Physioc Expedition: General Overview of Hormones, Secretion, Transport, and Clearance PDF

Bulama Alhassan Alhaji (Bsc, Msc ABU Zaria) PHYSIOC EXPEDITION DEPARTMENT OF HUMAN PHYSIOLOGY COLLEGE OF HEALTH SCIENCES AHMADU BELLO UNIVERSITY ZARIA GENERAL OVERVIEW OF HORMONE, SECRETION, TRA...

Bulama Alhassan Alhaji (Bsc, Msc ABU Zaria) PHYSIOC EXPEDITION DEPARTMENT OF HUMAN PHYSIOLOGY COLLEGE OF HEALTH SCIENCES AHMADU BELLO UNIVERSITY ZARIA GENERAL OVERVIEW OF HORMONE, SECRETION, TRANSPORT, MECHANISM OF ACTION OF HORMONE AND CLEARANCE FROM THE BLOOD. CONTENT INTRODUCTION AND GENERAL OVERVIEW OF HORMONES HORMONES SECRETION AND CLASSIFICATION HORMONE RECEPTORS MECHANISM OF ACTIONS OF HORMONES EFFECTS OF HORMONES REGULATION OF HORMONAL ACTION AND HORMONE CLEARANCE SUMMARY REFERENCES INTRODUCTION AND OVERVIEW OF HORMONES Hormones are chemical messenger produced in an endocrine gland and released into the circulation to effect a change in a specific target organ; Hormones regulate the internal environment, effecting homeostatic control, regulate reproductive processes, and affect mood and behavior Types Steroid hormones–cortisol, estrogen, testosterone; non steroid hormones–choleckystokinin, epinephrine, dopamine, insulin, norepinephrine, serotonin, vasopressin. (Hill, 2012) They are members of a class of signaling molecules produced by glands in multicellular organisms that are transported by the circulatory system to target distant organs to regulate physiology and behavior. The gland that secrete hormones comprise the endocrine signaling system. (Guyton and Hall, 2006) Hormones are used to communicate between organs and tissues. They affect distant cells by binding to their receptors resulting in change in cell function. When a hormone binds to a receptor, it results in activation of signal transduction pathway. Cells in multi-cellular organisms communicate with one another to coordinate their growth and metabolism. Cell to cell communicate is mainly via Extracellular signaling molecules or Hormones. Hormones carry information from Sensor Cells that sense changes in the environment to Target Cells that respond to the changes. Hormones tend to coordinate various metabolic processes in the body. (Guyton ad Hall, 2006) Hormone synthesis may occur in specific tissues of endocrine glands or in other specialized cells. Hormone synthesis occurs in response to specific biochemical signals induced by a wide range of regulatory systems. (Sembulingam and Sembulingam 2012) [Pick the date] Page 2 Fig 1: Overview of endocrine glands (Guyton and Hall, 2006) [Pick the date] Page 3 SECRETION AND CLASSIFICATION OF HORMONES Secretion of Hormones Hormone Secretion after a Stimulus and Duration of Action of Different Hormones. Some hormones, such as norepinephrine and epinephrine, are secreted within seconds after the gland is stimulated and may develop full action within another few seconds to minutes; the actions of other hormones, such as thyroxine or growth hormone, may require months for full effect. Thus, each of the different hormones has its own characteristic onset and duration of action each tailored to perform its specific control function (Guyton and Hall, 2006) Concentrations of Hormones in the Circulating Blood and Hormonal Secretion Rates. The concentrations of hormones required controlling most metabolic and endocrine functions are incredibly small. Their concentrations in the blood range from as little as 1 picogram (which is one millionth of one millionth of a gram) in each milliliter of blood up to at most a few micrograms (a few millionths of a gram) per milliliter of blood. Similarly, the rates of secretion of the various hormones are extremely small, usually measured in micrograms or milligrams per day. We shall see later in this chapter that highly specialized mechanisms are available in the target tissues that allow even these minute quantities of hormones to exert powerful control over the physiological systems (Guyton and Hall, 2006) TRANSPORT OF HORMONES IN THE BLOOD Water-soluble hormones (peptides and catecholamines) are dissolved in the plasma and transported from their sites of synthesis to target tissues, where they diffuse out of the capillaries, into the interstitial fluid, and ultimately to target cells. Steroid and thyroid hormones, in contrast, circulate in the blood while being mainly bound to plasma proteins. Usually less than 10 percent of steroid or thyroid hormones in the plasma exist free in solution. For example, more than 99 percent of the thyroxine in the blood is bound to plasma proteins. However, protein-bound hormones cannot easily diffuse across the capillaries and gain access to their target cells [Pick the date] Page 4 and are therefore biologically inactive until they dissociate from plasma proteins. The relatively large amounts of hormones bound to proteins serve as reservoirs, replenishing the concentrationof free hormones when they are bound to target receptors or lost from the circulation. Binding of hormones to plasma proteins greatly slows their clearance from the plasma (Guyton and Hall, 2006) Classification of Hormones Hormones are classified by various criteria: By Proximity of their site of synthesis to their site of action, By their chemical structure, By their degree of solubility in aqueous medium (Temple β01γ) (A). CLASSIFICATION BASED ON PROXIMITY OF THEIR SITE OF SYNTHESIS TO THEIR SITE OF ACTION (i). Autocrine Hormones: those that act on the same cells that synthesize them (ii). Paracrine Hormones: those that are synthesized very close to their site of action (iii). Endocrine Hormones: those that are synthesized by endocrine glands and transported in the blood to target cells that contain the appropriate receptors (Temple 2013) (B). CLASSIFICATION BASED ON CHEMICAL STRUCTURE (i). Peptides or Protein hormones: They constitute the highest percentage of hormones in the body. When they are secreted, they are then stored in the secretory vesicles until they are needed. They range in sizes from the numbers of amino acids present such as proteins with 3 amino acids (thyrotropin- releasing hormone) to proteins with almost 200 amino acids (growth hormones and prolactin). (Sembulingam and Sembulingam, 2012) The site of action for this hormones is the rough end of endoplasmic reticulum. They are converted to the active form (prohormones) from the inactive form (preprohormones). This takes place in the [Pick the date] Page 5 endoplasmic reticulum afterwhich they are sent to golgi apparatus for packaging into secretory vesicles (Temple, 2013) The vesicles containing these hormones are stored within the cytoplasm and many are bound to the cell membrane where granular content are extruded into interstitial fluids or into the circulatory medium-(the blood) by exocytosis. The stimulus for exocytosis is initiated by an increase in calcium level caused by depolarization of plasma membrane. As a property, these hormones are water soluble allowing them to enter the circulatory system easily where they are carried to their target tissues. (Guyton and Hall, 2006) They are synthesized as peptides or large polypeptides precursors that undergo processing before secretion; Examples: Thyrotropin Releasing Hormone (TRH), made up of three amino acid residues; Insulin, made up of 51 amino acid residues; Pituitary Gonadotrophins, made up of large Glycoproteins with subunits. (Sembulingam and Sembulingam 2012, Guyton and Hall, 2006) (ii). Amino acid derivatives: These are derived from tyrosine. The two groups of hormones derived from tyrosine are thyroid and adrenal medullary hormone which are all formed by the actions of enzymes in the cytoplasmic compartments of granular cells. The thyroid hormones are synthesized and stored in the thyroid gland and joined into macromolecules of the protein thyroglobulin stored in large follicles within the thyroid gland. (Guyton and Hall, 2006) Epinephrine and norepinephrine are formed in the adrenal medulla which normally secretes about four times more epinephrine than norepinephrine. These catecholamine are taken up into preformed vesicles and stored until secreted. They are also released from adrenal medullary cells by exocytosis similar to that of protein hormones. Once they enter circulation, they can exist in plasma in free form or in conjugation with other substances. (Sembulingam and Sembulingam, 2012) Examples: Adrenaline, Catecholamines, Thyroid Hormones (Temple, 2013) (iii). Fatty acid derivatives: Examples: Eicosanoids (Prostaglandins) (Temple, 2013) [Pick the date] Page 6 (iv). Steroid hormones: These are synthesized from cholesterol and are not stored. These hormones are lipid soluble consisting of cyclohexyl rings and one cyclopentyl ring merged into a single structure. Although the hormone storage is small in steroid producing cells, large stores of cholesterol esters in cytoplasm vacuoles can be mobilized for steroid synthesis after a stimulus. Steroid hormones easily diffuse through the cell membrane and enter the interstitial fluid and then the blood. (Sembulingam and Sembulingam, 2012) These are derivatives of Cholesterol; Example: Estradiol, Testosterone, Cortisol, Aldosterone. (Temple, 2013) (C). CLASSIFICATION BASED ON SOLUBILITY IN AQUEOUS MEDIUM IN CELLS (i). Hydrophilic Hormones (Lipophobic Hormones): Hormones that are soluble in aqueous medium; They cannot cross the cell membrane, Thus, they bind to receptor molecules on the outer surface of target cells, initiating reactions within the cell that ultimately modifies the functions of the cells; Examples: Insulin, Glucagon, Epinephrine. (Temple 2013) (ii). Lipophilic Hormones (Hydrophobic Hormones): Hormones that are not soluble in aqueous medium, but soluble in lipid; they can easily cross the cell membrane. Thus, they can enter target cells and bind to intracellular receptors to carry out their action; Examples: Thyroid hormones, Steroid hormones. (Temple 2013) [Pick the date] Page 7 (D). FUNCTIONAL CLASSIFICATION Systemic and Trophic Hormones Hormones may be classified based on functions into two categories; systemic hormones and trophic hormones. (i). A Systemic hormone is a hormone which acts on different somatic target cells to produce specific structural or functional effects. E.g. thyroid hormones, growth hormone, sex hormones. (ii). A trophic hormone is a hormone from one gland whose function is to stimulate the secretion of hormones from another gland. Trophic hormones are also called “tropic hormones” or “tropins’ e.g. adrenocorticotropic hormone (ACTH or corticotropin) and thyroid stimulating hormone (thyrotropin) of the anterior pituitary (Temple, 2013) HORMONE RECEPTORS Hormone receptors are the large proteins present in the target cells. Each cell has thousands of important receptors. Specificity for a particular hormone is a notable property of each receptor. (Sembulingam and Sembulingam 2012) (a). LOCATION (i). Protein, peptide and catecholamine hormones have their receptor located on the cell membrane.(Sembulingam and Sembulingam 2012) (ii). The primary receptors for the different steroid hormones are found mainly in the cytoplasm. (Sembulingam and Sembulingam 2012) (iii). The receptors for the thyroid hormones are located in the nucleus and believed to be in direct association with one or more of the chromosomes. ( Sembulingam and Sembulingam 2012) (c). INTRACELLULAR SIGNALLING AFTER HORMONE RECEPTOR ACTIVATION A lot of interactions occurs when a hormone has activated its receptors by binding to it. A few examples are considered below; [Pick the date] Page 8 (i). ION CHANNEL LINKED RECEPTORS These are cell membrane bound receptors that act through synaptic signaling on chemically excitable cells and convert chemical signals (ligand) to electrical ones. It is essential in neuronal activities. These ligands can be neurotransmitters or peptide hormones (Guyton and Hall, 2006) [Pick the date] Page 9 Almost all neurotransmitter substances like Ach and Norepinephrine combine with their receptors in the post synaptic membrane to cause a change in the structural components of their receptors. This may be in the form of opening and closing of channels for one or more ions. (Guyton and Hall 2006) Some may open or close for sodium, potassium and others for calcium. The altered movement of these ions result in observed effects on the post synaptic cells. (Guyton and Hall 2006) Most of the opening or closing of ion channel are done indirectly by coupling with G-protein- linked or enzyme- linked receptors. (Guyton and Hall, 2006) (ii). G PROTEIN -LINKED HORMONE RECEPTORS Many hormones activate receptors that indirectly regulate the activity of target proteins by coupling with Heterotrimetric GTP-binding proteins (G proteins). There are more than 1000 known G protein- coupled receptors all of which has seven transmembrane segments that loop in and out of the cell membrane. Some parts of the receptors that protrude into the cytoplasm get coupled to G-proteins which has three parts; α, and sub units. When the ligand binds to extracelllar part of the receptor, a conformational change occurs in the receptor that activates the G-proteins and induce intracellular signals that either open or close membrane ion channels Change the activity of an enzyme in the cytoplasm of the cell. (Guyton and Hall, 2006) (iii). ENZYME-LINKED HORMONE RECEPTORS Some receptors, when activated, function directly as enzymes or are closely associated with enzymes that they activate. These enzyme-linked receptors are proteins that pass through the membrane only once, in contrast to the seven transmembrane G protein–coupled receptors. Enzyme-linked receptors have their hormone-binding site on the outside of the cell membrane and their catalytic or enzyme- binding site on the inside. When the hormone binds to the extracellular part of the receptor, an enzyme immediately inside the cell membrane is activated (or occasionally inactivated). One example of an enzyme-linked receptor is the leptin receptor (Figure 74–5). Leptin is a hormone secreted by fat cells [Pick the date] Page 10 and has many physiological effects, especially in regulating appetite and energy. The leptin receptor is a member of a large family of cytokine receptors that do not themselves contain enzymatic activity but signal through enzymes associated with them. In leptin receptor, one of the signaling pathways occurs through a tyrosine kinase of the janus kinase (JAK) family,JAK2.The leptin receptor is a dimer (i.e. has two parts), and binding of leptin to the extracellular part of the receptor alters its conformation, enabling phosphorylation and activation of the intracellular associated JAK2 molecules. The activated JAK2 molecules then phosphorylate other tyrosine residues within the leptin receptor and complex to mediate intracellular signaling. The intracellular signals entails phosphorylation of signal transducer and activator of transcription (STAT) proteins, which activates transcription to initiate protein synthesis. Phosphorylation of JAK2 also leads to activation of other intracellular enzyme pathways such as mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K). Some of the effects of leptin occur rapidly as a result of activation of these intracellular enzymes. (Guyton and Hall, 2006) Other actions of leptin occur more slowly and require synthesis of new proteins. In hormonal control, leptin binds to adenylyl cyclase which catalyzes the formation of cAMP, a second messenger with multiple effects inside the cell. Cyclic guanosine monophosphate (cGMP), which is only slightly different from cAMP, serves in a similar manner as a second messenger for a few peptide hormones, such as atrial natriuretic peptide (ANP). (Guyton and Hall 2006) (d). INTRACELLULAR HORMONE RECEPTORS AND ACTIVATION OF GENES Several hormones, including adrenal and gonadal steroid hormones, thyroid hormones, retinoid hor- mones, and vitamin D, bind with protein receptors inside the cell rather than in the cell membrane. They readily cross the cell membrane and interact with receptors in the cytoplasm or nucleus because they are [Pick the date] Page 11 soluble in lipids. The activated hormone- receptor complex then binds with a specific regulatory (promoter) sequence of the DNA called the hormone response element, it either activates or represses transcription of specific genes and formation of messenger RNA (mRNA).Therefore, minutes, hours, or even days after the hormone has entered the cell, newly formed proteins appear in the cell and control or alter cell functions. An intra- cellular receptor can activate a gene response only if the appropriate combination of gene regulatory proteins is present, and many of these regulatory proteins are tissue specific. Thus, the responses of different tissues to a hormone are determined not only by the specificity of the receptors but also by the genes that the receptor regulates. (Guyton and Hall 2006) MECHANISM OF ACTIONS OF HORMONE To discuss the mechanism of action of hormones, they are classified according to their solubility. This is because the mechanism of action of a hormone is related to its solubility in either water or lipids. This classification places hormones into two groups namely; 1. Hydrophilic hormones (water soluble hormones), which include the peptide hormones and adrenaline. (Temple 2013) 2. Lipophilic hormones (lipid soluble hormones), which include the steroid hormones and iodothyronines (T3 and T4). (Temple 2013) (A). MECHANISM OF ACTION OF HYDROPHILIC HORMONES (i). FIRST MESSENGER MECHANISM The hormone itself constitute the first messenger. It binds to the receptor and activate the second messenger(s). (Sembulingam and Sembulingam 2012) Hydrophilic hormones bind to external receptors found in the cell membrane of the target cells. Binding of the hormone to the receptor activates the receptor which leads to one of the following reactions: [Pick the date] Page 12 1. Activation of tyrosine kinase (an internal part of the receptor): This catalyzes the phosphorylation of inactive cytoplasmic protein agents to phosphorylated active protein agents such as activators, catalysts, inhibitors. 2. Activation of guanylyl cyclase (an internal part of the receptor): This catalyzes the conversion of GMP into cGMP (cyclic GMP) leading to an increase in level of cytoplasmic cGMP. 3. Activation or inactivation of ion channels (Na+, K+, or Cl-): This raises or lowers ion influxes. 4. Activation of stimulatory G protein‟ (Gs protein) which leads to any of the following reactions: I. Activation of adenyl cyclase enzyme which converts ATP to cAMP (cyclic AMP) and increases the level of cytoplasmic cAMP. II. Activation of phosphodiestrase: This converts cGMP into 5‟-GMP and lowers the level of cytoplasmic GMP. IV. Activation of phospholipase Aβ: This converts membrane phospholipids into arachidonic acid. Arachidonic acid is a precursor of prostaglandins, thromboxanes or leukotrienes when it is converted by cyclooxygenase. V. Activation of phospholipase C: these results in the conversion of PIP2 (phosphotidylinositol diphosphate) into IP3 (inositol triphosphate) and DAG (diacyl glycerol). IP3 leads to mobilization of calcium ions while DAG triggers protein synthesis. (ii). Second Messenger Mechanisms For Mediating Intracellular Hormonal Functions cAMP SECOND MESSENGER One of the means by which hormones exert intracellular actions is to stimulate formation of the second messenger cAMP inside the cell membrane. The cAMP then causes subsequent intra- cellular effects of the hormone. (Guyton and Hall 2006) ADENYLYL CYCLASE–cAMP SECOND MESSENGER SYSTEM [Pick the date] Page 13 Some Hormones that Use the Adenylyl Cyclase–cAMP Second Messenger System 1. Adrenocorticotropic hormone (ACTH) 2. Angiotensin II (epithelial cells) 3. Calcitonin Catecholamines (b receptors) 4. Corticotropin-releasing hormone (CRH) 5. Follicle-stimulating hormone (FSH), Glucagon Human chorionic gonadotropin (HCG), 7. Luteinizing hormone (LH) 8. Parathyroid hormone (PTH) 9. Secretin Somatostatin Thyroid-stimulating hormone (TSH) 10. Vasopressin (V2 receptor, epithelial cells). (Guyton and Hall 2006) Binding of the hormones with the receptor allows coupling of the receptor to a G protein. If the G protein stimulates the adenylyl cyclase cAMP system, it is called a Gs protein (stimulatory G protein). When the adenylyl cyclase (a membrane-bound enzyme) is stimulated by the Gs protein, there is the conversion of a small amount of cytoplasmic adenosine triphosphate (ATP) into cAMP inside the cell. This then activates cAMP-dependent protein kinase, which phosphorylates specific proteins in the cell, triggering biochemical reactions that ultimately lead to the cell‟s response to the hormone. (Guyton and Hall 2006) The importance of this mechanism is that only a few molecules of activated adenylyl cyclase immediately inside the cell membrane can cause many more molecules of the next enzyme to be activated, which can cause still more molecules of the third enzyme to be activated, and so forth. In this way, even the slightest amount of hormone acting on the cell surface can initiate a powerful cascading activating force for the entire cell. On the other hand, if the hormone binds to an inhibitory G protein (denoted Gi protein), adenylyl cyclase will be inhibited, reducing the formation of cAMP and ultimately leading to an inhibitory action in the cell. Thus, depending on the coupling of the hormone receptor to an inhibitory or a stimulatory G protein, a hormone can either increase or decrease the concentration of cAMP and phosphorylation of key proteins inside the cell. It is worth noting that, different functions are elicited in different target cells, such as initiating synthesis of specific intracellular chemicals, causing muscle contraction or relaxation, initiating secretion by the cells, and altering cell permeability. A [Pick the date] Page 14 thyroid cell stimulated by cAMP forms the metabolic hormones thyroxine and triiodothyronine, while the same cAMP causes secretion of the adrenocortical steroid hormones in adrenocortical cells. It increases their permeability to water in epithelial cells of renal tubules. (Guyton and Hall, 2006) EFFECTS OF HORMONES Some of the effects of hormones on bodily functions are detailed below; (i). Regulating the growth and development of the body. A deficiency in a vital hormone such as growth hormone can lead to severely stunted growth in children and even dwarfism. By contrast, excess growth hormone can lead to acromegaly and gigantism or excessive height. Several other hormones such as thyroid hormones, cortisol, and insulin are also vital in growth and development. (Ananya, 2015) (ii). Activation and suppression of the immune system that is primarily mediated by cortisol and steroid hormones. (Ananya, 2015) (iii). The development of reproductive functions such as menstruation, pregnancy, lactation and childbirth. These are mediated by the sex hormones estrogen and testosterone. Other important hormones in the reproduction process include oxytocin for child birth, prolactin for lactation and luteinizing hormone (LH) and follicle stimulating hormone (FSH) for maintaining a normal menstrual cycle. (Ananya, 2015) (iv). Controlling secretion of other hormones. For example, thyroid stimulating hormone (TSH) released from the pituitary gland stimulates the release of the thyroid hormone thyroxine. The resulting increased level of thyroid hormone in the blood acts as a feedback signal to the pituitary to stop releasing TSH and the hormone therefore self-regulates its secretion. This method of inhibiting a hormone's own release is called feedback inhibition. (Ananya, 2015) (v). Other effects of hormones on bodily functions can include: (a). Maintaining salt and water balance (Ananya, 2015) (b). Mood swings and cognitive functions (Ananya, 2015) [Pick the date] Page 15 (c). Regulation of metabolic pathways by thyroxine, insulin and cortisol. These hormones aid the absorption and utilization of various nutrients in the body. (Ananya, 2015) (d). Controlling hunger and thirst. (Ananya 2015) (e). Controlling programmed cell death or apoptosis. (Ananya, 2015) (f). Regulation of metabolism (Ananya 2015) HORMONE CLEARANCE AND REGULATION OF HORMONAL ACTION Mechanisms of hormone clearance Clearance of Hormones From the Blood. Two factors can increase or decrease the concentration of a hormone in the blood. One factor is the rate of hormone secretion into the blood. The second is the rate of removal of the hormone from the blood, which is called the metabolic clearance rate and is usually expressed in terms of the number of milliliters of plasma cleared of the hormone per minute. To calculate this clearance rate, one measures (1) the rate of disappearance of the hormone from the plasma (e.g., nanograms per minute) and (2) the plasma concentration of the hormone (e.g., nanograms per milliliter of plasma). Then, the metabolic clearance rate is calculated with use of the following formula: Metabolic clearance rate= Rate of disappearance of hormone from the plasma/Concentration of hormone The usual procedure for making this measurement is the following: A purified solution of the hormone to be measured is tagged with a radioactive substance. Then the radioactive hormone is infused at a constant rate into the blood stream until the radioactive concentration in the plasma becomes steady. At this time, the rate of disappearance of the radioactive hormone from the plasma equals the rate at which it is infused, which gives one the rate of disappearance At the same time, the plasma concentration of the radioactive hormone is measured using a standard radioactive counting procedure. Then, using the formula just cited, the metabolic clearance rate is calculated. Hormones are “cleared” from the plasma in [Pick the date] Page 16 several ways, including (1) metabolic destruction by the tissues, (2) binding with the tissues, (3) excretion by the liver into the bile, and (4) excretion by the kidneys into the urine. For certain hormones, a decreased metabolic clearance rate may cause an excessively high concentration of the hormone in the circulating body fluids. For instance, this phenomenon occurs for several of the steroid hormones when the liver is diseased because these hormones are conjugated mainly in the liver and then “cleared” into the bile. Hormones are sometimes degraded at their target cells by enzymatic processes that cause endocytosis of the cell membrane hormone-receptor complex; the hormone is then metabolized in the cell, and the receptors are usually recycled back to the cell membrane. Most of the peptide hormones and catecholamines are water soluble and circulate freely in the blood. They are usually degraded by enzymes in the blood and tissues and rapidly excreted by the kidneys and liver, thus remaining in the blood for only a short time. For example, the half-life of angiotensin II circulating in the blood is less than a minute. Hormones that are bound to plasma proteins are cleared from the blood at much slower rates and may remain in the circulation for several hours or even days. The half-life of adrenal steroids in the circulation, for example, ranges between 20 and 100 minutes, whereas the half-life of the protein- bound thyroid hormones may be as long as 1 to 6 days (Guyton and Hall, 2006) Regulation of Hormonal Action The actions of hormones are always regulated. This involves two mechanisms; Up regulation: This is the condition in which fewer hormones are bound to their receptors. As such, binding of more hormones are triggered. (Guyton and Hall, 2006) Down regulation: This is the condition in which they are more hormones than the receptors. As such, binding of hormones are inhibited. (Guyton and Hall, 2006). Negative feedback Mechanism: this is the condition in which the initial release of a hormone leads to an inhibition in the further release of the same hormone e.g. Thyroxine secretion is regulated by negative feedback mechanism. (Barrett et al, 2010) [Pick the date] Page 17 SUMMARY Hormones are chemical substances secreted by ductless gland and are transported in the blood to their site of effect. They are located at different points based on their classes. Steroid hormones have their receptors on cytoplasm, Protein hormones have their receptors on cell membrane, and Amine derived hormones have their receptors in the nucleus. Lipophilic hormones directly activate their receptors to bring about cell response while Hydrophilic hormones activate their receptor and use second messengers for their action. Hormonal actions are usually regulated by up regulation and down regulation, positive and negative. Hormones have varied effects on the body including body physiology and mechanisms. [Pick the date] Page 18 REFERENCES Ananya Mandal (2015). Effects of Hormones. Retrieved from www.news- medical.net/health/Effects- of-hormones. American Physiological Society. 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