C23 - Endocrine Systems PDF

C23 – Endocrine systems I.​ Hypothalamo-hypophysis axis The endocrine system is a system that works continuously. In charge of the maintenance of the trophism of loads of tissues, the metabolism of a lot of tissues. The action of the hormones, especially of the hypothala...

C23 – Endocrine systems I.​ Hypothalamo-hypophysis axis The endocrine system is a system that works continuously. In charge of the maintenance of the trophism of loads of tissues, the metabolism of a lot of tissues. The action of the hormones, especially of the hypothalamus-hypophysial axis, are widespread. The hormone will have more than one target and will respond to a variety of tissues. The endocrine glands under the control of the axis are the ones receiving hormones of the anterior hypophysis. Generally speaking, these are hormones having a widespread action. Glands independent with the control of the axis are glands that control a single parameter so very specific target. 1.​ Endocrine glands under pituitary control Gland Hormone Target Role Chemical structure Thyroid gland Thyroxine (T4) and Most cells Increases metabolic rates: essential for Amine Triiodothyronin (T3) normal growth and nerve development Calcitonin Bone Decreases plasma Ca2+ concentration Peptide Adrenal cortex Zona fasciculata Cortisol Most cells Increases Glood glc ar the expense of Steroid (Glucocorticoid) proteins and fat stores stress Zona reticularis Females: bone and adaptation Steroid Androgen brain Pubertal growth spurt Ovaries (females) Estrogen Female sex organs Promotes follicular development, governs Steroid and body as a female development of secondary sexual whole characters, stimulates uterine and breast growth Bone Promotes closure of epiphyseal plate Progesterone Uterus Prepares for pregnancy Steroid Testes (male) Testosterone Male sex organs Stimulates sperm production, governs Steroid and body as a male development of secondary whole characters, promotes sex drive  Bone Enhances pubertal growth spurt Promotes closure of the epiphyseal plate Testes and ovaries Inhibin Anterior pituitary Inhibits secretion of FSH 2.​ Endocrine glands independent of pituitary control Gland Hormone Target Role Chemical structure Placenta Estrogen and Female sex organs Helps maintain pregnancy, prepares breasts Steroid Progesterone for lactation Human chorionic Ovarian corpus luteum Maintains corpus luteum of pregnancy Peptide gonadotropin (HCG) Pineal Gland Melatonin Brain, anterior Entrains body’s biological rhythm w pituitary, reproductive external cues. organs, immune Inhibits gonadotropins (reduction initiates system puberty) Acts as an antioxidant Thyroid Gland Calcitonin Bone Decreases Ca2+ plasma cct peptide C cells Adrenal cortex Zona Aldosterone Kidney tubules Increases Na+ reabsorption and K+ Steroid glomerulosa secretion Endocrine Insuline (β) Most cells Promotes cellular uptake, use and storage Peptide pancreas of absorbed Glc Glucagon (α) Most cells Maintains Glc levels in postabsorptive state Inhibits digestion and absorption of Somatostatin GIT nutrients Kidneys Renin (activating Zona glomerulosa of Stimulates aldosterone secretion Peptide angiotensin) adrenal cortex via Angiotensin II is a potent vasoconstrictor angiotensin Erythropoietin Bone marrow Stimulates erythrocyte production peptide Stomach Grehlin Hypothalamus Signals hunger and appetite Gastrin GIT, exocrine glands, Controls motility and secretion of digestive smooth muscles, enzymes and absorption pancreas, liver, gallbladder Small intestine Secretin and Endocrine pancreas Stimulates insulin secretion cholecystokinin (CKK) Glucose dependant Endocrine pancreas Stimulates insulin secretion insulinotropic peptide (GIP) Peptide YY3-36 Hypothalamus Signals satiety, supresses appetite Liver Insulin-like GF Bone and soft tissues Promotes growth Thrombopoietin Bone marrow Stimaltes palatelet production Skin Vit.D Intestine Increases absorption of ingested Ca2+ and PO43- Thymus Thymosin LT Enhances LT proliferation and function Heart Atrial natriuretic Kidney tubules Inhibits Na reabsoption peptide (ANP) Adipose tissue Leptin Hypothalamus Suppresses appetite, important for long-term control of body weight Other adipolines Multiple sites Role in metabolism and infection The overall functions of the endocrine in its regulatory role: the endocrine system exerts a wide-ranging effects throughout the body: -​ Regulation of nutrient metabolism -​ Inducing adaptive changes to stressful situation -​ Promoting smooth, sequential growth and development -​ Controlling reproduction -​ Regulating RBC production -​ Along w the ANS, controlling and integrating activities of both the circulatory and GIT. 3.​ Hormonal action The hormones have three level action: -​ Molecular level -​ Cellular level -​ Whole body level 4.​ Hypothalamus-hypophysis axis There are three nuclei sitting: -​ supraoptic, -​ paraventricular -​ arcuate. The supraoptic and paraventricular release vasopressin and oxytocin, and give rise to axons that are going towards the stalk in the posterior hypophysis where there’s the inferior hypophysial artery which is giving the capillary bed and the posterior hypophyseal vein collecting the blood. In the other part of the paraventricular and arcuate, there’s the release of the neurotransmitters into the first capillary bed originating from the superior hypophysial artery, which is giving rise to capillaries that are resulting in long portal vessels, veins, going into the anterior hypophysis. Then there’s the lateral hypophyseal vein which together with the posterior hypophyseal vein are going into the systemic venous circulation. There are short portal vessels that are creating communication between the anterior and the posterior which is to be considered example of neurosecretion where the neurotransmitter is released to the blood and takes a neuroendocrine secretion.  a.​ Hypothalamus and posterior pituitary Gland Hormone Target Role Chemical structure Posterior Antidiuretic Kidney tubules Increases H2O reabsorption Peptide pituitary hormone (ADH or hormones vasopressin) Arterioles Produces vasoconstriction Oxytocin Uterus Increases contractility Peptide Mammary glands Causes milk ejection b.​ Hypothalamus and anterior pituitary While on the anterior portion there’s the release of the releasing hormones in the medial eminence. They go out in the interstitial fluid, meet the cells there and basically induce the release of the hormones in the systemic circulation via the vein. Basically, this is a two-step process. The hypothalamus controls the hypophysis which in turn releases an hormone that will control something else which is usually another gland or in some cases a tissue. Role of the hypothalamic RH (releasing hormones) and IH (inhibiting hormones) The hypothalamus behaves like an endocrine gland (mixed function because is a neural tissue + endocrine function) releasing the RH (releasing hormones). The system is set up in this way: the hypophysis releases its hormones depending on the amount of the RH. There’ no need to have one stimulating and one inhibiting, normally there’s only one RH and it’s its amount that decides the amount of the corresponding hormone from the hypophysis. There’re 6 hormones in the anterior hypophysis so there’re six RHs of the hypothalamus which has also two peculiar hormones, dopamine (acting as a hormone in this case) and somatostatin. These two hormones are inhibiting hormones so there are two cases in which the prolactin and the proteohormone not only have the releasing hormone but also the inhibiting hormone. Considering the 6 hormones of the hypophysis, four of them will be modulated by means of the releasing hormone amount, the other two (prolactin and the proteohormone) have an agonist and antagonist action. These are called hypothalamic-hypophysiotrophic hormones. They always have this trophic, nourishing function meaning that it keeps the tissue trophic, alive with a good activity, other than because it produces hormones, alive in terms of cells production trophic on the tissue not only on that production of the tissue. This means that a deficit of the hormone will result not only in the deficit of the production of the hormones in the means of the target, but also a sort of regression in terms of the tissue elements and an excess is expected to result in hyperplasia, an excess of activity of the cells. It’s important to consider that the consequences of some imbalances can have an effect in deficit but also in excess. An excess of trophic function could push the cells to have a reproductive activity which can then escape the control system. 5.​ Major hypophysiotropic hormones For example, prolactin has the releasing factor, (prolactin is also an exception because it goes onto the tissue directly the target tissue, it doesn’t go on the mammary gland asking to produce hormone n°2 but it goes on the mammary gland asking for the biological effect, production of milk) The GH is an exception because it goes to two targets: the main one is the liver which is an exocrine gland but behaves like an endocrine gland responding to the GH action, releases the IGF (insulin-like grow factors -> somatomedins). IGFs 1 and 2 are the hormones that once realised into the blood, they’ll act following the GH command. So, the axis here, is peculiar not because there isn’t the second hormone which we have it, but because there’s the hypothalamic action, the hypophysial hormone and then the third hormone, the somatomedins which exert the biological effect. The GH however can act directly like the prolactin in some tissues, on which can directly exert the effect or can ask the local production of IGFs. 6.​ Feedbacks (-) a.​ Negative feedback control acting on neurosecretion Vasopressin: A decrease in plasma osmolarity will cause a negative feedback response to the hypothalamus who will decrease its tonic secretion. Other parameters which are also subject to detection and response include: calcium, potassium, sodium and glucose. b.​ Negative feedback on the endocrine axis The selection of control on a specific parameter of a widespread hormone doesn’t not allow a specific action on an organ w/o overriding other organs. This is particularly true for hormones that have pervasive actions such as thyroid, cortisol, gonadotropins, GH etc. The brain acts on trusting the production and amount of the last hormone produced the hormone amount will be the parameter monitored (right amount of hormone right function). Cortisol: a hormone released directly into the blood by the adrenal cortex will induce metabolic actions such as increases in blood glucose, amino acids or fatty acids. If their levels are out of balance, which of them will be selected to modulate the level of cortisol? The level of control is done at the level of the cortisol amount. The issue here is that there can be no choice made as to which one will have more of an influence, so the solution is to rely solely on the level of cortisol, and the control/modulation of the rest of the metabolic actions will follow. The feedback is also relevant for gonadotropins, involving FSH and LH levels and other infraradian rhythms such as estrogen and progesterone, consequences of FSH and LH secretion. Rising levels of estrogens will act on FSH secretion and on the anterior hypothalamus (arcuate and paraventricular) in a negative feedback. Inhibin will also act as a negative regulator. FSH and LH levels are a sufficient regulator. c.​ Negative feedback control acting on endocrine glands that are independent from the axis The hormones will act on a single parameter. Plasma Ca2+: The glands, parathyroid and thyroid C cells, are sensors of Ca2+ levels. A decrease of Ca2+ will enhance PTH levels and decrease calcitonin levels. 7.​ Feedback (+) Positive feedback is rare and occurs only in certain cases where there is a need of a function which requires amplification in a short window of time, typically with an explosive increase of function, and which relies on the fact that the source of stimulation will switch off the system (in the absence of stimulation). Examples of this include the onset of contractions in childbirth (Ferguson reflex). When a contraction occurs, the hormone oxytocin causes a nerve stimulus, which stimulates the hypothalamus to produce more oxytocin, which increases uterine contractions. This results in contractions increasing in amplitude and frequency. Lactation also involves positive feedback in that as the baby suckles on the nipple there is a nerve response into the spinal cord and up into the hypothalamus of the brain, which then stimulates the pituitary gland to produce more prolactin to produce more milk. Note that Oxytocin is necessary for the milk ejection reflex, or let-down, in response to suckling, to occur. Absence of either stimuli, that is in the absence of contraction or the baby suckling, will cut off the loop. 8.​ Rhythmic secretion Feedback mechanisms are not discrete (either have it or not), there are systems which continually modulate hormone release. What matters is the expectation of the parameter (in most cases the hormone), and in the cases of negative feedback this is referred to as a setpoint (the desired value). This is compared to the actual amount of the hormone, and the subsequent feedback loop which is to increase/decrease the parameter as necessary relative to the setpoint, this is what drives the continuous release. a.​ Circadian and diurnal rhythms and pulsatility The secretion rates of many hormones fluctuate up and down as a function of time. Diurnal (day/night) and circadian (24h) rhythms are the most common and are characterised by repetitive oscillations in hormone levels that cycle 1 every 24 hours. Inherent hormonal rhythmicity and entrainment are not accomplished by the endocrine themselves, bit result from the CNS changing the set point of these glands. Negative feedback control mechnisms operate to maintain whatever set point established for that time of day. Constant release doesn’t mean a fixed amount, the setpoint oscillates in accordance with a circadian rhythm. This means that the hypothalamus, for each hormone, expects the desired value to oscillate depending on the time of day. This is what the suprachiasmatic clock does, it communicates with the paraventricular zone of the hypothalmus, indicating the desired value for the specific time of day. In this way the paraventricular zone, will adapt the release of the hormone to the circadian rhythm. For instance, cortisol is expected to be high in the morning and lower in the evenings. The negative feedback, therefore, works on the value set by the suprachiasmatic clock for a particular hormone for a particular time of the day. There are some hormones, such as the gonadotropins in the females, which operate simultaneously on a circadian rhythm and a monthly rhythm, and so the suprachiasmatic clock has to adjust the values on a per day, and on a day-by-day basis according to a monthly (~28 day) cycle. Here everything begins with the neuron and the firing of action potentials, which are discrete signals, and this is what eventually allows for these fluctuations. In thinking about how this occurs, it is important to think about neurons that release their hormones in accordance to pulsatility. Pulsatility is a biochemical phenomenon in which chemical products are secreted in a regular temporal pattern. In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators 🡨 In the graph on the left, the arcuate nucleus activity is measured as pulses as a function of time, this is coupled with the assessments of tiny amount of blood sampled from the medial eminence. In the case on the right, it is the blood that is being sampled over the course of a day. In assessing the graph on the right, consecutive increases and decreases in frequency are observed, and in this context pulsatility means modulating frequencies following pulses. Here pulses do not refer to a single action potential but the frequency of action potentials. A higher number of pulses per min, refers to a higher amount of overall neurotransmitter, as compared to lower pulses and this is assessed as the number of peaks per window of time. So here as the hormone enters the blood a digital signal becomes an analog signal to the anterior hypophysis, for which DLH is accordingly released. If the assessment is made each hour, an average of the pulsatility is observed instead, in the plot a sinusoid is obtained by the different values per time and only through higher resolution it is possible to see the oscillation of the pulses. In the blood there is a huge oscillation at the level of the medial eminence, then the analog will reduce the oscillation because the average will be obtained. An average is observed because the scale of measuring is in the terms of hours, if the resolution was increased and minutes were used instead, the separate peaks would be seen – if every minute would be monitored the following would be observed: a higher frequency of oscillation when there is the peak of the hormone and a lower number of peaks when there is a lower hormonal value. A similar idea is observed on the graph on the right, here concentrations of ACTH are compared to concentrations of glucocorticoids (adrenal hormones). The peaks of the adrenal hormones are slightly more difficult to see in relation to the ACTH, partially because the sampling of the hormones of ACTH are closer to the neurons where greater sensitivity to the pulsatility can be observed, whereas the concentrations of the glucocorticoid are measured more distally in the blood – and so the result is lesser sensitivity to the frequency of oscillation. The higher early morning cortisol levels can be seen in this graph as well. The median eminence at the base of the hypothalamus serves as an interface between the neural and peripheral endocrine systems. It releases hypothalamic-releasing hormones into the portal capillary bed for transport to the anterior pituitary, which provides further signals to target endocrine systems. These series of graphs various hormone levels are plotted. Comparing cortisol, with growth hormone and TSH – it is seen that they are not in the same phase, despite being in the same period, and that is because they do different things. Also, in looking at PTH, which is a hormone that is not involved in the aforementioned axis, but still has a tiny oscillation. Phase is a distinguishable part of a sequence or cycle occurring over time while period is the length of time for an event to run its course. 9.​ Neuroendocrine reflex Mant endocrine control systems involve neuroendocrine reflexes, which include neural and hormonal components. The purpose of such reflexes is to increase hormonal secretion. Some endocrine control systems include bith feedback control (maintain cst basal level of the hormone) and neuroendocrine reflexes (causes sudden bursts in response to sudden need). Ie: cortisol (stress hormone) secreted by the zona fasciculata of the adrenal cortex during a stress response. 10.​Pituitary adenoma In certain cases, there can be disorder of endocrine release due to tumours affecting the hypophysis. As such, tumours can dysregulate release of single or multiple hormones which can result in relevant distress because there is a complete unbalancing of the hormonal secretions. II.​ Anterior pituitary Endocrine systems are wireless because they rely on the bloodstream and can act distally with respect to the origins of secretion. Hormones are chosen by the brain, and with this delegation typically what follows are slow and long-lasting responses. 1.​ Hormones: blood-born hormonal and neurohormonal messengers A neurohormone is any hormone produced and released by neuroendocrine cells (also called neurosecretory cells) into the blood. The hypothalamus releasing hormones (neurohypophysial hormones) in specialized hypothalamic neurons which extend to the median eminence and posterior pituitary. Hormone secretions are made by epithelial cells that belong to the gland/endocrine tissue, while the neurohormone is a neurotransmitter, which also enters the interstitial fluid and ends up in the blood to find its eventual target. For example, the adrenal medulla, produces adrenomedullary hormones in chromaffin cells, cells which are very similar in structure to post-synaptic sympathetic neurons, and hence their behaviour as neurohormonal tissue. These adrenal medullary cells are modified postganglionic neurons, and preganglionic autonomic nerve fibers lead to them directly from the central nervous system. These adrenal medullary cells are modified postganglionic neurons, and preganglionic autonomic nerve fibers lead to them directly from the central nervous system. Because the ANS, specifically the sympathetic division, exerts direct control over the chromaffin cells, the hormone release can occur rather quickly. In response to stressors, such as exercise or imminent danger, medullary cells release the catecholamines adrenaline and noradrenaline into the blood. 2.​ Response vs distance travelled Endocrine action refers to hormones entering blood and affecting distant target. Paracrine and autocrine action differ in the sense that they may or may not be the target of hormones, it can only be considered a hormone if the acting chemical also goes on into the blood to affect other tissues. Paracrine action is local action, and autocrine action is a chemical (or hormone) acting on the same cell that produced. For ex. the release of estrogen from the ovaries acts locally on follicle (which is the major target of estrogen), but the estrogen which is released in the blood makes its way to act on different targets in the body including endometrium, cervix, etc. endocrine and paracrine action. The same correspondence is true for testosterone in the testis. 3.​ Types of hormones There are four groups of hormones organised by biochemical structures: ​ Peptides (less than 20 amino acids) and proteins (greater than 20 amino acids) ​ Steroid – cholesterol derivatives ​ Amino acids – ex. tyrosine which go on to become thyroid hormones ​ Fatty acid derivatives/eicosanoids – will not address these one because they belong to a sperate domain The structure is relevant because the biochemical nature of hormones is significant in every step in the life of the hormone and in the action of the hormone. These differences are significant in terms of production, storage, receptor interactions, blood transport, etc. From the following tables, it can be seen that a good number of hormones belong to the protein family. There are very potent hormones belonging to the steroid family, including the sexual hormones, cortisol, aldosterone and vitamin D. In the amino acid derivatives, which include the catecholamines and the thyroid hormones (2 classes).  4.​ Biosynthesis, storage and secretion of hormones a.​ Peptide/protein hormones Peptide hormones make up the largest family of hormones. They can range from 3-100 amino acids (AA). They are water soluble. They are often produced in the form of a prohormones, larger molecular weight precursors that need to be cleaved before being activated in the form of a hormone. In regard to energy cost, peptide hormones are produced in the form of preprohormones. A preprohormone is the precursor protein to one or more prohormones, which are in turn precursors to peptide hormones. In general, the protein consists of the amino acid chain that is created by the hormone-secreting cell, before any changes have been made to it. Preprohormone prohormone hormone b.​ Amine hormones They are derviatives of Tyrosine, Tryptophan and Glutamate. Thyroid Hormones The thyroid hormones are a double tyrosine, with either 3 (T3) or 4 (T4) iodine atoms. Normally, T4 is release in greater amount than T3 (in humans, the ratio of T4 to T3 released into the blood is approximately 14:1). T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-deiodinase). T4 can lose an iodine at the level of the target tissue, and there will be situations where the iodine will be removed at the wrong position. This means the at the level of the hypothalamus and the hypophysis, there needs to be the awareness that there will be a percentage of the hormone that is lost to this effect, because this axis is constantly summating/computing hormone amounts in addition to the other mechanisms that inactivate the hormone in the blood. Important to note that these molecules are lipid soluble, which is in contrast to the catecholamines which are water soluble. Thyroid hormones are basically a « double” tyrosine with the cirtical incorporation of 3 ro 4 iodine atoms. It is lipid solble. Catecholamines As mentioned before despite the same precursor, they are in fact water soluble. Catecholamines are both neurohormones secreted like peptide hormones and neurotransmitters, and these include epinephrine, and norepinephrine. Remaining Amine Hormones -​ melatonin and serotonin are derived from tryptophan -​ and histamine derived from glutamic acid c.​ Steroid hormones Steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it, and all are lipid soluble. The classes of steroid hormones are as follows: Glucocorticoids: cortisol is the major representative in most mammals Mineralocorticoids: aldosterone being most prominent Androgens: such as testosterone Estrogens: including estradiol and estrone Progestogens (also known a progestins): such as progesterone Normally in the long chain of synthesis that goes from the precursor to the final chemical, it is typically the final chemical that is found in the highest amount and most powerful with respect to the function. In the picture below are the classes of the steroid hormones and some of the pathways that lead to their production. Some important things to note in this diagram is the main chemical representative for each class of hormone, and how some hormones can act as intermediates for other hormones. When thinking about hormones, being water soluble or lipid soluble is not an issue for the body but the consideration remains that the hormones have to enter the blood. Lipid soluble hormones aren’t completely insoluble but have a small fraction of the molecule which cannot interact with water. One thing to consider for peptide hormones is that when they are not needed, they can be stored in cells inside vesicles. The same is not true for steroid hormones, because they will escape the lipid membrane. This in turn means that the production and release of peptide hormones are two separate processes, while for the lipid hormones is instead a single process. This is relevant for the control of the hormones, because the brain needs to know the difference in order to modulate the velocity and frequency of release of hormones in the case of needs. Features of Steroid Hormones (this slide was not directly discussed in the lecture) ​ Are not packaged, but synthesized and immediately released ​ Enzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ER ​ The cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol- containing low density lipoproteins. ​ Lipoproteins taken up from plasma are most important when steroidogenic cells are chronically stimulated. ​ Steroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells ​ The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the steroidogenic acute regulatory protein (star) 5.​ Transport of hormones in the blood While the transport of hydrophilic hormones in the blood is relatively straight forward (directly soluble), the insoluble nature of lipophilic necessitates the use of carriers/plasma proteins. For each lipid soluble hormone there are specific proteins that receives the hormone in the blood, therefore thyroid and steroid hormones. If there is a total amount of hormone release by the gland and a majority is bound to the protein, there will be an amount that remains in free faction. Most homones circulate in the blood in a free solution at a nmol concentration. Steroid hormones and thyroid hormones circulate bound to specific carrier p° synthesized in the liver. Binding allows: -​ Protection against the loss of the hormone in the kidney -​ Slows the arte of degredation by decreasing cellular uptake -​ Buffer changes in free hormone concentration -​ May facilitate or impede delivering of hormones to particular cells In the image below the reaction happening between hydrophobic hormones with the plasma protein in blood is shown. The size and direction of the arrow represents the overall equilibrium of this binding reaction. Bound hormones (PlasmP-Hormone) are in equilibrium with a small fraction of unbound hormones (can be less than 1%) in free plasma solution. The free fraction or the unbound hormone is the one that directly interacts with the target. As this is removed from the solution, the equation above will resolve the equilibrium by reverting some of the bound hormone to the unbound hormone to maintain the free fraction. Steroid and thyroid hormones require carrier proteins, and even some peptidic hormones also have carrier proteins despite not needing them. Circulating levels of free hormones in the blood remain in minimal amounts, at nanomolar or picomolar concentrations. The concentration of free plus bound equals total hormone concentration in the blood but only free is active, as seen in the reaction. Biological responses are related to the concentration of hormones that reach the cells, rather than the total amount present in blood, so then increasing in a binding protein (pregnancy) or reduction (liver disease) may produce changes in the total amount event though the free concentration is the same! How can the hormone recognize the appropriate target? One of the advantages of the blood is that it travels everywhere, but the specificity to the target is dependent on the receptor of the hormone – key and lock. Depending on the biochemical structure of the hormone the location of the receptor may be variable, for peptidic hormones for instance the receptor is on the wall of the plasma membrane. The message in this case isn’t necessarily the hormone but the events that follow binding. Steroid hormones on the other hand have their receptors inside the cell, either in the cytoplasm or the nucleus. But in being bound to a protein how does it traverse the lipid membrane of the target cell? This is where the free fraction comes into play. The free fraction is the relevant metric to be looked at by a physician, in a constant condition it is easy to infer the total amount of free fraction will be a percentage of the total amount, so in knowing a total amount it is possible to infer the free fraction. But why is it important to measure the free fraction? Since the plasma proteins are released by the liver and there can be situations (like pregnancy) where the setpoints are loosened, the imbalance is in the total amount (bound + unbound), and this doesn’t result an imbalance in the free fraction. If there is no problem in the gland, the brain will correct the hormone released to match and maintain the same level of free fraction, taking into account the level of plasma protein. For instance, where there is an increase in plasma protein level there will be a decrease in the free fraction because the equilibrium will be shifted to accommodate this increase, and so in response the hypothalamus will make the necessary changes to increase hormone production and release to maintain the free fraction level. This is important because it maintains a level of control that is separate from the protein production. Protection from the liver is also of importance, since it is a processing organ that is capable of modifying chemical species, and as a result the hormone can be lost in this way. This is important because the principles of the endocrine system (in relation to the other systems of the body) mimic the principles of pharmacology, in terms of dosage, administration, kinetics, dynamics etc. 6.​ Half-life of hormones Is defined as the time required for the concentration of the hormone to be reduced by exactly one half of its original concentration. The half-life of the hormone depends on: -​ Rate of degradation -​ Rapidity of escape from blood and equilibration with interstitial fluids (metabolic clearance rate) Half-life and duration of the hormonal effect Half-life corresponds to the time taken for the clearance and inactivation of the hormone. There is an important distinction which is that the half-life doesn’t correspond to the duration of hormonal effect (can last longer or shorter relative to the half-life), and which can depend on factors related to the transcription of genes for example. Steroid hormones are not water soluble and are carried in the blood via specific bindings globulins. -​ Corticosteroid binding globulin carries cortisol -​ Sex steroid binding globulin carries testosterone and estradiol In some cases, steroid is produced (androgen) and then uptaken to be converted by the target cell (estrogen). Peptide/protein hormones circulate free in the blood, but can be bound to carriers. 7.​ Action Surface binding hydrophilic hormones function largely by activating 2nd messenger within the target cell. This activation directly alters the activity of the pre-existing IC p°, usually enzymes to produce the desired effect. Lipophilic hormones function by activating specific genes in the target cell to cause the formation of new IC proteins, which in turn produce the desired effect. 8.​ Responsiveness In order to have a biological effect a threshold related to the number of activated receptors, must be met. A linear relationship with the biological effect begins after threshold, and the effect stops when the number reaches the plateau or the point of saturation. Between threshold and saturation, the body can regulate a few factors depending on requirements. In the blood, the amount of the hormone is the parameter analysed and in the receiving tissue, cells can modulate the number of receptors. This means that effect depends only on the hormones but also on the number of receptors for that hormone. The hormone level can be sensed by cells that in turn regulate the number of their receptors, and so the cell mechanically tries to maintain the effect at the same level. The cell can either down-regulate (preventing the target cells from overreacting to a prolonged high concentration) or up-regulate (sustaining the vitality of target cells despite a prolonged low concentration of hormone) the receptors depending on the conditions. The responsiveness of a target cell can be varied by regulating the number of hormone specific receptors. The receptor number and affinity can be altered in specific circumstances. Down regulation is when the plasma concentration of a hormone is chronically high, the total number of target cell receptors for the hormone is reduced. It is essential for specific local negative feedback to prevent the cell from overacting to a chronically high concentration of a hormone. Up regulation is when the plasma concentration of a hormone is chronically low, causing the gradual increase of receptor cells. It allows the sustentation of the vitality of cell facing a prolonged low concentration of hormone. Additionally, there are other factors related to cell responsiveness: -​ Permissiveness: another hormone must be present in a sufficient amount for the full exertion of another hormones effect on its target. enhances another hormone o​ Thyroid hormone increases the receptors for Epi in epinephrine’s target cells. W/o thyroid hormone, the epinephrine is marginally effective. -​ Synergism: occurs when the actions of several hormones are complementary and their combined effect is greater than the sum of their seperaye effects. o​ Synergestic action of FSH and testosterone, both which are needed to maintain the normal rate of sperm production. -​ Anatgonism: hormone causes the loos of another hormone’s receptos reducing the effectiveness of the second hormones o​ Progesterone inhibits the uterine responsiveness to estrogen by causing the loss of estrogen receptors.