of considerable physiological relevance in clinical situations.  Transport and Metabolism of Hormone Once hormone is released into the bloodstream it may circulate freely if it is water soluble. In general, amines, peptides and proteins circulate in free form (exception is IGF), whereas steroids are bound to transport proteins. Specific transport proteins (globulins) have saturable, high- affinity binding sites. These proteins include thyroid hormone-binding globulin (TBG), testosterone-binding globulin (TeBG) etc. Binding of hormones to carrier proteins has a profound impact on the hormone clearance rate from the circulation. The metabolic clearance rate (MCR) of a hormone defines quantitatively ist removal from plasma. Liver and kidney perform the bulk of hormone clearance. This process includes degradation by variety of enzymatic mechanisms such as hydrolysis, oxidation, hydroxylation, methylation, decarboxylation, sulfation and glucuronidation.  Hormone Receptors When a hormone arrives at a target cell, the first step in delivering its message is interaction with a specific protein receptor. Receptors have: (a) a ligand-binding domain that noncovalently but stereospecifically binds the correct hormone for that receptor (b) an effector domain that responds to the presence of the hormone bound to the ligand domain and initiates the generation of the biological response(s) The interaction between the ligand-binding domain and the effector domain is most likely achieved by a conformational change in the receptor so that the effector site may interact with other cellular constituents to initiate the next steps in the signal transduction process. In general, steroid hormones and thyroid hormone interact with receptors that are within the cell, either the nucleus or the cytoplasm, whereas protein hormones, prostaglandins, and the catecholamines interact with the extracellular ligand binding domains of plasma membrane spanning receptors. Receptors Discriminate Precisely Hormones are present at very low concentrations in the extracellular fluid, generally, in a range of 10-15 mol/L. This is a much lower concentration than that of the many structurally similar moleculs (amino acids, peptides, vitamines etc) that circulate at 10-3 range. Hormones start their action by binding specific receptors Several features of hormone-receptor interaction are important: i)binding should be specific ii)binding should be saturable iii)binding should occure within the concentration range of the expected biologic response  Hormone Receptors G-Protein Coupled Receptors Tyrosine Kinases Receptors Nuclear Receptors Family Membrane receptors for hormones and other extracellular signals have three clearly identifiable domains: the extracellular component, the membrane-spanning component, and the intracellular component. The diameter of a typical cell membrane is 100 Å, requiring 20–25 amino acid residues organized into an α-helix to cross the membrane once. Since the membrane is hydrophobic, it is not surprising that a receptor’s membrane-spanning region consists largely of hydrophobic and noncharged amino acids. The nuclear receptors are a group of ancient evolutionarily related transcription factors. There are 48 members of this class. G-Protein Coupled Receptors About 350 GPCRs have hormones, growth factors, and other small molecules as ligands. The receptor itself has seven α-helical membrane spanning regions. This folding generates three extracellular and three intracellular loops. In some GPCRs palmitoylation of a cysteine residue in the carboxy region results in another loop. The N-terminus of GPCRs is highly variable, as expected from the variety of signals to which these proteins respond. Small molecules and small peptides have access to a cleft within the helices for binding, whereas larger proteins, such as the glycoprotein gonadotrophins, bind to a site within a longer, more elaborate N-terminus. Receptor Tyrosine Kinases Receptor tyrosine kinases, or RTKs, are single membrane spanning receptors and are defined by the presence of tyrosine kinase activity as the main cytoplasmic constituent and initiator of signal transduction. There are 58 receptor tyrosine kinases encoded in the human genome, several of which are important in hormone signaling. In their monomeric forms RTKs are single membrane-spanning receptors. The insulin and IGF-1 receptors, members of the same family exist as dimers of two hemireceptors, each consisting of two subunits, the extracellular α-subunit and the intracellular β-subunit, joined by disulfide bonds. A further set of disulfide bonds joins the two hemireceptors to form the dimerized receptor that then binds one molecule of ligand. The Nuclear Receptor Family Sequencing of the human genome has revealed 48 members of this class, of which about half appear to be orphans, i.e., no activity- modulating ligand has yet been identified for them. Each of these proteins functions as a DNA-binding protein, regulating, in a ligand dependent. The receptors for thyroid hormone (TR) and 1α,25(OH)2-vitamin D3 (VDR) are typically found in the nucleus of target cells where they (especially TR) may be bound to corepressor molecules which suppress DNA transcription. The receptors for cortisol (GR) and aldosterone (MR) are in the cytoplasm prior to ligand binding, where they are bound to chaperone proteins (heat shock proteins) that maintain them in an inactive state. Nuclear receptor structure. Primary structural organization. Shown are the structural features of nuclear receptors for thyroid hormone (TRα and TRβ), 1,25- dihydroxyvitamin D3 (VDR), the retinoic acid (RXR), estrogen (ERα and ERβ), cortisol (GR), aldosterone (MR), progesterone (PR B), and testosterone (AR). These receptors share a highly conserved DNA binding domain (C, green) and a short nonconserved region (D, blue), which serve as a hinge between the N- terminal and C-terminal portions of the molecule. The ligand binding domain (gold) is less conserved than the DNA binding domain, but is approximately the same size and adopts approximately the same three-dimensional structure in all the receptors. The difference in size between the receptor proteins is the highly variable N terminal A/B domain (pink). Two elements that are necessary for control of gene transcription, termed activation functions, exist, AF-1 in the A/B domain and AF-2 in the E/F domain. Three-dimensional structure of the DNA- and ligand-binding domains of the nuclear receptors. Recognition of the specific DNA sequence to be bound lies within the CI zinc finger (closest to the DNA) whereas CII is involved with receptor dimerization. The ligand-binding domains of the nuclear receptors are less conserved than the DNA-binding domain, but they share many common features. There are twelve α-helices arranged in three layers. The ligand binding pocket is within the more variable region. In addition to ligand binding, there are sites for a dimerization surface, a coregulator binding surface, and ligand-dependent transcriptional activation moiety, AF-2. Steroid hormone receptor zinc fingers. The amino acids in the DNA binding domain of a steroid hormone nuclear receptor are represented by circles. The coordination of a Zn2+ atom (blue) by four cysteines (pink) causes the formation of a loop. One of these, C1, which contains the P-box (light green), is involved in binding to the specific DNA binding site (hormone response element) and discriminating between closely related sites for different hormones. The D-box (dark green) in the second zinc finger, CII, plays a role in receptor dimerization. Measurement of Hormone–Receptor Interactions Hormone specific antibodies are the key to the radio-immunoassay When a constant amount of hormone specific antibody is incubated with a fixed amount of the radioactively labelled hormone, a certain fraction of the radioactive hormone binds to the antibody. If, in addition to the radiolabelled hormone, unlabelled hormone is also present, the unlabelled hormone competes with and displaces some of the labelled hormone from its binding site on the antibody. This binding competition can be quantified by reference to a standard curve obtained with known amounts of unlabeled hormone. The degree to which labeled hormone is displaced from antibody is a measure of the amount of (unlabeled) hormone in a sample of blood or tissue extract. By using very highly radioactive hormone, researchers can make the assay sensitive to picograms of hormone in a sample. Unlabeled hormone competes with labeled hormone for binding to the antibody; the amount of labeled hormone bound varies inversely with the concentration of unlabeled hormone present.  k+1 R + L ↔ RL k–1 Receptor Ligand Receptor-Ligand Complex (Hormone) Ka = k+1/ k–1 = [RL]/[R] [L] = 1/Kd Ka – association constant; Kd – dissociation constant The total number of possible binding sites – Bmax The number of unoccupied sites – [R] The number of occupied or ligand-bound sites – [RL] Bmax = [R] + [RL] The number of unbound sites [R] = Bmax – [ RL] The equilibrium expression Ka = [RL]/[L] (Bmax – [ RL]) [RL]/[L] = [Bound]/[Free] = Ka (Bmax – [ RL]) because Ka (Bmax – [ RL]) = 1/Kd (Bmax – [ RL]) [Bound]/[Free] = 1/Kd (Bmax – [ RL])  Determinants of the Hormone Concentration at the Target Cell 1. The rate of synthesis and secretion of the hormones. 2. The proximity of the target cell to the hormone source (dilution effect). 3. The dissociation constants of the hormone with specific plasma transport proteins (if any). 4. The conversion of inactive or suboptimally active forms of the hormone into the fully active form. 5. The rate of clearance from plasma by other tissues or by digestion, metabolism, or excretion. Determinants of the Target Cell Response 1. The number, relative activity and state of occupancy of the specific receptors on the plasma membrane or in the cytoplasm or nucleus. 2. The metabolism (activation or inactivation) of the hormone in the target cell. 3. The presence of other factors within the cell that are necessary for the hormone response. 4. Up- or down-regulation of the receptor consequent to the interaction with the ligand. 5. Postreceptor desensitzation of the cell, including down-regulation of receptor. Regulation of Hormone Activity The secretion of most of, if not all, hormones is regulated by closed- loop systems known as feedback mechanisms. The endocrine system as a whole is organized in a hierarchy of closed loop system that operate between cells. To achieve this control, many bodily functions are regulated not by a single hormone but by several hormones that regulate each other. For example, for many hormone systems, the hypothalamus secretes so- called releasing hormones, which are transported via the blood to the pituitary gland. There, the releasing hormones induce the production and secretion of pituitary hormones, which in turn are transported by the blood to their target glands (e.g., the adrenal glands, gonads, or thyroid). In those glands, the interaction of the pituitary hormones with their respective target cells results in the release of the hormones that ultimately influence the organs targeted by the hormone cascade. Regulation of Hormone Activity Feedback mechanisms are negative and positive. Negative feedback: hormone A has negative influence on hormone B. An example of this type of feedback can be found in the stimulation of adrenal cortisol secretion by the adenohypophysis hormone ACTH and the resulting inhibition of ACTH release by increased plasma cortisol levels. Positive feedback: hormone A has not diminishing but simulative influence on hormone B. An example of this type of feedback can be relationship between LH and estradiol. During menstrual cycle gradual increase in plasma LH levels stimulates the production of estradiol by the ovary, estradiol induces an abrupt increase in LH secretion and induces ovulation. Upon reaching maximal levels, plasma LH decline. This phenomenon exemplifies the self-limiting nature of positive feedback systems. Regulation of Hormone Activity Constant feedback from the target glands to the hypothalamus and pituitary gland ensures that the activity of the hormone system involved remains within appropriate boundaries. Thus, in most cases, negative feedback mechanisms exist by which hormones released by the target glands affect the pituitary gland and/or hypothalamus. In some instances, a so-called short-loop feedback occurs, in which pituitary hormones directly act back on the hypothalamus. The sensitivity with which these negative feedback systems operate can change at different physiological states or stages of life. For example, the progressive reduction in sensitivity of the hypothalamus and pituitary to negative feedback by gonadal steroid hormones plays an important role in sexual maturation. Classification of Hormones by Mechanism of Action Hormones can be classified according to chemical composition, solubility properties, location of receptors, and nature of the signal used to mediate hormone action within the cell. A classification based on the last two properties is illustrated in here: I. Hormones that bind to intracellular receptors II. Hormones that bind to cell surface receptors Classification of Hormones by Mechanism of Action I. Hormones that bind to intracellular receptors Androgens Calcitriol (1,25[OH]2-D3) Estrogens Glucocorticoids Mineralocorticoids Progestins Retinoic acid Thyroid hormones (T3 and T4) Classification of Hormones by Mechanism of Action II. Hormones that bind to cell surface receptors A. The second messenger is cAMP α2-Adrenergic catecholamines β-Adrenergic catecholamines Adrenocorticotropic hormone (ACTH) Antidiuretic hormone Calcitonin Chorionic gonadotropin, human (CG) Corticotropin-releasing hormone Follicle-stimulating hormone (FSH) Glucagon Lipotropin (LPH) Luteinizing hormone (LH) Melanocyte-stimulating hormone (MSH) Parathyroid hormone (PTH) Somatostatin Thyroid-stimulating hormone (TSH) Classification of Hormones by Mechanism of Action II. Hormones that bind to cell surface receptors B. The second messenger is cGMP Atrial natriuretic factor Nitric oxide C. The second messenger is calcium or phosphatidylinositols (or both) Acetylcholine (muscarinic) α1-Adrenergic catecholamines Angiotensin II Antidiuretic hormone (vasopressin) Cholecystokinin Gastrin Gonadotropin-releasing hormone Oxytocin Platelet-derived growth factor (PDGF) Substance P Thyrotropin-releasing hormone (TRH) Classification of Hormones by Mechanism of Action II. Hormones that bind to cell surface receptors D. The second messenger is a kinase or phosphatase cascade Adiponectin Chorionic somatomammotropin Epidermal growth factor Erythropoietin Fibroblast growth factor (FGF) Growth hormone (GH) Insulin Insulin-like growth factors I and II Leptin Nerve growth factor (NGF) Platelet-derived growth factor Prolactin General Features of Hormone Classes Group I Group II Types Steroids, Polypeptides, Iodothyronines, Proteins, Calcitriol, Glycoproteins, Retinoids Catecholamines Solubility Lipophilic Hydrophilic Transport Yes No proteins Plasma Long (hours to days) Short (minutes) half-life Receptor Intracellular Plasma membrane Mediator Receptor-hormone cAMP, complex cGMP, Ca2+ Metabolites of complex phosphoinositols, kinase cascades The Hypothalamus and Its Hormones The hypothalamus (neuronal cells) is a small region located within the brain that controls many bodily functions, including eating and drinking, sexual functions and behaviours, blood pressure and heart rate, body temperature maintenance, the sleep-wake cycle, and emotional states. The hypothalamus serves as the major link between the nervous and endocrine systems. The complex interplay of the actions of various neurotransmitters regulates the production and release and inhibitory of hormones from the hypothalamus. These hormones get in the hypothalamic-hypophyseal portal system, thereby reach pituitary gland.  The Hypothalamus and Its Hormones Corticotropin-releasing hormone Growth hormone-releasing (CRH), which is part of the hormone hormone (GHRH), which is an system regulating carbohydrate, essential component of the protein, and fat metabolism as well system as sodium and water balance in the promoting the organism’s growth body Somatostatin, which also Gonadotropin-releasing hormone affects bone and muscle growth (GnRH), which helps control sexual but has the and reproductive functions, opposite effect as that of GHRH including pregnancy and lactation Dopamine, a substance that (i.e., milk production functions primarily as a Thyrotropin-releasing hormone neurotransmitter but also has (TRH), which is part of the hormone some hormonal effects, such as system controlling the metabolic repressing lactation until it is processes of all cells and which needed after childbirth. contributes to the hormonal regulationof lactation.  The Pituitary and Its Major Hormones The pituitary (also sometimes called the hypophysis) is a gland about the size of a small marble and is located in the brain directly below the hypothalamus. The pituitary gland consists of two parts: the anterior pituitary and the posterior pituitary. The Anterior Pituitary produces several important hormones that either stimulate target glands (e.g., the adrenal glands, gonads, or thyroid gland) to produce target gland hormones or directly affect target organs. The pituitary hormones include adrenocorticotropic hormone (ACTH); gonadotropins (gonadotropins comprise two molecules, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)); thyroid-stimulating hormone (TSH); growth hormone (GH); and prolactin.  The Pituitary and Its Major Hormones The Posterior Pituitary does not produce its own hormones; instead, it stores two hormones—vasopressin and oxytocin—that are produced by neurons in the hypothalamus. Both hormones collect at the ends of the neurons, which are located in the hypothalamus and extend to the posterior pituitary. Vasopressin (AVP) promotes the reabsorption of water from the urine in the kidneys. AVP release from the pituitary is controlled by the concentration of sodium in the blood as well as by blood volume and blood pressure. Alcohol also has been shown to inhibit AVP release. Conversely, certain other drugs (e.g., nicotine and morphine) increase AVP release, as do severe pain, fear, nausea, and general anesthesia, thereby resulting in lower urine production and water retention. Oxytocin stimulates the contractions of the uterus during childbirth. In nursing women, the hormone activates milk ejection.  The Adrenal Glands and Their Hormones The adrenal glands are small structures located on top of the kidneys. Structurally, they consist of an outer layer (i.e., the cortex) and an inner layer (i.e., the medulla). The adrenal cortex produces numerous hormones, primarily corticosteroids (i.e., glucocorticoids and mineralocorticoids). The cortex is also the source of small amounts of sex hormones; The adrenal medulla generates two substances; adrenaline and noradrenaline as part of the fight-or-flight response to various stress factors. The primary glucocorticoid in humans is cortisol (also called hydrocortisone), which helps control carbohydrate, protein, and lipid metabolism. The primary mineralocorticoid in humans is aldosterone, which also helps regulate the body’s water and electrolyte balance.  The Gonads and Their Hormones The gonads (i.e., the ovaries and testes) synthesize steroid sex hormones that are necessary for the development and function of both female and male reproductive organs and secondary sex characteristics. (1) estrogens (e.g., estradiol), which exert feminizing effects; (2) progestogens (e.g., progesterone), which affect the uterus in preparation for and during pregnancy; (3) androgens (e.g., testosterone), which exert masculinizing effects. In addition to the reproductive functions, sex hormones play numerous essential roles throughout the body. For example, they affect the metabolism of carbohydrates and lipids, the cardiovascular system, and bone growth and development.  The Thyroid and Its Hormones The thyroid gland, which consists of two lobes, is located in front of the windpipe (i.e., trachea), just below the voice box (i.e., larynx). The gland produces two structurally related hormones, thyroxine (T4) and triiodothyronine (T3), that are iodinated derivatives of the amino acid tyrosine. T3 is a much more active hormone, and most of the T4 produced by the thyroid is converted into T3 in the liver and kidneys. Thyroid hormone in general serves to increase the metabolism of almost all body tissues. Thyroid hormone stimulates the production of certain proteins involved in heat generation; metabolic processes involving carbohydrates, proteins, and lipids that help generate the energy required. Thyroid hormone plays an essential role in the development of the central nervous system during late fetal and early postnatal developmental stages. Finally, thyroid hormone is required for the normal development of teeth, skin, and hair follicles as well as for the functioning of the nervous, cardiovascular, and gastrointestinal systems. The Parathyroid Glands and Their Hormones The parathyroid glands produce PTH. This hormone increases calcium levels in the blood, helping to maintain bone quality and an adequate supply of calcium, which is needed for numerous functions throughout the body (e.g., muscle movement and signal transmission within cells). Many of the functions of PTH require or are facilitated by a substance called 1,25-dihydroxycholecalciferol, a derivative of vitamin D. Specifically, PTH causes reabsorption of calcium from and excretion of phosphate in the urine. PTH also promotes the release of stored calcium from the bones as well as bone resorption, both of which increase calcium levels in the blood. Finally, PTH stimulates the absorption of calcium from the food in the gastrointestinal tract. Consistent with PTH’s central role in calcium metabolism, the release of this hormone is not controlled by pituitary hormones but by the calcium levels in the blood. Thus, low calcium levels stimulate PTH release, whereas high calcium levels suppress it.  The Pancreas and Its Hormones The pancreas is located in the abdomen, behind the stomach, and serves two distinctly different functions. First, it acts as an exocrine organ, because the majority of pancreatic cells produce various digestive enzymes that are secreted into the gut and which are essential for the effective digestion of food. Second, the pancreas serves as an endocrine organ, because certain cell clusters (i.e., the Islets of Langerhans) produce two hormones—insulin and glucagon—that are released into the blood and play pivotal roles in blood glucose regulation.  Hormone Systems Blood sugar levels directly control insulin and glucagon release by the pancreas, and calcium levels in the blood regulate PTH release. Conversely, many hormones produced by target glands are regulated by pituitary hormones, which in turn are controlled by hypothalamic hormones. Examples of such regulatory hormonal cascades include the hypothalamic-pituitaryadrenal (HPA) axis, the hypothalamic-pituitary- gonadal (HPG) axis, and the hypothalamic-pituitary-thyroidal (HPT) Axis. Hypothalamic-Pituitary Adrenal (HPA) axis Hypothalamic-Pituitary-Gonadal (HPG) axis Hypothalamic-Pituitary-Thyroidal (HPT) axis  Hormone Systems Any disturbances in the HPA axis can result in serious medical consequences. For example, insufficient hormone production by the adrenal cortex causes Addison’s disease, which is characterized by muscle weakness, dehydration, loss of appetite (i.e., anorexia), nausea, vomiting, diarrhea, fever, abdominal pain, tiredness, and malaise. Patients with this disease exhibit low levels of plasma cortisol but high levels of ACTH. The increase in ACTH levels represents a vain attempt by the pituitary to stimulate hormone production in the unresponsive adrenal cortex. Equally deleterious is the excessive glucocorticoids (cortisol) production that results from excess ACTH release (i.e., Cushing’s syndrome). Those patients experience symptoms such as muscle weakness and wasting, back pain from osteoporosis, a tendency to bruise easily, redistribution of body fat (i.e., a rounded “moon” face, prominent abdomen, and thin legs), and various psychological disturbances. Because of the negative feedback mechanism of the HPA axis, the patient’s cortisol levels are high and the ACTH levels are low.  LITERATURE Anthony W. Norman and Helen L. Henry, (2015) Hormones, Third Edition, Academic Press. Thomas M. Devlin-Textbook of Biochemistry with Clinical Correlations- John Wiley & Sons; 7th edition (2011) Robert K. Murray-Harper’s Illustrated Biochemistry (Lange Medical Book)- McGraw-Hill Medical; 31th edition (2018) David L. Nelson, Michael M. Cox - Lehninger Principles of Biochemistry - Worth Publishers Inc.,U.S.; 6th edition (2013)