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The Endocrine System Introduction to Endocrinology

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<ul><li>Overview and functions of endocrine system </li></ul><ul><li>Endocrine glands and types of secretion </li></ul><ul><li>Hormones and their function </li></ul><ul><li> - hormones receptors </li></ul><ul><li> - types of hormones </li></ul><ul><li> - mechanism of hormone action </li></ul><ul><li>Regulation of endocrine system </li></ul><ul><li>Endocrine and nervous systems </li></ul>

3.
Homeostasis of Some Body Parameters is Necessary for Life <ul><li>Cells of the body require specific conditions to survive and function </li></ul><ul><li>Maintenance of body conditions in a stable steady state is called homeostasis </li></ul><ul><li>Some of the body parameters kept in a steady state: </li></ul><ul><li>Body temperature: regulated close to 37 deg C </li></ul><ul><li>Blood pH: kept at 7.4 </li></ul><ul><li>Arterial blood pressure: maintained around 120/80 mm Hg </li></ul><ul><li>Failure of homeostasis causes diseases and sometimes death </li></ul>

4.
The Major Control Systems in the Body are the Nervous and Endocrine Systems The Nervous System Uses Electrical Transmission of Signals The Endocrine System Uses Chemical Transmission of Signals <ul><li>Like a radio or TV: signal broadcast to whole body- to pick it up cells need specific receptors </li></ul><ul><li>Endocrine organs secrete hormones into the blood </li></ul><ul><li>Delivery time of chemical signal less than a minute (entire blood supply circulates </li></ul><ul><li>about once every minute) </li></ul><ul><li>Hormones are broken down rapidly, but they set in motion effects that may </li></ul><ul><li>persis t a fter the hormones are gone: stimulate metabolism, turn on genes, etc.. </li></ul><ul><li>Much of the endocrine system is controlled by the nervous system: hypothalamus </li></ul><ul><li>and pituitary control a wide range of hormones through trophic hormones </li></ul>

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Adrenal glands Divided into 2 regions; secrete hormones that influence the body's metabolism, blood chemicals, and body characteristics, as well as influence the part of the nervous system that is involved in the response and defense against stress. Hypothalamus Activates and controls the part of the nervous system that controls involuntary body functions, the hormonal system, and many body functions, such as regulating sleep and stimulating appetite. Ovaries and testicles Secrete hormones that influence female and male characteristics, respectively. Pancreas Secretes a hormone (insulin and glucagon ) that controls the use of glucose by the body. Parathyroid glands Secrete a hormone that maintains the calcium level in the blood. Pineal body Involved with daily biological cycles. Pituitary gland Produces a number of different hormones that influence various other endocrine glands. Thymus gland Plays a role in the body's immune system. Thyroid gland Produces hormones that stimulate body heat production, bone growth, and the body's metabolism.

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Evolution of Endocrine Systems Most animals with well-developed nervous and circulatory systems have an endocrine system. The vertebrate endocrine system consists of glands and diffuse cell groups scattered in epithelial tissues . More than fifty different hormones are secreted. Endocrine glands arise during development for all three embryologic tissue layers (endode rm, mesoderm, ectoderm). The type of endocrine product is determined by which tissue layer a gland originated in. Glands of ectodermal and endodermal origin produce peptide and amine hormones; mesodermal-origin glands secrete hormones based on lipids.

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Types of secretion Endocrine secretion – substance released by cell into blood stream that affects distant cells Exocrine secretion – substance released by cell into a duct that leads to epithelial surface (onto skin or into gut). Action doesn’t depend on receptors in target tissue. Endocrine and exocrine secretions are glandular secretions ; they come from specialized secretory cells that are clumped together to form a gland. Secretion may have several sites of action simultaneously .

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Distinguish different communication pathways Paracrine: Cell produces hormone that stimulates or inhibits itself Cell produces hormone that stimulates or inhibits its neighbor Cells sit side by side. One has hormone on surface, the other has the receptor. Juxtacrine :

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The term hormone is derived from Greek verb which means to excite First was used by William Bayliss and Ernest Starling in 1902 to describe the action of secretin (hormone of duodenum) Based more on physiological effects hormones are signal molecules, products of glandular cells, which are secreted into the the internal medium, mostly into the blood. Acting target cells and in turn they respond with changing of functional and nutritional status

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<ul><li>What do hormones do? </li></ul><ul><li>Stimulate cell function (e.g. insulin stimulates glucose uptake) </li></ul><ul><li>Inhibit cell function (e.g. somatostatin inhibits Growth hormone </li></ul><ul><li>secretion) </li></ul><ul><li>Maintain status quo (e.g. maintain blood calcium level) </li></ul><ul><li>Stimulate or inhibit cell division (growth or renewal of tissues or </li></ul><ul><li>organs) </li></ul><ul><li>Stimulate cell differentiation </li></ul><ul><li>Stimulate “programmed cell death” or protect cells from this </li></ul><ul><li>process (apoptosis) </li></ul>

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H Gland (secretory cell) M Metabolic organ R Target tissue (target cell) effects Receptor Our endocrine system is a collection of glands that produce hormones that regulate our body's growth, metabolism, and sexual development and function. The hormones are released into the bloodstream and transported to tissues and organs throughout your body.

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<ul><li>Hormones are active at low concentration, so the glandular production </li></ul><ul><li>is usually small. </li></ul><ul><li>Endocrine system includes system of hormone distribution and </li></ul><ul><li>elimination: </li></ul><ul><li>a few hormones circulate simply dissolved in the blood, but most are carried in the blood bound to plasma proteins </li></ul><ul><li>elimination takes place through liver and kidneys </li></ul><ul><li>Cell secret hormones into the blood stream </li></ul><ul><li>Vascular system is a conduit for hormone </li></ul><ul><li>May have a widespread effect </li></ul><ul><li>Endocrine cells may in turn be regulated by other hormones (sometimes from distant </li></ul><ul><li>part from the body) </li></ul><ul><li>The endocrine system is made up of subsystems; each has a regulatory </li></ul><ul><li>circuitry </li></ul>

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The endocrine system establishes as adequate hormone concentration at the level of receptors on target cells.

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Functions Structure Hormone acts on thyroid follicle cells to stimulate throid hormone synthesis 2 proteins:  is 96 amino acids;  is 112 Thyrotropin (TSH) stimulates cells of adrenal gland to increase steroid synthesis and secretion polypeptide = 39 amino acids Corticotropin (ACTH) pigmentation  polypeptide = 13 amino acids  polypeptide = 18 amino acids  polypeptide = 12 amino acids Melanocyte-stimu- lating hormone (MSH) general anabolic stimulant, increases release of insulin-like growth factor-I (IGF-I), cell growth and bone sulfation protein of 191 amino acids Growth hormone (GH) responds to osmoreceptor which senses extracellular [Na + ], blood pressure regulation, increases H 2 O readsorption from distal tubules in kidney polypeptide of 9 amino acids CYFQNCPRG (C's are disulfide bonded) Vasopressin uterine contraction, causes milk ejection in lactating females, responds to suckling reflex and estradiol, lowers steroid synthesis in testes polypeptide of 9 amino acids CYIQNCPLG (C's are disulfide bonded) Oxytocin Pituitary Hormones

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acts on lactotrope to release prolactin this may be TRH Prolactin-releasing factor (PRF) acts on gonadotrope to release LH and FSH polypeptide of 10 amino acids Gonadotropin-releasing factor (GnRF) acts on corticotrope to release ACTH and  -endorphin (lipotropin) protein of 41 amino acids Corticotropin-releasing factor (CRF) Hypothalamic Hormones acts on lactotrope to inhibit prolactin release may be derived from GnRH precursor, 56 amino acids Prolactin-releasing inhibiting factor (PIF) ovarian follicle development and ovulation, increases estrogen production; acts on Sertoli cells of semiferous tubule to increase spermatogenesis 2 proteins:  is 96 amino acids;  is 120 Follicle-stimulating Hormone (FSH) increases ovarian progesterone synthesis, luteinization; acts on Leydig cells of testes to increase testosterone synthesis and release and increases interstitial cell development 2 proteins:  is 96 amino acids;  is 121 Luteinizing hormone (LH) protein of 197 amino acids protein of 197 amino acids Prolactin

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acts as a vasodilator protein of 37 amino acids, product of the calcitonin gene derived by alternative splicing of the precursor mRNA in the brain Calcitonin gene-related peptide (CGRP) produced in parafollicular C cells of the thyroid, regulation of Ca 2+ and P i metabolism protein of 32 amino acids Calcitonin responds to TSH and stimulates oxidations in many cells iodinated dityrosin derivatives Thyroxine and triiodothyronine Thyroid Hormones stimulates TSH and prolactin secretion polypeptide of 3 amino acids Thyrotropin-releasing factor (TRF) inhibits GH and TSH secretion polypeptide of 14 and 28 amino acids Somatostatin stimulates GH secretion protein of 40 and 44 amino acids Growth hormone releasing factor (GRF)

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secreted from duodenum at pH values below 4.5, stimulates pancreatic acinar cells to release bicarbonate and H 2 O 27 amino acids Secretin produced by stomach antrum, stimulates acid and pepsin secretion, also stimulates pancreatic secretions 17 amino acids Gastrin inhibits secretion of gastric acid, enhances insulin secretion polypeptide of 42 amino acids Glucose-dependent insulinotropic polypeptide (GIP) originally called gastric inhibitory polypeptide potentiates glucose-dependent insulin secretion, inhibits glucagon secretion, inhibits gastric emptying Two forms: 31 amino acids, GLP-1(7-37) and 30 amino acids, GLP-1(7-36)amide Glucagon-like peptide 1 (GLP-1) formerly called enteroglucagon Hormones and Peptides of the Gut regulation of Ca 2+ and P i metabolism, stimulates bone resorption thus increasing serum [Ca 2+ ], stimulates P i secretion by kidneys protein of 84 amino acids Parathyroid hormone (PTH) Parathyroid Hormone

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suppresses glucose-induced insulin secretion, inhibits bicarbonate and protein secretion from pancreas 36 amino acids Pancreatic Polypeptide, PP CNS function in pain (nociception), involved in vomit reflex, stimulates salivary secretions, induces vasodilation antagonists have anti-depressant properties 11 amino acids Substance P a member of the tachykinin family that includes neurokinin A (NKA) and neurokinin B (NKB) inhibits release and action of numerous gut peptides, e.g. CKK, gastrin, secretin, motilin, GIP; also inhibits insulin and glucagon secretion from pancreas 14 amino acid version Somatostatin produced by hypothalamus and GI tract, relaxes the GI, inhibits acid and pepsin secretion, acts as a neurotransmitter in peripheral autonomic nervous system, increases secretion of H 2 O and electrolytes from pancreas and gut 28 amino acids Vasoactive intestinal peptide (VIP) controls gastrointestinal muscles 22 amino acids Motilin stimulates gallbladder contraction and bile flow, increases secretion of digestive enzymes from pancreas 33 amino acids Cholecystokinin, CCK

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increases glycogenolysis, regulation of gastrointestinal activity polypeptide of 36 amino acids Pancreatic polypeptide produced by  -cells of the pancreas, increases lipid mobilization and glycogenolysis in order to increase blood glucose levels polypeptide of 29 amino acids Glucagon inhibition of glucagon and somatotropin release 14 amino acid version Somatostatin produced by  -cells of the pancreas, increases glucose uptake and utilization, increases lipogenesis, general anabolic effects disulfide bonded dipeptide of 21 and 30 amino acids Insulin Pancreatic Hormones homology to EGF and binds to the EGF receptor (EGFR) 2 peptides: 78 amino acid truncated form and 84 amino acid form with 6 additional N-terminal amino acids Amphiregulin effects on hypothalamic function in appetite, controls feeding behavior and energy homeostasis, levels increase during starvation to induce food intake 36 amino acids 6 receptors Neuropeptide Tyrosine, NPY inhibits gastric motility by inhibiting cholinergic neurotransmission, inhibits gastric acid secretion 36 amino acids Peptide Tyrosine Tyrosine, PYY

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maturation and function of male secondary sex organs steroid; testosterone Androgens (testicular) implantation of ovum and maintenance of pregnancy steroid; progesterone Progestins (ovarian) maturation and function of female secondary sex organs steroids; estradiol and estrone Estrogens (ovarian) Gonad Hormones produced in ovarian corpus luteum, inhibits myometrial contractions, secretion increases durin g gestation 2 proteins of 22 and 32 amino acids Relaxin inhibition of FSH secretion 1 protein (  is 134 amino acids;  is 115 and 116 amino acids Inhibins A and B acts like prolactin and GH protein of 191 amino acids Placental lactogen activity similar to LH 2 proteins:  is 96 amino acids;  is 147 Chorionic gonadotropin mimic action of progesterone steroids Progestins maintenance of pregnancy steroids Estrogens Placental Hormones

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responsible for essential hypertension through stimulated synthesis and release of aldosterone from adrenal cells polypeptide of 8 amino acids derived from angiotensinogen (present in the  2 -globin fraction of plasma) which is cleaved by the kidney enzyme renin to give the decapeptide, angiotensin I, the C-terminal 2 amino acids are then released (by action of angiotensin-converting enzyme, ACE) to yield angiotensin II Angiotensin II Liver Hormones lipid mobilization, arteriole contraction tyrosine derivative Norepinephrine (noradrenalin) glycogenolysis, lipid mobilization, smooth muscle contraction, cardiac function derived from tyrosine Epinephrine (adrenalin) Adrenal Medullary Hormones maintenance of salt balance steroids; aldosterone Mineralocorticoids diverse effects on inflammation and protein synthesis steroids; cortisol and corticosterone Glucocorticoids Adrenal Cortical Hormones

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regulation of circadian rhythms N -acetyl-5-methoxytryptamine Melatonin Pineal Hormones released from heart atria in response to hypovolemia, acts on outer adrenal cells to decrease aldosterone production; smooth muscle relaxation several active peptides cleaved from a 126 amino acid precursor Atrial natriuretic peptide (ANP) Cardiac Hormones responsible for maintenance of calcium and phosphorous hoemostasis, increases intestinal Ca 2+ uptake, regulates bone mineralization derived from 7-dehydrocholesterol Calcitriol [1,25-(OH) 2 -vitamin D 3 ] Kidney Hormones

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<ul><li>True hormones are secreted into the blood by endocrine glands. E.g. thyroxine, epinephrine (adrenaline), testosterone, estradiol, insulin </li></ul><ul><li>Neurohormones are secreted by nerve cells, Antidiuretic Hormone (ADH) and oxytocin </li></ul><ul><li>Pheromones are air-borne signals secreted by exocrine glands and stimulate target cells in another animal, usually of the opposite sex. Sex pheromones have been found in insects, mammals, reptiles. Mammals that &quot;mark their territory&quot; with urine, feces, and scent glands do so through the action of pheromones. Androstenone (in pigs) of a male pheromone that elicits a pattern of behavior in females. </li></ul><ul><li>Interferons are proteins released by cells in response to viral infection. They stimulate the release of antiviral proteins (enzymes) that act to destroy the virus. Interferons also activate the immune system to attack cancer cells. </li></ul><ul><li>Prostaglandins are fatty acid-based chemicals that are made in most of the tissues of the body. They have a diverse range of actions, including inflammation, fever, and development of pain. Many of their actions are associated with control of smooth muscle cells in blood vessels. Medication that reduces swelling and inflammation, and reduces fever work by counter acting prostaglandins. </li></ul>

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Hormones are grouped into three classes based on their structure: Steroids P eptides A mines

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Steroids Steroids are lipids derived from cholesterol. Steroid hormones are secreted by the gonads, adrenal cortex, and placenta.

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Structure of some steroid hormones and their pathways of formation

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Peptides and Amines Peptides are short chains of amino acids; most hormones are peptides. They are secreted by the pituitary, parathyroid, heart, stomach, liver, and kidneys. Amines are derived from the amino acid tyrosine and are secreted from the thyroid and the adrenal medulla. Solubility of the various hormone classes varies.

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Mechanisms of Hormone Action The endocrine system acts by releasing hormones that in turn trigger actions in specific target cells. Receptors on target cell membranes bind only to one type of hormone. More than fifty human hormones have been identified; all act by binding to receptor molecules. The binding hormone changes the shape of the receptor causing the response to the hormone. There are two mechanisms of hormone action on all target cells. Nonsteroid Hormones or Hormones with Cell Surface Receptors Steroid Hormones or Hormones with Intracellular Receptors

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Nonsteroid Hormones (water-soluble) or Hormones with Cell Surface Receptors Protein and peptide hormones, catecholamines and prostaglandins find their receptors decorating the plasma membrane of target cells. Binding of hormone to receptor initiates a series of events which leads to generation of so-called second messengers within the cell (the hormone is the first messenger ). The second messengers then trigger a series of molecular interactions that alter the physiologic state of the cell. Synonym signal transduction .

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Structure of Cell Surface Receptors <ul><li>Cell surface receptors are integral membrane proteins and, as such, </li></ul><ul><li>have regions that contribute to three basic domains: </li></ul><ul><li>Extracellular domains: Some of the residues exposed to the outside of the </li></ul><ul><li>cell interact with and bind the hormone - another term for these regions is </li></ul><ul><li>the ligand-binding domain . </li></ul><ul><li>Transmembrane domains: Hydrophobic stretches of amino acids are </li></ul><ul><li>&quot;comfortable&quot; in the lipid bilayer and serve to anchor the receptor </li></ul><ul><li>in the membrane. </li></ul><ul><li>Cytoplasmic or intracellular domains: Tails or loops of the receptor that are </li></ul><ul><li>within the cytoplasm react to hormone binding by interacting in some way </li></ul><ul><li>with other molecules, leading to generation of second messengers. </li></ul><ul><li>Cytoplasmic residues of the receptor are thus the effector region of the molecule </li></ul>

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Several distinctive variations in receptor structure

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Second Messenger Systems Consider what would happen if, late at night, you noticed a building on fire … Second messenger Examples of hormones which utilize this system Cyclic AMP Epinephrine and norepinephrine, luteinizing hormone, follicle stimulating hormone, thyroid – stimulating hormone, calcitonin, parathyroid hormone, antidiuretic hormone Protein kinase activity Insulin, growth hormone, prolactin, oxytocin, erythropoietin, several growth factors Calcium and/or phosphoinositides Epinephrine and norepinephrine, angiotensin II, antidiuretic hormone, gonadotropin-releasing hormone, thyroid-releasing hormone Cyclic GMP Atrial naturetic hormone, nitric oxide.

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Second messengers activate other intracellular chemicals to produce the target cell response

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<ul><li>Glucagon binds its receptor in the plasma membrane of target cells (e.g. hepatocytes). </li></ul><ul><li>Bound receptor interacts with and, through a set of G proteins, </li></ul><ul><li>turns on adenylate cyclase, which is also an integral membrane protein . </li></ul><ul><li>Activated adenylate cyclase begins to convert ATP to cyclic AMP, </li></ul><ul><li>resulting in an elevated intracellular concentration of cAMP. </li></ul><ul><li>High levels of cAMP in the cytosol make it probable that protein </li></ul><ul><li>kinase A will be bound by cAMP and therefore catalytically active. </li></ul><ul><li>Active protein kinase A &quot;runs around the cell&quot; adding phosphates </li></ul><ul><li>to other enzymes, thereby changing their conformation and </li></ul><ul><li>modulating their catalytic activity … </li></ul><ul><li>Levels of cAMP decrease due to destruction by </li></ul><ul><li>cAMP-phosphodiesterase and the inactivation of adenylate cyclase. </li></ul>

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Steroid Hormones or Hormones with Intracellular Receptors Receptors for steroid and thyroid hormones are located inside target cells, in the cytoplasm or nucleus, and function as ligand-dependent transcription factors . T he hormone-receptor complex binds to promoter regions of responsive genes and stimulate or inhibit transcription from those genes. T he mechanism of action of steroid hormones is to modulate gene expression in target cells

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Structure of Intracellular Receptors <ul><li>Steroid and thyroid hormone receptors are members of a large </li></ul><ul><li>group (&quot;superfamily&quot;) of transcription factors. T hese receptors </li></ul><ul><li>are composed of a single polypeptide chain that has three distinct domains: </li></ul><ul><li>The amino-terminus : t his region is involved in activating </li></ul><ul><li>or stimulating transcription by interacting with other components of </li></ul><ul><li>the transcriptional machinery. The sequence is highly variable among </li></ul><ul><li>different receptors. </li></ul><ul><li>DNA binding domain : Amino acids in this region are responsible </li></ul><ul><li>for binding of the receptor to specific sequences of DNA. </li></ul><ul><li>The carboxy-terminus or ligand-binding domain : the region </li></ul><ul><li>that binds hormone. </li></ul>

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Hormone-Receptor Binding and Interactions with DNA Being lipids, steroid hormones enter the cell by simple diffusion . Thyroid hormones enter the cell by facilitated diffusion . The receptors exist either in the cytoplasm or nucleus, which is where they meet the hormone. When hormone binds to receptor, a series of events occurs: <ul><li>Receptor activation . I nduced by binding hormone. The major consequence </li></ul><ul><li>of activation is that the receptor becomes competent to bind DNA . </li></ul><ul><li>Activated receptors bind to &quot;hormone response elements&quot; , which are </li></ul><ul><li>short specific sequences of DNA which are located in promoters of </li></ul><ul><li>hormone-responsive genes. </li></ul><ul><li>Transcription from those genes to which the receptor is bound is </li></ul><ul><li>affected. R eceptor binding stimulates transcription. </li></ul><ul><li>The hormone-receptor complex thus functions as a transcription factor. </li></ul>

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Steroid hormones bind, once inside the cell, to the nuclear membrane receptors, producing an activated hormone-receptor complex. The activated hormone-receptor complex binds to DNA and activates specific genes, increasing production of proteins.

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Endocrine Systems and Feedback Cycles The endocrine system uses cycles , negative feedback and a ntagonistic pairs of hormones to regulate physiological functions. Negative feedback regulates the secretion of almost every hormone. Cycles of secretion maintain physiological and homeostatic control. These cycles can range from hours to months in duration.

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Negative feedback in the thyroxine release reflex A ntagonistic pairs of hormones <ul><li>Insulin causes the level of blood sugar (glucose) to drop when it has risen. </li></ul><ul><li>Glucagon causes it to rise when it has fallen. </li></ul>

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Endocrine-related Problems <ul><li>Overproduction of a hormone </li></ul><ul><li>Underproduction of a hormone </li></ul><ul><li>3. Nonfunctional receptors that cause target cells to become </li></ul><ul><li>insensitive to hormones </li></ul>

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Biological Cycles Cycles involve hibernation, mating behavior, body temperature and many other physiological processes. Rhythms or cycles that show cyclic changes on a daily (or even a few hours) basis are known as circadian rhythms . Many hormones, such as ACTH-cortisol, TSH, and GH show circadian rhythms. The menstrual cycle is controlled by a number of hormones s ecreted in a cyclical f ashion. Thyroid secretion is usually higher in winter than in summer. Childbirth is hormonally controlled, and is highest between 2 and 7 AM. Internal cycles of hormone production are controlled by the hypothalamu s , specifically the suprachiasmic nucleus (SCN). According to one model, the SCN is signaled by messages from the light-detecting retina of the eyes. The SCN signals the pineal gland in the brain to signal the hypothalamus, etc.

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The Nervous and Endocrine Systems There is a stalk links the pituitary to the hypothalamus, which controls r elease of pituitary hormones. The hypothalamus contains neurons that control releases from the anterior pituitary. Seven hypothalamic hormones are released into a portal system connecting the hypothalamus and pituitary, and cause targets in the pituitary to release eight hormones.

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The location and roles of the hypothalamus and pituitary glands