H171 Endocrinology Lectures 2024 PDF

H171 Endocrinology Lectures 2024 Prof. Faadiel Essop Room 3027, BMRI Email: [email protected]  Resources Silverthorn: Human Physiology – an integrated approach (8th ed) Parts of chapters 7, 22 & 23  What do we...

H171 Endocrinology Lectures 2024 Prof. Faadiel Essop Room 3027, BMRI Email: [email protected]  Resources Silverthorn: Human Physiology – an integrated approach (8th ed) Parts of chapters 7, 22 & 23  What do we mean by ‘’endocrinology’’? Friederich Henle (1841) was the first to recognize “ductless glands,” i.e. glands that secrete their products into the bloodstream and not into specialized ducts Claude Bernard (1855) distinguished the products of these ductless glands from other glandular products by the term “internal secretions” & the first suggestion of what was to become the Friederich Henle modern hormone concept 1809-1885 Etymology of ‘’endocrinology’’: - endo referring to ‘’internal’’ & krinein meaning ‘’separate’’ (both terms from Ancient Greek) - thus, the hidden meaning implies the quality of specialized glands to secrete hormones Claude Bernard 1813-1878 https://www.aace.com/all-about-endocrinology/what-endocrinology https://www.britannica.com/science/endocrinology Endocrine versus exocrine glands https://www.chegg.com/flashcards/advanced-nutrition-chapter-2- 75582285-60a7-4708-8c7b-9ccc269a72d6/deck  Endocrine versus exocrine glands Endocrine glands: Ductless glands, i.e. no tubes to carry to various parts Secretions released directly into blood which carries them to various parts of the body Exocrine glands: Possess ducts & secretions are carried through such ducts Such ducts may open outside the body to release secretions (for e.g. sweat, milk) or may be released onto another surface within the body (for e.g. digestive juices) https://www.toppr.com/ask/content/concept/types-of-glands-201158/  What do we mean by ‘’hormone’’? Hormone: From the Greek hormon meaning: "that which sets in motion“ Ernest Starling (1905) coined the term ‘’hormone’’ that he defined as: “a substance produced by glands with internal secretion, which serve to carry signals through the blood to target organs” Ernest Starling Biology Dictionary (2019): 1866-1927 ‘’A hormone is a biological compound used by multicellular organisms to organize, coordinate, & control the functions of their cells and tissues. These chemicals can control everything from metabolism to behavior“. https://www.etymonline.com/word/hormone https://biologydictionary.net/hormone/  What do we mean by ‘’endocrinology’’? Friederich Henle (1841) was the first to recognize “ductless glands,” i.e. glands that secrete their products into the bloodstream and not into specialized ducts Claude Bernard (1855) distinguished the products of these ductless glands from other glandular products by the term “internal secretions” & the first suggestion of what was to become the Friederich Henle modern hormone concept 1809-1885 Etymology of ‘’endocrinology’’: - endo referring to ‘’internal’’ & krinein meaning ‘’separate’’ (both terms from Ancient Greek) - thus, the hidden meaning implies the quality of specialized glands to secrete hormones Endocrine system: System of glands & cells that make hormones that are released directly into the blood and travel to tissues and organs all over the body to elicit a specific action(s) Claude Bernard 1813-1878 This system responsible for long-term ongoing functioning of the body: for e.g. controls growth & development, sexual development & function, reproduction, sleep, heart rate & blood pressure, hunger, metabolism, mood, responses to stress https://www.aace.com/all-about-endocrinology/what-endocrinology https://www.britannica.com/science/endocrinology  Most important endocrine glands that secrete hormones Note: organs/tissues like stomach, small intestine, heart, kidneys, and placenta (during pregnancy) also secrete some hormones https://www.toppr.com/ask/content/concept/types-of-glands-201158/ Heart-derived hormones Not examinable material!  Biomarkers for heart failure Not examinable material! Ibrahim NE, Heart Failure 2018; 123(5): 614-629  Most important endocrine glands that secrete hormones Note: organs/tissues like stomach, small intestine, heart, kidneys, and placenta (during pregnancy) also secrete some hormones The pancreas is an example of a heterocrine gland https://www.yaclass.in/p/science-cbse/class-10/control-and-coordination- https://www.toppr.com/ask/content/concept/types-of-glands-201158/ 10298/receptors-and-hormones-9821/re-a84894da-635c-4e69-b8e3-d27f15562c3c  Endocrinology & major themes of physiology? Structure and function across all levels of organization molecular interactions (molecules can bind to each other); compartmentation (cell membranes) Energy transfer, storage and usage Information flow, storage, and use within single organisms and within a species of an organism Homeostasis and the control systems that maintain it Physiology & levels of organization: membrane composition Peripheral proteins: Found on the inner or outer surface of the lipid bilayer Can also be attached to the internal or external surface of an integral protein Perform specific functions for the cell, e.g. as enzymes Integral proteins: Embedded in the cell membrane Includes for e.g. channel proteins that selectively allows materials into or out of the cell https://openstax.org/books/anatomy-and-physiology-2e/pages/3-1-the-cell-membrane Physiology & levels of organization: membrane transport Silverthorn, CH5, p168 Physiology & levels of organization: membrane proteins Silverthorn, CH5, p176 Physiology & levels of organization: membrane proteins Active transport: Moves substances against their concentration gradients Uses carrier proteins Conformation change requires energy, either directly or indirectly – Primary (direct) active transport ▪ Uses ATP directly – Secondary (indirect) active transport ▪ Uses potential energy stored in concentration gradients of one molecule to push another molecule against its gradient  Endocrinology & major themes of physiology? Structure and function across all levels of organization molecular interactions (molecules can bind to each other); compartmentation (cell membranes) Energy transfer, storage and usage ATP is essential for growth, reproduction, movement, homeostasis Information flow, storage, and use within single organisms and within a species of an organism generational transfer of information; information flow coordinates function; local vs. long-distance information flow; information flow is crucial for structure & function Homeostasis and the control systems that maintain it Information flow allows for integration & is crucial for structure and function Silverthorn, CH1, p40 Cardiovascular system: key role in information flow & cell-to-cell communication Silverthorn, CH14, p459  Information flow & cell-to-cell communication https://www.mechanobio.info/what-is-mechanosignaling/ what-types-of-signals-do-cells-use-to-communicate  Information flow & cell-to-cell communication Endocrine system: communicates using hormones that are distributed via the circulatory system Hormones target those cells with matching receptors Nervous system: uses a combination of electrical & https://www.mechanobio.info/what-is-mechanosignaling/ chemical signals to communicate over long distances what-types-of-signals-do-cells-use-to-communicate Silverthorn, CH6, p202 Information flow & cell-to-cell communication https://www.ncbi.nlm.nih.gov/books/NBK20/ Endocrine system & integrated responses: optimal functioning https://courses.lumenlearning.com/suny-wmopen-biology2/chapter/why-it-matters-overview-of-body-systems/  Endocrinology & major themes of physiology? Structure and function across all levels of organization molecular interactions (molecules can bind to each other); compartmentation (cell membranes) Energy transfer, storage and usage ATP is essential for growth, reproduction, movement, homeostasis Information flow, storage, and use within single organisms and within a species of an organism generational transfer of information; information flow coordinates function; local vs. long-distance information flow; information flow is crucial for structure & function Homeostasis and the control systems that maintain it ensures organismal survival in changing external environments; maintains relative stable internal environment & consistency  Endocrine system & homeostasis Definition of homeostasis: -a self-regulating process by which biological systems maintain stability while adjusting to changing external conditions This concept explains how an organism can maintain more-or-less constant internal conditions that allow it to adapt & to survive in the face of a changing (and often) hostile external environment The disruption of homeostatic mechanisms is what leads to disease, and effective therapy must be directed toward re-establishing these homeostatic conditions, working with rather than against Nature https://www.frontiersin.org/articles/10.3389/fphys.2020.00200/full  What constitutes a hormone? A hormone is a chemical signal Hormones are secreted by a cell or group of cells Hormones are secreted into the blood Secretion from a cell to ECF or external environment Hormones are transported to a distant target Transported by blood Growth factors act at short distance Hormones exert their effect at very low concentrations Act in 3 basic ways (1) Rates of enzymatic reactions (2) Transport of ions or molecules across cell membranes (3) Gene expression and protein synthesis  The three major classes of human hormones Hydrophilic Hydrophobic Hydrophilic & Hydrophobic (Amines) https://www.ncbi.nlm.nih.gov/books/NBK20/ Peptides are molecules consisting of 2 to 50 amino acids whereas proteins are made up of 50 or more amino acids Peptides also tend to be less well defined in structure than proteins Protein or peptide hormones are the most numerous, ranging in size from just 3 to over 200 amino acids Hormone class differences List of some major human hormones Silverthorn, CH7, p234/5 Synthesis: peptide hormones Silverthorn, CH7, p237 Synthesis: peptide hormones Peptide hormone synthesis, storage, and release: Preprohormone is a large, inactive precursor Prohormone is processed to smaller form but still inactive Active hormone stored in vesicle; requires signal to be released Transported in the blood and half-life of peptide hormones Relatively short half-life Cellular mechanism of action of peptide hormones Bind surface membrane receptors Cellular response through signal transduction system Silverthorn, CH7, p237 Synthesis: peptide hormones Peptide hormone synthesis, storage, and release: Preprohormone is a large, inactive precursor Prohormone is processed to smaller form but still inactive Active hormone stored in vesicle; requires signal to be released Transported in the blood and half-life of peptide hormones Relatively short half-life Cellular mechanism of action of peptide hormones Bind surface membrane receptors Cellular response through signal transduction system Silverthorn, CH7, p237  Peptide hormones: intracellular storage https://www.yaclass.in/p/science-cbse/class-10/control-and-coordination- 10298/receptors-and-hormones-9821/re-a84894da-635c-4e69-b8e3-d27f15562c3c Silverthorn, CH5, p194 Peptide hormones: release into bloodstream Silverthorn, CH5, p194 Peptide hormones: example of clearance The pancreas releases pulses of insulin into the portal vein to be delivered to hepatocytes Insulin is hydrophilic in nature and requires no carrier proteins Most of secreted insulin is cleared (or ‘’extracted’’) by the liver during its first pass (∼60–70%) Insulin not extracted by the liver appears in the systemic circulation & used by peripheral tissues It is then further extracted by the liver during the second pass through the hepatic artery Thus, the liver acts as a modulator of insulin delivery to extrahepatic peripheral tissues Half-life of insulin less than 9 minutes  Hormones act by binding to receptors Cellular mechanism of hormone action Depends on binding to target cell receptors Initiates biochemical responses Hormone action must be terminated Half-life indicates length of activity Peptide hormones: receptor-mediated effects Peptide hormones are lipophobic & thus unable to cross membrane of target cell They therefore bind to specific surface membrane receptors Such binding initiates a cellular response via a signal transduction system Many peptide hormones operate via cAMP second messenger systems Some peptide hormones work via tyrosine kinase activity (e.g. insulin) Changes triggered include e.g. opening or closing membrane channels, modulating metabolic enzymes, or transport proteins Silverthorn, CH7, p238  Synthesis: steroid hormones Silverthorn, CH7, p239 Chemical structures are not examinable material https://www.adrenal.com/adrenal-gland/overview  Steroid hormones: release into bloodstream Cortisol is an example of a steroid hormone & is released from the adrenal cortex in a pulsatile fashion Due to its hydrophobic nature, it is not stored in vesicles & simply diffuses out of cells Most cortisol (90%) is transported in circulation by being bound to a glycoprotein called corticosteroid-binding globulin (CBG) Corticosteroid-binding CBG also buffers cortisol concentrations in circulation despite its pulsatile globulin (CBG) complex with secretion cortisol For the rest of the cortisol, 7% bound to albumin, while 3-4% is free in circulation; note ‘free’ cortisol is the active agent to elicit changes https://www.mdpi.com/2077-0383/10/21/5204 https://proteopedia.org/wiki/index.php/Corticosteroid-binding_globulin  Steroid hormones: release into bloodstream Cortisol plays a major part in the body's metabolic reaction to stress, e.g. illness, injury, and trauma or mental ill-health Forms part of the “fight-or-flight” response that allows the body to react quickly to a perceived “threat’’ Cortisol secretion is a product of the complex interaction between the hypothalamus and pituitary glands in the brain and the adrenal glands - hypothalamic-pituitary-adrenal (HPA) axis Cortisol is released for many hours after encountering a stressor Once the required cortisol concentration is achieved, it exerts negative feedback to the hypothalamus & re-establishes systemic homeostasis Silverthorn, CH7, p248 https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.14644 Steroid hormones: release into bloodstream Cortisol secretion follows a natural 24-hr cycle In healthy individuals, peak levels are reached about 30 min after waking This early peak is known as the cortisol awakening response (CAR) Cortisol levels decline throughout the day, with lowest levels occurring during the early sleeping phase Prolonged exposure to stressors can lead to HPA axis overstimulation, resulting in fluctuating cortisol levels https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.14644  Steroid hormones: example of clearance Corticosteroids are metabolized through enzymatic transformations These processes attenuate their physiologic activity & increase water solubility to enhance their urinary excretion Cortisol clearance occurs largely in the liver & kidney Cortisol (free) half-life varies between 60-120 minutes  Steroid hormones: receptor-mediated effects The response to a lipid-hormone is usually a change in gene expression For example, steroids enter target cells & bind to protein receptors in the cytoplasm or nucleus Protein-receptor complexes then act as transcription factors in the nucleus, regulating transcription of specific genes Silverthorn, CH7, p239  Steroid hormones: some properties Synthesized in only a few organs Adrenal cortex of adrenal gland & gonads Steroid hormone synthesis and release – Made as needed, not stored Transport in the blood and half-life of steroid hormones – Bind carrier proteins in blood – Longer half-life (example: cortisol = 69-90 minutes in blood) Cellular mechanism of action of steroid hormones Cytoplasmic or nuclear receptors stimulate genomic effects Cell membrane receptors stimulate nongenomic responses  Hydrophilic hormones: some properties Properties of water-soluble hormones: Relatively low concentrations in blood (plasma) Plasma concentrations can vary significantly Effects manifest relatively quickly Transported in a “free state” (i.e. they dissolve in plasma and do not need protein carriers) Bind to target cell membrane receptors Effects are usually due to modification of intracellular protein function (e.g. activation or inactivation of enzymes) Important examples: insulin, epinephrine, ADH  Hydrophobic hormones: some properties Properties of fat-soluble hormones: Plasma concentrations are relatively stable Effects manifest relatively slowly (vs. water-soluble hormones) Transported in the “bound state” - they cannot dissolve in plasma, and hence need to bind to carrier proteins Bind to receptors in the cytoplasm, nucleus or cell membranes of target cells Effects are usually due to actions on the DNA of cells (gene activation/inactivation) Important examples: testosterone, estradiol, cortisol Hormone class differences  Synthesis: amine hormones Some derived from tryptophan Melatonin from pineal gland Most derived from tyrosine Single tyrosine gives rise to catecholamines Epinephrine, norepinephrine, and dopamine Behave like peptide hormones Two tyrosine molecules give rise to thyroid hormones Behave like steroid hormones Chemical structures: not examinable material! Silverthorn, CH7, p240  Synthesis: amine hormones Catecholamines: Any of various naturally occurring amines that function both as hormones & neurotransmitters Characterized by a catechol group to which an amine is attached Include: dopamine, epinephrine (adrenaline), & norepinephrine (noradrenaline) Chemical structures: not examinable material! https://www.pharmacy180.com/article/catecholamines-2203/  Synthesis: amine hormones Derived from tryptophan Melatonin from pineal gland Derived from tyrosine Single tyrosine gives rise to catecholamines Epinephrine, norepinephrine, and dopamine Behave like peptide hormones Two tyrosine molecules give rise to thyroid hormones Behave like steroid hormones Chemical structures: not examinable material! Silverthorn, CH7, p240 Reminder: catecholamines also act as neurotransmitters Silverthorn, CH11, p398  Catecholamines: clearance Nearly all epinephrine in circulation originates from the adrenal medulla Most norepinephrine is derived from sympathetic nerve terminals (brain & peripheral tissues) Most catecholamine metabolism occurs in the liver & kidneys Primary catecholamine metabolites & their conjugates are excreted in urine However, for most neurotransmitters there is re-uptake by pre- or postsynaptic cells Both epinephrine and norepinephrine remain in circulation for a very short time; half-life of 1-3 minutes Chemical pathways (above) are not examinable material https://cvpharmacology.com/norepinephrine Amine hormones: receptor-mediated effects Epinephrine elicits multiple effects in mediating the body’s response to short-term stress Binds to specific receptors on cell membranes of target cells This triggers the release of messenger molecules that can activate enzymes with downstream effects Liver cell  Hormone release: control Reflex pathways have similar components Stimulus, sensor, input signal, integration, output signal, one or more targets, & response Many endocrine reflexes involve the nervous system Neurohormones are secreted into the blood by neurons The endocrine cell is the sensor in simple endocrine reflexes, while output signal is a hormone or neurohormone  Hormone release: control (simple reflex) Note: parathyroid glands found in the neck next to thyroid glands Endocrine cell directly senses stimulus & response by secreting hormone Silverthorn, CH7, p242  Neurohormones Neurohormones are chemical signals released into the blood by a neuron Human nervous system produces 3 major groups of neurohormones: a) Catecholamines produced by modified neurons in adrenal medulla b) Hypothalamic neurohormones secreted from posterior pituitary c) Hypothalamic neurohormones that control hormone release from anterior pituitary Pituitary hormones Also called: neurohypophysis & secretes hormones made in hypothalamus Also called: adenohypophysis & its hormones referred to as adenohypophyseal secretions Silverthorn, CH7, p244  Pituitary hormones The posterior pituitary stores and releases two neurohormones Hormones produced in the hypothalamus Such hormones packaged into secretory vesicles that then transported to posterior pituitary When hypothalamus is stimulated, posterior pituitary secretes two neurohormones: vasopressin (antidiuretic hormone [ADH]) & oxytocin The anterior pituitary secretes six hormones Epithelial origin, thus a true & major endocrine gland Such hormone secretion falls under the control by hypothalamic neurohormones Tropic (or trophic) hormones secreted by the anterior pituitary exert their actions on other endocrine glands Prolactin (PRL), thyrotropin (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)  Pituitary hormones Portal system: consists of two sets of capillaries connected (one after the other) by a set of small veins Silverthorn, CH7, p244 Pituitary hormones Silverthorn, CH7, p245  Pituitary hormones Hypothalamic-hypophyseal (pituitary) portal system Hypothalamic neurons produce neurohormones Released into 1st capillary bed in portal system Portal veins carry neurohormones to next capillary bed in the anterior pituitary Anterior pituitary endocrine cells produce trophic hormones Released into circulation to reach their target tissues Portal system ensures that small amount of hormone remains concentrated in tiny volume of blood & goes directly to its target (anterior pituitary)  Hypothalamic-anterior pituitary hormones Hypothalamic neurohormones that control release of anterior pituitary hormones – usually identified as ‘’releasing hormones’’ or ‘’inhibiting hormones’’ Trophic hormones often end with the suffix ‘’-tropin’’ Hypothalamic & anterior pituitary hormones have multiple names e.g. somatostatin is also called growth hormone-inhibiting hormone Silverthorn, CH7, p246  Hypothalamic-anterior pituitary hormones Not examinable material! https://basicmedicalkey.com/pituitary-function-and-pathophysiology/ Hypothalamic-anterior pituitary hormones TRH: Thyrotropin-releasing hormone CRH: Corticotropin-releasing hormone GHRH: Growth hormone-releasing GHIH hormone GHIH: Growth hormone-inhibiting hormone GnRH: Gonadotropin-releasing hormone TSH: Thyroid-stimulating hormone ACTH: Adrenocorticotropic hormone GH: Growth hormone FSH: Follicle-stimulating hormone LH: Luteinizing hormone Silverthorn, CH7, p246  Anterior pituitary hormones control growth, metabolism & reproduction Prolactin (PRL) Controls milk production (lactation) in the female breast Has a hypothalamic release-inhibiting hormone Growth hormone (GH) Also called somatotropin Affects metabolism Stimulates hormone production in the liver Has a hypothalamic release-inhibiting hormone  Anterior pituitary hormones control growth, metabolism & reproduction Two gonadotropins Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Controls hormones in the gonads (ovaries and testes) Sex hormones (steroids) Thyroid-stimulating hormone Also called thyrotropin Controls hormone synthesis and secretion in the thyroid Thyroid hormones (amines) Adrenocorticotropic hormone Also called adrenocorticotropin Controls hormone synthesis and secretion in the adrenal cortex cortisol (steroid) Short and long-loop feedback systems The hormone, not the response, is the feedback signal Long-loop negative feedback Peripheral endocrine gland produces hormone that suppresses secretion of anterior pituitary and hypothalamic trophic hormones Most dominant feedback mechanism Short-loop negative feedback Pituitary hormone suppresses hypothalamic trophic hormone production Secondary feedback mechanism Ultra-short-loop negative feedback Occurs in hypothalamus & pituitary Autocrine or paracrine signals to regulate secretion Silverthorn, CH7, p248 Short and long-loop feedback systems Many anterior pituitary trophic hormones (THs) (e.g., ACTH, TSH, GH, LH, FSH) are regulated by hypothalamic releasing hormones (HRHs) Releasing hormones secreted by the hypothalamus reach the pituitary via the hypothalamic-pituitary portal system (HPPS) Long feedback loops involve negative feedback of the target cell hormone at the pituitary gland & hypothalamus The short feedback loop involves the anterior pituitary trophic hormone feeding back at the hypothalamus The ultra-short feedback loop involves the anterior pituitary hormone feeding back at the anterior pituitary https://basicmedicalkey.com/pituitary-function-and-pathophysiology/  Half-life & metabolic clearance of hormones Numbers not examinable material, focus on the principles! https://slideplayer.com/slide/9958671/ Comparison of hormone classes Silverthorn, CH7, p236 Comparison of hormone classes https://ib.bioninja.com.au/standard-level/topic-6-human- physiology/66-hormones-homeostasis-and/types-of-hormones.html Endocrinology & major themes of physiology: examples Structure and function across all levels of organization molecular interactions (molecules can bind to each other); compartmentation (cell membranes) Energy transfer, storage and usage ATP is essential for growth, reproduction, movement, homeostasis Information flow, storage, and use within single organisms and within a species of an organism generational transfer of information; information flow coordinates function; local vs. long-distance information flow; information flow is crucial for structure & function Homeostasis and the control systems that maintain it ensures organismal survival in changing external environments; maintains relative stable internal environment & consistency  Endocrinology & major themes of physiology: examples Fight-or-flight Reproduction Birth Growth Metabolism Blood O2 Blood volume Chronic stress Endocrinology & major themes of physiology: examples Reproduction  Synthesis: sex (or gonadal) hormones Ovary & testis secrete cholesterol-derived steroid hormones Gonadal hormones are part of the hypothalamic-pituitary- gonadal (HPG) axis & regulated by pituitary hormones FSH & LH FSH & LH are both regulated by gonadotropin-releasing hormone (GnRH) secreted from the hypothalamus Two major functions of gonads (in adults): a) steroid hormone production & b) gametogenesis Testosterone is the primary androgen & plays a critical role in development of primary & secondary male sex characteristics, & spermatogenesis Estradiol & progesterone are the primary female hormones & responsible for egg development, menstrual cycle & breast development Chemical structures not examinable material! https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1 Sex (or gonadal) hormone release: control Inhibins are gonadal messengers that exert a physiological negative feedback control on FSH release at the pituitary gland https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1  Hormone release & actions: testosterone Gonadal hormones are lipophilic & hence they require protein carriers to travel in the blood In general, they are bound to: -Sex hormone–binding globulin (SHBG): 40% -Other proteins (primarily albumin & corticosteroid- binding globulin): 54%–60% -Free hormone (the only biologically active form): 2% As they are lipophilic → can freely cross cell membranes to bind to intracellular receptors Once bound to receptors → translocation to the nucleus Hormone–receptor complex can bind DNA and affect gene expression Hormone metabolism occurs in the liver & such metabolites are then excreted in urine https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1  Testosterone: physiological role The normal range of testosterone levels in adults is: https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1 Men: 270 – 1,070 ng/Dl, peaking at 20 years of age Women: 15 – 70 ng/Dl https://www.sciencedirect.com/science/article/pii/S2589790X21001335  Testosterone: age-dependent effects https://www.freepik.com/premium-vector/estrogen-testosterone-level-color-chart-sex-hormone-production-by-age-vector- infographic-diagram-with-low-high-balance-hormones-female-male-body-woman-man-silhouette_22984891.htm  Ovarian hormones Hormones produced by the ovaries include: Estrogens E2 (or also called estradiol): primary estrogen produced in reproductive-aged female E1: primary estrogen in menopausal females Estriol (E3): primarily produced in pregnancy Progestins Only produced in significant quantities after ovulation Progesterone Progesterone-like compounds Inhibins, activins, androgens https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1  Hormone release Estradiol is transported bound to albumin (60%) & 30% to SHBG Progesterone is mainly bound to albumin in circulation & to a lesser extent to cortisol-binding globulin Both are metabolized by the liver & metabolites excreted by the kidney https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1 Hormone release & actions Receptors are mainly located in the cytoplasm attached to heat shock proteins (hsp) Upon ligand binding the hsp are released & receptors dimerize and are then translocated to the nucleus In some target tissues testosterone must first be converted to dihydrotestosterone (DHT) before it interacts with its receptor Two forms of estradiol receptor have been identified (α, β) which form different dimers as indicated Progesterone can form homo- and heterodimers and interacts with a GRE consensus sequence on DNA Abbreviations: ERE, estrogen response element; GRE, glucocorticoid response element https://www.ncbi.nlm.nih.gov/books/NBK20/ Ovarian hormone release: control There are positive & negative feedback loops in the hypothalamic-pituitary-ovarian axis Estrogens & progestins can trigger both a positive and a negative influence on the hypothalamus and pituitary gland - this depends on the phase of the cycle Estrogens provide negative feedback until the middle of the cycle At this point estrogen begins stimulating the gonadotropic cells in the pituitary This leads to a luteinizing hormone (LH) surge which triggers ovulation Note: ‘’estrogen’’ refers to a group of 3 hormones: E1, E2 & E3 https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1  Ovarian hormone release: control Hypothalamus secretes GnRH in a pulsatile fashion to trigger the anterior pituitary to release: FSH: Stimulates follicular development & egg maturation Stimulates cells within the ovary to produce E2 LH: Stimulates cells within the ovary to produce testosterone* A surge during midcycle triggers ovulation *Here, most testosterone converted to E2 https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1 Ovarian hormones https://www.hormones-australia.org.au/the-endocrine-system/ovaries/  Testosterone & estrogen: age-dependent effects https://www.freepik.com/premium-vector/estrogen-testosterone-level-color-chart-sex-hormone-production-by-age-vector- infographic-diagram-with-low-high-balance-hormones-female-male-body-woman-man-silhouette_22984891.htm Endocrinology & major themes of physiology: examples Birth Childbirth (parturition) & lactation: hormones Parturition begins with labor – rhythmic uterine contractions Not sure what triggers parturition, but increased CRH levels secreted by placenta may be implicated Cervical stretch starts positive feedback loop to increase contractions Contractions reinforced by oxytocin release by posterior pituitary Increased oxytocin & CRH leads to prostaglandin production in uterus Prostaglandins – very effective to increase uterine muscle contractions Delivery of baby stops the positive feedback loop Silverthorn, CH26, p868 Childbirth (parturition) & lactation: hormones Progesterone inhibits uterine contractions throughout the first several months of pregnancy As pregnancy enters its seventh month the progesterone levels plateau & then decrease Estrogen levels continue to rise in the maternal circulation The increasing ratio of estrogen to progesterone enhances the sensitivity of uterine muscle to stimuli that promote contractions During eighth month of pregnancy there is an increase in fetal cortisol which boosts estrogen secretion by the placenta This further overpowers the uterine-calming effects of progesterone https://courses.lumenlearning.com/suny-ap2/chapter/maternal-changes-during-pregnancy-labor-and-birth/ Childbirth (parturition) & lactation: hormones During pregnancy the mammary glands develop under direction of estrogen, GH & cortisol Prolactin (anterior pituitary) can stimulate milk production, but its secretion inhibited by PIH (hypothalamus) During latter stages of pregnancy PIH levels decrease & prolactin levels increase sharply Suckling also inhibits PIH production Prior to deliver the mammary glands secrete small amounts of colostrum – thin, low-fat secretion After delivery (lower estrogen, progesterone) the glands produce milk with 4% fat, high amounts of calcium & maternal immunoglobulins Ejection of milk from glands is known as let-down reflex & requires oxytocin Oxytocin triggers muscle contractions in the breast Oxytocin release can also be triggered by cerebral stimuli e.g. child crying & thoughts about the child Silverthorn, CH26, p869  Oxytocin the love hormone? https://edition.cnn.com/2020/02/14/health/ https://www.sciencedirect.com/science/article/pii/S1550413107000691 brain-on-love-wellness/index.html Endocrinology & major themes of physiology: examples Growth Growth hormones Growth is a continuous process although growth rates not steady in children & adolescents (spurts occur) This depends on GH (or somatotropin) & also others such as thyroid hormones, insulin & sex hormones Other factors influencing growth includes adequate diet, absence of chronic stress & genetics GH is released throughout life but biggest role in children GH secretion (anterior pituitary) depends on GHRH & GHIH (or somatostatin) – latter two secreted by hypothalamus GH: Growth hormone (or called somatotropin) GHRH: Growth hormone-releasing hormone GHIH: Growth hormone-inhibiting hormone (or called somatostatin) Silverthorn, CH23, p776 Growth hormones 50% carried in circulation by being bound to growth hormone- binding protein GH target tissues include endocrine & non-endocrine cells GH acts as a trophic hormone to stimulate secretion of IGFs from the liver and other tissues IGFs act in concert with GH to stimulate protein synthesis (skeletal muscle) They also act in concert to increase blood glucose concentrations (i.e. lowering glucose uptake by muscle, & by increasing liver gluconeogenesis & lipolysis) GH: Growth hormone (or called somatotropin) GHRH: Growth hormone-releasing hormone GHIH: Growth hormone-inhibiting hormone (or called somatostatin) IGF: Insulin-like growth factor Silverthorn, CH23, p776  Growth hormones (IGFs) No need to memorize the figure - rather focus (& build) on the principles https://app.lecturio.com/#/article/2953?return=%23%2Fwelcome%3Ffv%3D1 as highlighted in previous slide Growth hormones Silverthorn, CH23, p776 Growth hormones: age-dependent changes HGH plays a key role in repair mechanisms The secretion peaks in the early hours of the morning before normal wakening HGH secretion diminishes with age & most rapid decline occurs in middle age Such a decline is associated with depression GH: Growth hormone (or called somatotropin) HGH: Human growth hormone (term used interchangeably with GH) https://www.priory.com/psychiatry/Growth_Hormone_Depression.htm Growth hormones: age-dependent changes https://www.priory.com/psychiatry/Growth_Hormone_Depression.htm Growth hormones: disorders Severe GH deficiency in children leads to dwarfism This can be either due to a problem with GH synthesis or defective GH receptors Over-secretion of GH in children leads to giantism After cessation of growth during adolescence GH continues to act on cartilage & soft tissues Acromegaly is a condition characterized by lengthening of the jaw, coarse facial features & growth of hands and feet These are relatively rare diseases Silverthorn, CH23, p777  Tissue & bone growth Growth can be divided into two types: a) soft tissue growth & b) linear bone growth Soft tissue growth requires growth hormone, thyroid hormone & insulin Tissue protein synthesis & cell division needs growth hormone & IGFs Hormones can influence cells to undergo hypertrophy or hyperplasia Hyperplasia: increase in tissue or organ size due to higher cell number Example: endometrial proliferation under influence of estrogen during menstrual cycle Hypertrophy: enhanced tissue or organ size due to increase in cell size – due to greater functional demand Example: cardiac hypertrophy in response to hypertension https://teachmephysiology.com/histology/tissue-structure/cellular-adaptations/  Bone growth Bone growth requires hormones together with adequate amounts of protein & calcium Bones: extensive calcified extracellular matrix formed when calcium phosphate crystals precipitate & attach to collagenous lattice Bones: an outer layer of dense, compact bone & inner layer of spongy or trabecular bone Spaces in collagen-calcium matrix are filed by living cells Blood vessels supply such cells with nutrients & oxygen Silverthorn, CH23, p779  Bone growth Bone is a dynamic tissue that is constantly being formed & broken down Linear bone growth occurs at specialized bands of cartilage called epiphyseal plates Osteoblasts secrete calcium phosphate & a protein mixture (osteoid) on top of cartilage base The combination of calcium phosphate & osteoid creates new bone Once done with their job, osteoblasts revert to a less active form known as osteocytes Osteoclasts secretes acid that dissolves calcified matrix – a process known as resorption (or breakdown) Chondrocytes (close to epiphyseal plate) are collagen producing cells of cartilage & lays down new cartilage to lengthen the bone(s) Older chondrocytes (closer to diaphysis) die and leave spaces that osteoblasts invade Silverthorn, CH23, p779  Bone growth Ossification is the process of bone formation by osteoblasts Chondrocytes on epiphyseal side divide & secrete hyaline cartilage The chondrocytes which are pushed from the epiphysis, mature & are destroyed by calcification Osteoblasts replace cartilage with bone on the diaphyseal side of the plate & this results in a lengthening of the bone As cartilage grows, the entire structure grows in length & is turned into bone Once cartilage are unable to grow further then the structure can no longer elongate Silverthorn, CH23, p779 https://courses.lumenlearning.com/wm-biology2/chapter/bone-growth-and-development/  Bone growth Long bones stop growing at around the age of 18 in females and the age of 21 in males - called epiphyseal plate closure Here the cartilage cells stop dividing & all of it replaced by bone The epiphyseal plate fades & leaves a structure called the epiphyseal line, while epiphysis & diaphysis fuse Appositional growth is the increase in the diameter of bones by the addition of bone tissue at the surface of bones Osteoblasts at the bone surface secrete bone matrix & osteoclasts on the inner surface break down bone A balance between these two processes allows the bone to thicken without becoming too heavy Silverthorn, CH23, p779 https://courses.lumenlearning.com/wm-biology2/chapter/bone-growth-and-development/ Bone growth: age-dependent effects During childhood & teenage years the bone density accumulates, and it grows in both size & strength New bone is added to the skeleton faster than old bone is removed/resorbed Bone formation continues faster than resorption until peak bone mass is reached (25–30 years old) Bone density is then maintained for 10 years & bone mass remains relatively stable (remodelling phase) After age of 35, men and women gradually lose their bone density as part of the aging process Menstrual cycle in women ceases (45-55 years) & they start to lose bone rapidly (decreased estrogen production) By the age of 65, men & women tend to lose bone tissue at the same rate & this continues throughout life Kruger and Nell AIDS Res Ther (2017) 14:35 DOI 10.1186/s12981-017-0162-y  Bone growth Most of body’s calcium (99%) is found in bones Non-bone calcium is critical to the body’s function with multiple functional roles (refer table) Due to its critical function, plasma calcium levels are very closely regulated Calcium homeostasis follows principle of mass action, i.e. total body calcium = intake minus output Total body calcium is distributed among 3 compartments: extracellular fluid (ECF), intracellular, & bone Calcium intake: via diet & absorbed in small intestine Calcium output: primarily via kidneys & small amount in feces Silverthorn, CH23, p780 Bone growth: control Calcium is absorbed in the small intestine (only 1/3 of ingested calcium absorbed) Three hormones regulate movement of calcium between intestine, bone & kidney These are: parathyroid hormone (PTH), calcitriol (vitamin D3) & calcitonin PTH & calcitriol are the most important ones in adult humans PTH secreted by 4 small parathyroid glands (on thyroid gland) Silverthorn, CH23, p780  Bone growth: control Relatively low plasma calcium levels is the stimulus for PTH release PTH functions to act on the bone, kidney & intestine to increase plasma calcium levels PTH raises plasma calcium levels in 3 ways: - increases intestinal absorption of calcium (enhanced by calcitriol [vitamin D3] actions) - enhances renal absorption of calcium; also stimulates renal calcitriol synthesis - mobilizes calcium from bone; PTH activates osteoblasts to secrete paracrine molecules to lead to maturation and activation of osteoclasts Such actions raise blood calcium levels that result in decreased PTH synthesis in a negative feedback loop Silverthorn, CH23, p782  PTH: dysregulation Hyperparathyroidism: disorder caused by PTH overproduction May result due to for e.g. tumors or hyperplasia of parathyroid cells Results in excessive calcium reabsorption from bone & can significantly decrease bone density and lead to weakening of bones (risk of osteoporosis & fractures) This leads to hypercalcemia (too high blood calcium levels) that can decrease the responsiveness of the nervous system Calcium deposits can also occur in tissues and organs & result in impaired function PTH: dysregulation Parathyroid cells possess a calcium sensor that is genetically set for a certain calcium level (9.0 in our example) Hyperparathyroidism: tumor developing & there is a disturbance on the calcium sensor for a parathyroid cell This changes the setting for the calcium to a higher number (11.0 in our example) Normal parathyroid cells “turn off” with increasing calcium levels while the abnormal parathyroid cell continues to produce PTH https://www.hyperparathyroidmd.com/hyperparathyroidism/ PTH: dysregulation https://www.hyperparathyroidmd.com/hyperparathyroidism/  PTH: dysregulation Hypoparathyroidism: disorder caused by abnormally low blood calcium levels May be caused by impaired PTH secretion or action This complication may develop following injury/damage or surgery involving the thyroid gland Low blood calcium increases membrane permeability to sodium, resulting in muscle twitching, cramping, spasms, or convulsions Severe deficits can paralyze muscles, including those involved in breathing & can be fatal Bone growth: control Calcitriol enhances intestinal & renal absorption of calcium Body synthesizes calcitriol obtained via dietary intake and/or in skin via sunlight using precursor molecules Calcitriol synthesis occurs in two steps, i.e. initially by the liver & then the kidney Calcitriol also stimulates calbindin synthesis Of note, prolactin also stimulates calcitriol synthesis Silverthorn, CH23, p783 Bone growth: control Silverthorn, CH23 Bone growth: control Silverthorn, CH23, p784 Bone growth: control Silverthorn, CH23, p780 Bone growth: control (summary) https://courses.lumenlearning.com/suny-ap2/chapter/the-parathyroid-glands/  Bone growth: pathology Osteoporosis definition (WHO): a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk Noh, J.-Y.; Yang, Y.; Jung, H. Molecular Mechanisms and Emerging Therapeutics for Osteoporosis. Int. J. Mol. Sci. 2020, 21, 7623. https://doi.org/10.3390/ijms21207623  Bone growth: pathology Mechanisms driving osteoporosis are multifactorial and may include attenuated estrogen levels and increased inflammation https://www.frontiersin.org/articles/10.3389/fimmu.2021.687037/full Endocrinology & major themes of physiology: examples Metabolism  Metabolism: cortisol synthesis Adrenal glands (on top of kidneys) secrete multiple hormones Cortisol is the main glucocorticoid secreted by the adrenal cortex Silverthorn, CH23, p766 Metabolism: cortisol’s control of secretion Cortisol secretion is continuous & follows a strong diurnal rhythm (i.e. active during the day) Secretion normally peaks in the morning & is lower during the night Cortisol secretion increases with stress https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.14644 Metabolism: cortisol’s control of secretion The hypothalamic-pituitary-adrenal (HPA) pathway controls cortisol secretion The hypothalamus secretes corticotropin-releasing hormone (CRH) into portal system & transported to anterior pituitary CRH stimulates release of adrenocorticotropic hormone (ACTH) from the anterior pituitary ACTH acts on adrenal cortex to promote synthesis & release of cortisol Cortisol then transported in plasma (bound to cortisol- binding globulin [CBG]) to act on target cells Cortisol then acts as a negative feedback signal to inhibit CRH & ACTH secretion Silverthorn, CH23, p768 Metabolism: cortisol actions in target cells Glucocorticoid receptors (GRs) are usually found in the cytoplasm & associated with heat shock proteins (hsp) HSPs are displaced when cortisol diffuses across the cell membrane & binds to GRs After activation, the hormone-receptor complex translocates into the nucleus The site of receptor binding on DNA is known as the glucocorticoid response element (GRE) GRs stimulate or suppress gene transcription (downstream of GRE) Cortisol may also exert effects via membrane receptors, i.e. cortisol-binding globulin (CBG) can bind to cell surface receptors Cortisol may then bind to the CBG-receptor complex and activate adenylate cyclase This allows cortisol to also exert non-genomic actions https://www.ncbi.nlm.nih.gov/books/NBK20/ Metabolism: cortisol actions Cortisol increases blood glucose levels -opposing insulin’s action in peripheral tissues (decreasing glucose uptake via GLUT4 receptors) -increasing glucose production (gluconeogenesis) & release from the liver Cortisol stimulates the release of amino acids from muscle Such amino acids can be taken up by the liver & be converted to glucose (gluconeogenesis) Cortisol mildly increases lipolysis & elevates mobilization of fatty acids from adipose tissues Thus, it increases glucose & free fatty acids in circulation to increase utilization for energy production Cortisol also has varied actions on a wide range of other tissues https://www.ncbi.nlm.nih.gov/books/NBK20/ Metabolism: cortisol Silverthorn, CH23, p766 Metabolism: hypercortisolism (Cushing’s syndrome) Silverthorn, CH7, p252 Metabolism: hypercortisolism (Cushing’s syndrome) Hypercortisolism is also known as Cushing’s syndrome – first described by Dr. Harvey Cushing in 1932 Can also arise due to high doses of exogenous administration of this hormone Symptoms include hyperglycemia, muscle protein breakdown & lipolysis (causing tissue wasting) Increased food intake – fat deposition in face & trunk but thin arms and legs Silverthorn, CH23, p769 Metabolism: hypocortisolism (Addison’s disease) Hypocortisolism is also known as Addison’s disease – first described by Dr. Thomas Addison in 1855 This condition is rare & causes include infections (e.g. TB) & cancer It can also manifest as an inherited disorder of such glands This can lead to adrenal insufficiency https://rmi.edu.pk/disease/addisons-disease Metabolism: thyroid hormones Thyroid gland possesses two cell types: C cells – secrete calcitonin Follicular cells – secrete thyroid hormones Thyroid hormones are derived from tyrosine & contain the element iodine The hollow center of thyroid follicles is filled with colloid – sticky glycoprotein mixture Follicular cells use the sodium-iodide symporter to take up dietary iodide (I-) The hormones T3 and T4 are taken outside (from follicular cells) into circulation via protein carriers T3 & T4 have limited solubility in plasma and hence transported by binding to thyroid-binding globulin (TBG) T3 is several fold more active than T4 Target cells make most of their T3 using deiodinases to remove an iodine from T4 Thyroid receptor isoforms are found in the nucleus Silverthorn, CH23, p771 Metabolism: control of thyroid hormones Thyrotropin-releasing hormone (TRH) secreted from hypothalamus Controls secretion of thyroid- stimulating hormone (TSH) from anterior pituitary TSH acts on thyroid glands to promote T3 & T4 synthesis Thyroid hormones act as negative feedback loop to prevent over secretion Silverthorn, CH23, p773  Metabolism: effects of thyroid hormones T3 and T4 cause increased nutrient breakdown & use of oxygen to produce mitochondrial ATP T3 and T4 initiate the transcription of genes involved in glucose oxidation ATP production is now higher, but the process is inefficient & increased heat is released This so-called calorigenic effect (calor = “heat”) raises body temperature Adequate levels of thyroid hormones are also required for protein synthesis & for fetal and childhood tissue development and growth Thyroid hormones have a complex interrelationship with reproductive hormones & aspects of reproductive function Thyroid hormones increase the body’s sensitivity to catecholamines (from adrenal medulla) by upregulation of receptors in the blood vessels High T3 and T4 levels accelerate heart rate, strengthen cardiac output & increase blood pressure https://courses.lumenlearning.com/suny-ap2/chapter/the-thyroid-gland/ Metabolism: thyroid pathologies Graves' disease is an autoimmune disease that leads to thyroid gland overactivity & hyperthyroidism Thyroid gland tumors can also lead to this complication Dr. Robert Graves described the condition in 1835 Thyroid-stimulating immunoglobulins mimic TSH action by binding to TSH receptors on thyroid gland This leads to T3 and T4 hypersecretion & symptoms Hyperthyroidism can lead to increased metabolic rate, excessive body heat & sweating, diarrhea, weight loss, tremors, increased heart rate Individual’s eyes may bulge (called exophthalmos) as antibodies produce inflammation in soft tissues of the orbits Individuals may also develop a ‘’goiter’’, i.e. an abnormal enlargement of the thyroid gland Silverthorn, CH23, p774  Metabolism: thyroid pathologies Not examinable material! https://bio.davidson.edu/Courses/Immunology/Students/Spring2003/Breedlove/GravesDisease.html  Metabolism: thyroid pathologies Silverthorn, CH23, p774 https://www.mayoclinic.org/diseases-conditions/graves-disease/symptoms-causes/syc-20356240 Metabolism: thyroid pathologies The most common cause of hypothyroidism is an autoimmune disease called Hashimoto's disease This is named after Dr. Hakaru Hashimoto who first described this condition in 1912 Other causes include a lack of iodine in the diet, thyroiditis, radiation, surgery This leads to lower T3 & T4 secretion and no negative feedback to hypothalamus & anterior pituitary In absence of negative feedback, TSH secretion increases & it enlarges the thyroid gland Symptoms include lower metabolic rate and protein synthesis & accumulation of mucopolysaccharides under the skin Such molecules attract water & cause the puffy appearance of myxedema (severe hypothyroidism) Silverthorn, CH23, p774 Metabolism: thyroid pathologies Silverthorn, CH23, p774 https://drawittoknowit.com/course/pathology/glossary/pathophysiologic- disorder/hypothyroidism-hashimoto-s-thyroiditis-etc  Metabolism: insulin & glucagon Somatostatin = Growth hormone-inhibiting hormone Silverthorn, CH22, p744  Metabolism: postprandial glucose levels Dietary intake Post-meal rise in circulating blood glucose levels Postprandial glucose test – amount glucose in blood following a meal Magnitude & time of peak plasma glucose varies Non-diabetics usually peaks at 60 mins; rarely exceeds 7.7 mmol/L Returns to preprandial levels 2-3 hr Graph not examinable material – focus on principles! JACC 2008; 51: 249-255  Metabolism: differing postprandial excursions Graph not examinable material – focus on principles! Am J Clin Nutr 2002;75:254-262  Metabolism: modulation of postprandial excursions Graphs not examinable material – focus on principles! JACC 2008; 51(3); 249-255  Metabolism: a tale of two states Meal (energy intake) Metabolism Absorptive state Post-absorptive state (fed state) (fasted state) lasts up to 4 hrs aim to replace fuels glucose main fuel fatty acids main fuel anabolic catabolic energy stored energy breakdown  Metabolism: fate of dietary glucose Meal Glucose Liver: 30% Other organs: 70% Glycolysis & citric acid cycle – ATP production Excess stored as glycogen (liver, muscle) Excess stored as fat (adipose tissue)  Metabolism: fate of dietary amino acids Meal Amino acids Liver: 1. Low glucose intake: synthesis of lipoproteins & amino acids used for energy plasma proteins (converted to pyruvate) Other cells: 2. amino acid intake: synthesis of structural & excess converted to fat functional proteins Metabolism: amino acids to fat synthesis links Alanine Cysteine Glycine Serine Threonine Silverthorn, CH22, p737 Metabolism: insulin & glucagon Silverthorn, CH22, p745 Metabolism: insulin & glucagon Silverthorn, CH22, p745 Metabolism: fasted state Silverthorn, CH23, p741 Metabolism: glucagon effects Silverthorn, CH22, p750 Metabolism: insulin & glucagon Silverthorn, CH22, p745  Metabolism: insulin secretion https://www.yaclass.in/p/science-cbse/class-10/control-and-coordination- 10298/receptors-and-hormones-9821/re-a84894da-635c-4e69-b8e3-d27f15562c3c Silverthorn, CH 5, p194 Metabolism: insulin secretion Silverthorn, CH 5, p194 Metabolism: glucagon-like peptide (gut hormone) Nature Rev Drug Disc. 2009; 8: 369-385 Metabolism: control of insulin secretion Sherwood, CH 19, p708 Metabolism: control of insulin secretion Sherwood, CH 22, p746  Metabolism: insulin-mediated muscle glucose uptake http://www.youtube.com/watch?v=FkkK5lTmBYQ&feature=related Silverthorn, CH 22, p748 Metabolism: insulin-mediated muscle glucose uptake Silverthorn, CH 22, p749 Metabolism: insulin-mediated liver uptake Silverthorn, CH 22, p749 Metabolism: synergism In synergism, the effect of interacting hormones is more than additive Thus, the combined effect of the two (or three) hormones are greater than the sum of the two (or three) hormones Mechanisms not clear but the hormones may have overlapping effects on target 2nd messenger systems In contrast, a permissive hormone allows another hormone to exert its full effect Thus, one hormone cannot exert its effects unless a second hormone is present For example, maturation of reproductive system requires GnRH (hypothalamus), gonadotropins (anterior pituitary) & steroid hormones (gonads) However, if insufficient thyroid hormone available this maturation is delayed Thyroid hormone therefore has a permissive effect on reproductive maturation Silverthorn, CH 7, p249  Metabolism: insulin & glucagon effects Blood glucose Blood glucose  cell  cell  cell  cell Glucagon Insulin Glucagon Insulin Blood glucose Blood glucose to normal to normal Sherwood Figure 19-17 Metabolism: insulin properties Silverthorn, CH 22, p745 Metabolism: glucagon properties Silverthorn, CH 22, p750  Metabolism: diabetes (early descriptions) 1552 BC: Hesy-Ra, a physician in the 3rd Egyptian Dynasty documents frequent urination (polyuria) 500-400 BC: Charak & Sushrut, Hindu physicians – ‘’madhumeha’’ (sweet urine); also noticed ants congregated around urine of sick individuals; noticed most prevalent in those overweight and indulging in sweet & fatty foods  Metabolism: diabetes (early descriptions) 1st Century AD: Aretaeus, a Greek physician describes medical condition ‘’melting down of the flesh and limbs into urine’’ – coins term ‘’diabetes’’ (meaning ‘’siphon’’ or ‘’passing through’’) ‘’Diabetes is a dreadful affliction, not very frequent among men, being a melting down of the flesh and limbs into urine. The patients never stop making water and the flow is incessant and painful, their thirst unquenchable, drinking excessive, and disproportionate to the large quantity of urine, for yet more urine is passed. One cannot stop them from drinking or making water…the patients are affected by nausea, restlessness and a burning thirst, and within a short time they expire.’’  Metabolism: diabetes (middle ages) 980-1037 AD: Avicenna, provided detailed account in his ‘’Canon of Medicine’’ describing abnormal appetite, decline of sexual function and emphasized taste i.e. sweet urine; urine tasters  Metabolism: diabetes (terminology) d. 1809 AD: John Rollo, added the term ‘’mellitus’’ (Latin: ‘’honey’’) to diabetes; before this condition also known as the ‘’pissing evil’’. He proposed that sugar is formed in stomach from vegetable intake & thus prescribed animal-based diet (meat, fat) as treatment.  Metabolism: diabetes (insulin discovery) Frederick Banting d.1941 James Collip d.1965 Leonard Thompson JJR Macleod d.1935 Charles Best d.1978 Isolation of insulin, first trial on 14-year-old Leonard Thompson (1922) – after second injection of insulin extract his blood glucose normalized & marked clinical improvement. 1923: Nobel prize (Physiology or Medicine) awarded jointly to Banting and Macleod.  Metabolism: diabetes (blood tests) Average lifespan of red blood cells: 100-120 days https://www.youtube.com/watch?v=wbpIdCj57_Y http://slideplayer.com/slide/1678079/ Metabolism: diabetes (blood tests) 126 mg/dL = 7.0 mmol/L 200 mg/dL = 11.1 mmol/L 100-125 mg/dL = 5.6-6.9 mmol/L 140-199 mg/dL = 7.8-11.1 mmol/L 99 mg/dL = 5.5 mmol/L 140 mg/dL = 7.8 mmol/L Metabolism: type 1 vs type 2 diabetes Biotechnology Advances Vol 39; March–April 2020, Metabolism: type 2 diabetes (mechanisms – simplistic!) https://nurseslabs.com/diabetes-mellitus/ Endocrinology & major themes of physiology: examples Blood O2  Blood oxygen levels: erythropoietin (Epo) effects Epo production (mostly by kidney) is controlled by feedback loop mechanism Its effects are mediated via a high affinity cell surface receptor (Epo-R) expressed on immature erythroid cells Factors that affect oxygen delivery to the kidney can increase Epo production & stimulate erythropoiesis This includes e.g. higher altitude, anemia, low hemoglobin levels, defective cardio-pulmonary function decreasing renal perfusion The kidneys sense low oxygen levels & produce Epo to increase red cell mass production in the bone marrow The additional circulating erythrocytes now increase the oxygen carrying capacity of blood This increase in oxygen capacity attenuates the effects on the kidney & lowers Epo production via a negative feedback loop Not examinable material – top part of figure! Critical Reviews in Oncology/Hematology 64 (2007) 139–158  Blood oxygen levels: EPO pleiotropic effects Pleiotropic: ‘’producing more than one effect’’ Front. Physiol., 17 January 2020; Volume 10 – 2019  Blood oxygen levels: erythropoietin (Epo) doping Epo gene expression in kidneys & liver is controlled at transcriptional level Drugs that stabilize transcription factors (such as HIF) increase Epo expression GATA inactivators release the Epo promoter from GATA-2 (transcription factor) inhibition Androgenic steroids, GH & IGF-1 enhance Epo production & the proliferation of erythrocytic progenitors Not examinable material! Blood 2011 Sep 1;118(9):2395-404  Blood oxygen levels: erythropoietin (Epo) doping https://www.linkedin.com/pulse/why-blood-doping-good-thing- https://capstonefindlay.wordpress.com/2015/05/10/pros-of- ethics-athletics-vs-brandon-marcello-phd/ synthetic-epo-usage/ Blood oxygen levels: erythropoietin (Epo) doping https://daily49er.com/opinions/2015/09/02/more-track-doping- incidents-plague-the-sport/ Endocrinology & major themes of physiology: examples Blood volume Blood volume: arginine vasopressin (AVP) Antidiuretic hormone (ADH) is used as an alternate term for AVP Three factors control AVP release by posterior pituitary: blood pressure, blood volume & plasma osmolarity Plasma osmolarity is most potent stimulus for AVP release AVP acts on collecting duct of kidney by stimulating insertion of water pores (aquaporins) into apical membrane Thus, water moves from the lumen (via osmosis) into circulation to increase blood pressure Silverthorn, CH 20, p662 Blood volume: arginine vasopressin (AVP) Silverthorn, CH 20, p662 Blood volume: aldosterone Aldosterone is a steroid hormone that is synthesized in the adrenal cortex Aldosterone regulates reabsorption of Na+ from distal nephron into circulation As it regulates Na+-K+-ATPase, it also leads to K+ secretion into lumen of nephron It acts on principal cells (P cells) in the distal nephron epithelium It moves into P cells via simple diffusion, binds a cytoplasmic receptor & triggers transcription New protein channels are synthesized that increase Na+ uptake into circulation Increased Na+ osmotically conserves more water in ECF Silverthorn, CH 20, p667 Blood volume: aldosterone Silverthorn, CH 20, p667 Blood volume: angiotensin (ANGII) Angiotensin II is part of a multistep pathway to control blood pressure It is referred to as RAS (renin-angiotensin system) or RAAS (renin-angiotensin-aldosterone system) Angiotensin-converting enzyme (ACE) plays a key role to convert ANGI to ANGII ANGII is a potent vasoconstrictor & does so at several levels (refer bottom part of diagram) For example, it causes synthesis & release of aldosterone from the adrenal gland Of note, Na+ retention increases osmolarity & this stimulates thirst to also increase blood pressure Silverthorn, CH 20, p669 Blood volume: atrial natriuretic peptide (ANP) ANP is a peptide hormone produced by cardiac atrial cells Released when myocardial cells stretch more ANP can bind to a membrane receptor to trigger a cGMP 2nd messenger system It enhances Na+ & water excretion by the kidney to lower blood pressure Thus, it causes urinary Na+ loss (natriuresis) and water loss (diuresis) ANP can act at multiple sites (refer bottom part of diagram) Brain natriuretic peptide (BNP) is a related hormone (secreted by cardiac ventricular cells) with similar actions as ANP Silverthorn, CH 20, p670  Blood volume: hypertension Hypertension Primary Secondary 90 - 95% of all hypertension cases Lifestyle modifications Causes generally unknown Risk factors may include: -obesity, diabetes -genetic Drug treatments -hyperlipidemia -diet (high salt), smoking, alcohol intake -stress  Blood volume: hypertension Not examinable material!  Blood volume: hypertension Not examinable material!  Blood volume: hypertension Not examinable material!  Stress: terminology “response of the body to any demand, whether it is caused by, or results in, pleasant or unpleasant conditions” Hans Selye (1936) Selye first used the term ‘’stress’’ to represent the effects of anything that seriously threatens homeostasis Both internal & external factors can affect the body’s homeostasis Stressor: any factor or event that causes stress We can be exposed to a variety of stressors e.g. physical/physiological changes in body, environmental changes, life events, behaviors, imaginary situations Sharma et al., HSOA J Med: Study & Research, 2018 Schneiderman et al., Annu Rev Clin Psychol, 2005  Stress: acute versus chronic Acute stress: occurs for a relatively short period of time, i.e. comes quickly & goes quickly Episodic stress: when acute stress felt frequently Chronic stress: accumulated effects of stressor for a relatively long time Sharma et al., HSOA J Med: Study & Research, 2018  The integrated stress response Complex mechanisms that integrate brain & body allows for coping with stressful situations The perception of stressors involves different networks depending whether its a physical or psychological stressor The activation of the SAM pathway & HPA axis generates a coordinated response that starts within seconds & can last for days This allows for an almost immediate restoration of homeostasis To accomplish this, the stress response systemically promotes energy mobilization, metabolic changes, activation of the immune system and suppression of the digestive and reproductive systems The central (brain) effects, combined with proinflammatory signaling lead to alterations in cellular excitability & synaptic and neuronal plasticity Collectively, these body-brain effects mediate alterations in physiology and behavior that enable adaptation and survival Godoy et al., Frontiers in Behavorial Neuroscience 2018; 145: 1002-1019  Chronic stress & acute myocardial infarction F M } Smoking M F } Diabetes M F } Hypertension F M } Abdominal obesity M F } Psychosocial stress F M } Fruit & Veggies F F M } Exercise M } Alcohol M F } ApoB/ApoA1 0.25 0.5 1.0 2 4 8 16 Odds Ratio Not examinable material! Yusuf et al., Lancet 2004; 364: 937-952  Stress & Takotsubo syndrome Acute heart failure Transient ventricular contractile dysfunction Apical ballooning Acute emotional/physical stress Not examinable material! Singh et al., Circulation 2022; 145: 1002-1019  Stress & Takotsubo syndrome (or broken heart syndrome) Not examinable material! During 2016, Debbie Reynolds died one day after her daughter Carrie Fisher  Chronic stress: management -behavior/attitude ‘’Positive affect is defined as the experience of pleasurable emotions such as joy, happiness, excitement, enthusiasm, and contentment’’. Not examinable material! Eur Heart J 2010; 31: 1065-1070  Chronic stress: management -behavior/attitude Not examinable material! JACC 2011; 58: 1222-1228 Health & wellness: good relationships the key? And in the naked light I saw Ten thousand people, maybe more People talking without speaking People hearing without listening People writing songs that voices never share And no one dared Disturb the sound of silence