Endocrinolgoy Exam III Notes
Endocrinolgoy Exam III Notes BIL365
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This 31 page Study Guide was uploaded by Ashi Ma on Tuesday February 10, 2015. The Study Guide belongs to BIL365 at University of Miami taught by Professor Richard Tokarz in Winter2015. Since its upload, it has received 69 views. For similar materials see Endocrinology in Biology at University of Miami.
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Date Created: 02/10/15
Dr Tokarz Endocrinology Exam 3 Notes Growth HormonesFactors GH and Somatomedins GH most important stimulator of growth during juvenile period 0 Thyroid hormones adrenal hormones and insulin also required 0 Adolescent growth spurt due to input of gonadal steroid hormones GH stimulates synthesis and release of somatomedins Somatomedins o lnsulinlike growth factor1 IGF1general growth most studied 0 lnsulinlike growth factor2 lGF2fetal growth 0 Production of lGFl not limited to liver but may be increased by GH in many tissues including cells in epiphyseal growth plate of bones Role of GH and IGF1 in Promoting Growth GH from pituitary goes into blood and acts on liver and bone via IGF Dual Effector Theory of Somatotrobin Action GH directly promotes differentiated state of certain cell types such as prechondrocytes in epiphyseal plates of bone that synthesize amp secrete lGFs IGF l stimulates multiplication of GH induced differentiated cell types clonal expansnon Dual Effector Hypothe5s of GH Action GH Germinal o CeHLayer 1 Development oi IGFI Responsiveness lGFI I lGFl 2 Expression ofIGEl Gene 9 5 7 q Prolllleretlue GP IGH GM I E Celllsayer gt V 1 LocalF39roduction oflGFl g g 2 Stimulation of Clonal g 39 39 r 7 r Expainsioniby Ailtorgrineil g e o I o Paracrine Mechanisms E E D m IV 77 I 7 r a Cytoplasmic Maturation 0 70 w39 IGFl in Normal Adults Acromedalic Patients and Patients with GH De ciencv Normal adults at around 200mgmL serum of lGFl Acromegalicmuch higher than normal at 500 to 1000 IGFl Hypopituitary dwarfs have lower than normal IGFl IGF1 and Insulin Receptors are Similar Insulin more potent in metabolic effects than IGF IGFmore for all around growth Control of GH Secretion bv SST and GHRH SST is inhibitory GHRHstimulatorygrowth hormone releasing hormone Direct and Indirect Actions of GH on growth and metabolism gt Feedback Mechanism gt Hypothalamus lt Growth Hormone Indirect Actions L Direct Actions Prolactin Placental Lactogen Antinsulin Effects Insulin Fat Cells I Carbohydrate Metabolism Fat Cells Lipolysis Lipogenesis Protein Synthesis Y Chondrocytes Diabetogenlc ActIVIty FFA amp Glycerol Glucose K J Cartilage Formation Growth Hormone Signal Transduction Pathway Dimer is formed after binding of GH JAK not tyrosine kinase Receptor itself is not a tyrosine kinase STATssignal transducers and activators of transcription Endocrine Disorders related to GH Human pancreatic tumor Lesions defects in tissue 0 Lesions can be in pituitary gland liver and peripheral tissue Insulin Required for Normal Growth Increased cellular uptake of glucose and AA InsulinIGF signaling pathways regulate aging o Decreased signaling increases life span in nematodes rodents and ies o Might explain relationship between longevity and caloric restriction observed in many species Klotho Protein AntiAging Hormone Klothotransmembrane protein Binds to cell surface receptor and represses intraceIIuIar signals of insulin and IGF1 In mice a defect in Klotho gene expression accelerates aging whereas overexpression extends lifespan Gene variants of Klotho gene associated with human aging Epidermal Growth Factor EGF Found in saliva of male rodentsdevelopment of epidermal structures Eyelid opening tooth eruption in rodents Topical applicationimportant in wound healing Major growth promoting agent in breast milk EGF Receptor RTK family Over expressed in many tumor types including coorecta cancer More receptors poorer prognosis AntiEGF receptor drugs used to treat cancer 0 Eg Cetuximab Erbitux an gG monoclonal antibody against EGF receptor NGF Effects Development and maintenance of sympathetic neurons and sensory neurons of spinal cord Tropic effect on basal choinergic neurons in brain Erythropoietin EP Synthesized in kidney in response to hypoxemia Induces differentiation of erythrocytes from precursor cells in bone marrow Acclimation to high altitude Synthetic EP to treat anemia egay used to increase performance Exponential Increase in Serum Ervthr0poietin with the Degree of Anemia Normal levels1201809L Biogenesis and Actions of Erythropoietin HypoxiaD kidney EP erythroblasts erythrocytes and bone marrow Platelet Derived Growth Factor PDGF Proliferation of smooth muscle and broblasts Released foowing platelet aggregation Promote wound healing Attracts in ammatory cells macrophages Potent vasoconstrictor Atherosclerotic lesion proliferation of SM cells win arterial wall FGFsFibroblast Growth Factors A large family of growth factors Aberrant expression may cause cell transformation via autocrine mechanisms Stimulate mitogenic activity in cells of epithelial mesenchymal and neural origin Promote angiogenesis and wound healing Role in carcinogenesis by stimulation of blood vessel growth ampor inducing proteases such as plasminogen activator that degrades the ECM TGFTransforming Growth Factors 0 amp 3 Named based on ability to transform normal cells to tumor cells Produced by both normal and neoplastic cells TGFd is similar structure ot EGF and binds to EGF receptor 0 Stimulates cell proliferation in many tissues TGFB inhibits cell proliferation except for broblasts 0 Antibodies to it are used to prevent scarring from burns caused by excess broblast proliferation Angiogenic Factors Stimulate angiogenesis formation of new blood vessels Angiogenin FGFs TGFs Important in wound healing tumor growth and other conditions requiring neovascularization o lschemic heart 0 Diabetic retinopathy Thymus Gland and Thymosins Thymus gland in upper thorax above heart 0 Atrophies after puberty Produces thymosins such as thymosin dl Differentiation of competent T lymphocytes Thymosins used in treatment of primary immunode ciency and cancer lnhibins and Activins Disul de bonded dimers o lnhibins comprised of an or and 3 subunit 0 Activins comprised of 2 3 subunits Product of gonads and other tissues Reproductive effects 0 lnhibins inhibit FSH release 0 Activins stimulate FSH release Thyroid Gland and Thyroid Hormones Human Thyroid Gland Larynx Pyramidal lobe Trachea I 7 Thyroid Gland Follicles quot Multiple follicles in the thyroid gland 39 Histological Section of Thyroid Gland and Follic g l Colloid 1 Thyroid Hormones L 56 Thyroxine 353 5 tetraiodothyronine f Mir3929 Egquot Triiodothyronine 353 triiodothyronine Ln Reverse T Structures of lodothyronines All contain OH group at the end Two benzene rings linked via an 0 Preview of Synthesis and Release of Thyroid Hormones Synthesis of iodothyronines T4 and T3 Release of T4 and T3 by hydrolysis of thyroglobulin Step 1 Thyroglobulin TG Synthesis Large globular glycoprotein 2 tyrosine Synthesized in rER Packaged in exocytotic vesicles Deposited in lumen of follicle Step 2 lodide Accumulation Requires energy Nal symporter in basal membrane o Pendrin a protein found at apical membrane transports I into lumen in exchange for CI Stimulated by TSH Iodide in thyroid to serum ratio of about 39 in euthyroid individuals Monovalent Anion Inhibitors of Iodide Transbort o Thiocyanate o Perchlorate o Chlorate o Iodate Step 3 Iodide Binding to Tyrosine in TO Occurs at or near umina surface Oxidation of iodide to quotactive iodidequot or I I H202 peroxidase D H20 and 02 0 One iodide added forms 3monoiodotyrosine MIT Two iodides added forms 35 diiodotyrosine DIT Step 4 Oxidative Coupling Formation of iodothyronines Requires thyroid peroxidase enzyme 0 Converts diiodotyrosine to thyroxine Coupling scheme for iodothyronine formation Iodine organi cation D cleavage site D free radical formation D coupling Thioamide Inhibitors of Oxidative Coupling and active iodide formation 0 Thiourea o Thiouracil o Propylthiouracil o Methimazole Hydrolysis of TG and Release of Thyroid Hormones Involves Iysosomes and hydrolytic enzymes W pH 34 Summary of Thyroid Hormone Synthesis and Release quot d FBIoodTle h i 7 EFF Lg led Pituitary I TSH Targe t ff a 1 V QEucosve e c iMiP 4 MP 29 wide 3 4 a DEIMIMBSB G5 P PE39I IIOSG J39l i i L TT3 lod olymsines a Iodide Cycle GB P E Recycle NADPH Tissues lTGl L 050an Secondary 3 5 Lysomme r V Q 6 N ucleus Y yNADF I r Pemxrde Generating System 7 DNA i i 5 0 l gr lg 2 5 Tra 39 1 I I I V PM mug MA gt Thyroglobulin H202 39 ng GIISynmesis Peroxidase V Colloid Droplet t Ed if Endocymsfigliz quot393 53 Thyrogldbulin Reabsorption Lacunae Oxidalive Coupfing 39 Follicular Lumen Dir tiIT MIT DIT 31 I 11 I Colloid Spacer Ta Ta Copyright 23930 Pearson Prentice Hall Inc Thyroid Hormone Binding Proteins Thyroid hormones poorly soluble in water gt99 bound to binding proteins 0 Thyroxinebinding globulin most important o Thyroxinebinding prealbumin transthyretin o Albumin Certain drugs such as saicyates and phenytoin decrease binding of thyroid hormones for binding proteins T3 vs T4 Activitv T3 is biologically more active than T4 85 nuclear binding T4 is the prohormone for T3 T4 is converted to T3 by extrathyroidal monodeiodination of T4 by 5 monodeiodinase enzyme 80 converted TSH Stimulates via increased cAMP Glucose uptake Iodide uptake TG synthesis Higher Brain Centers I 1 I Follicular cleII mitoses Hypothgjamus h i Endocytosrs of TG lm If Thyroid Follicles in Different States of Activity l Hypothyroid Fluxtar 9quotng Euthyroid Hyperthyroid CNS Pituita ryThyroid Axis Thyroid Hormone Functions his Maturation and Differentiation Amphibian metamorphosis Salmon smolti cation Targetllssues o Adapts sh to life in salt water Maturation and Differentiation cont Maturation of human brain w GH Effects structures derived from the integument 0 Hair humans 0 Pelage mammals o Moting of feathers birds 0 Shedding of skin reptiles Promotes cellular differentiation 0 Stimulates hyauronidase which breaks down hyauronic acid to smaller oigosaccharides o Differentiating cells have less hyauronic acid Metabolic Actions Hyperthyroidism increased basal metabolic rate BMR 0 Increased 02 consumption and heat production Hypothyroidism decreased BMR o Decreased 02 consumption and heat production Mechanisms of heat production 0 Increased lipid and carbohydrate metabolism 0 Increased NaKATPase Sodium theory of Thermogenesis Sodium transport accounts for 2040 of cellular energy 0 ATP hydrolysis required for transport 0 Liberates heat Mechanism of Thyroid Hormone Actions Genomic T3 binding most important Copyright 3 2007 Pearson Prentice Hall Ilnc Thyroid receptor TR in nucleus Heterodimer binds to HRE TR receptor for 9cis retinoic acid receptor RXR most important for biological activity TR receptor for T3 and Receptor for 9cis Retinoic receptor RXR The TR receptor and RXR receptor dimerize Mechanism of NonGenomic Thyroid Hormone Actions T4 is most potent Nonnuclear receptor Effects plasma membrane functions ion pumps channels 0 Increased NaK ATPase in mitochondria generates heat Pathophysiology Simple or endemic goiter Lack of iodide Goitrogens substances in environment that interfere w thyroid gland function eg cassava Hypothyroidism Too little thyroid hormone or action Simple or endemic goiter lack of iodide Hashimoto s thyroiditis autoimmune disease chronic lymphocytic thyroiditis Low T3 syndrome inadequate conversion of T4 to T3 Cretinism Lack of thyroid hormone early in development Stunted growth and mental retardation Hypothyroidism in Adults Puffy face Frowzy hair Dull apathetic appearance Mentally slow Myxedema of Hypothyroidism Swelling of skin and subcutaneous tissues osmotic edema secondary to increase deposition of connective tissue components such as hyaluronic acid and chondroitin sulfate Also used to describe clinical syndrome secondary to hypothyroidism such as myxedema coma and myxedema madness Treatment of Hypothyroidism Oral administration of synthetic thyroid hormone such as Synthroid levothyroxine sodium salt Hyperthyroidism Too much thyroid hormone or action Symptoms collectively termed thyrotoxicosis Graves Disease Most common form of hyperthyroidism Autoimmune disease Antibody to TSH receptor long acting thyroid stimulator LATS an lgG Exopthalamos A Symptom of Grave s Disease Protruding eyeballs LATS bind to TSH receptors in retro orbital connective tissue In ammatory process causing swelling in muscle and connective tissues behind eyes Hamburger thyrotoxicosis Contamination of meat with beef thyroid gland Problem with gullet trimmers Treatment of Hyperthyroidism Antithyroid drugs Surgery to remove portion of thyroid gland Manifestations of Hyperthyroidism and Hypothyroidism TABLE 13i2 Major physiological manifestations of hyperthyroidism and hypothyroidism Hyperthyroidism Hypothyroidism Elevated T4lf3 levels Decreased or absent T4T3 levels Elevated basal metabolic rate EMR hypermetabolism Low basal metabolic rate BMR hypometabolism Increased perspiration Decreased perspiration Rapid pulse increased cardiac output hypertension Slow pulse decreased cardiac output hypotension Increased body temperature sensation of warmness Lowered body temperature sensation of coldness Heat intolerance Cold intolerance Warm moist palms Coarse dry skin subdermal thickening Nervousness anxiety excitability restlessness insomnia Lethargy decreased mentation depression paranoia sleepiness tiredness Weight loss Weight gain Muscle wasting Loss of hair dry and brittle texture Increased appetite Edema of face and eyelids Menstrual irregularities Menstrual irregularities Exophthalmos in some individuals Carotenemia increased plasma levels of carotenes Goiter primary or secondary origin Go iter may or may not be present Copyright 2007 Pearson Prentice Hall Inc Catecholamines and Sympathoadrenal System Catecholamines Contain a 34 dihydroxyphenyl group termed cathechol DopamineDnorepinephrineepinephrine Sympathoadrenal System Sympathoadrenal o Pertaining to the sympathetic nervous system amp adrenal medulla o Involving the sympathetic nervous system amp the adrenal glands especially increased sympathetic activity that causes increased epi and norepi secretion Autonomic Nervous System Nerves of the peripheral nervous system other than somatic neurons that supply skin and all visceral organs Subdivided into parasympathetic nervous system and sympathetic nervous systems Both systems composed of preganglionic and postganglionic neurons Differences bw Parasvmpathetic Nerves and Svmpathetic Nerves Origin in spinal cord cranialsacral vs thoracolumbar Length of nerves long preganglionic vs short preganglionic nerves Neurotransmitters at postganglionic synapses acetylcholine vs norepinephrine Norepinephrine NE and Epinephrine Epi Norepinephrine has primary amine Epinephrine has secondary amine Human Adrenal Glands Located above the kidneys Chromaffin Cells of Adrenal Medulla Stain brown with chromate Termed pheochromocytes or blasts Arise from neuroectoderm and innervated by sympathetic neurons that originate in thoracolumbar portion of spinal cord Equivalent to a sympathetic ganglion without postganglionic processes Stimulated during development by gucocorticoids Secrete catechoamines Epi most important Ne 10 ExtraAdrenal Chromaffin Tissue Paraaortic bodies Paraganglia Organs of Zuckerkandl Catecholamine Svnthesis Phenylamine tyrosinedopadopaminenorepinephrineepinephrine Tyrosine hydroxylaserate limiting enzyme Storage and Release of Catecholamines from Chromaffin Cells Epi and norepinephrine in vesicles with protein chromogranin o Epi 9X more abundant than NE Acetylcholine released from preganglionic sympathetic neurons stimulates release by causing an in ux of Ca Metabolism Adrenal Catecholamines T 12 of epi and NE is 1015 sec Epi and NE degraded an excreted in urine by the action of 2 enzymes 0 Monoamine oxidase MAO in neural tissue 0 Cathecholamineomethyltransferase COMTin endotheium heart liver and other tissues Inactive metabolites present in urine 0 3methoxy4hydroxymandelic acid vanillylmandelic acid VMA primary metabolite in ureine o 3methoxy4hydroxyphenylglycol MPG Adrenergic Receptors ARs Nterminus and Cterminus ends Ahlquist Dual Receptor Hypothesis A and B adrenergic receptors Alpha and Beta ARs differ in relative responsiveness Alpha ARs o Epigtnegtisoproterenol ISO BARs o lSOgtepigtNE Epinephrine Effects on SM Epi binds to both 0 and B ARs Effect of 0 AR binding dominant contraction Effect of B AR binding silent would be relaxation Blocking 0 AR binding with an antagonist allows effect of B binding to be expressed relaxation Experimental Demonstration of Epi Effect amp Reversal on Smooth Muscle Epi reversal Epi binds to the receptors in the smooth muscle membrane Phenomenon of natural epinephrine reversal auto inhibition Effect of epi binding to B AR expressed after long period of binding and muscle relaxes Prevents prolonged vasoconstriction due to Epi binding to 0 AR smooth muscle contraction 0 Example of auto inhibition of Epi action AIphaAdrenerdic Receptor Subtvoes Alphal o Postsynaptic ces nervemuscle junction Alpha2 o Presynaptic cells at all noradrenergic synapses Additional subtypes o AlphalA vascular system Negative Feedback Mechanism for Inhibition of Sympathetic Neuron Secretion Reuptake transporter present BetaAR Receptor Subtvoes Betal 0 Heart increased heart rate 0 sogtgtepiNE Beta2 o Lungs bronchodilation o sogtepigtgtNE hormonal effect Beta3 0 Fat ces catabolism AR Agonists and Antagonists Agonists o Clandine speci c for alpha2 o lsoproterenol nonseective B Antagonists o Phentoamine nonseective or o Propranool nonseective B Beta blocker Inderal Mechanism of Action of Receptor Subtypes Alphas o Alphal increases P3 and DG 0 Alpha2 decreases cAMP Betas o All subtypes increase cAMP Multiple Mechanisms of AR Signal Transduction Receptors in membrane Adenyy cycase Factors Affecting Receptor Mediated Effects Receptor types amp subtypes o Alphal vs alpha2 Relative receptors 0 More ocARs than BARs or vice versa 0 Only BARs Catecholamine o Epi vs NE Important Generalities about ARs Both ocARs and BARs in target cells or only BARs 0 There are no ocARs alone Binding to ocARs mask effects of binding to BARs in smooth muscle AARssmooth muscle contraction BARsrelaxation except intestinal smooth muscle Alphal AR and BetalAR contraction in cardiac muscle AlphaARs decrease cellular secretion BetaARs increase secretion Physiological Effects of Epi Liver o BetaARs increase glycogenolysis and glucose Muscle o BetaARs increase glycogenolysis increased lactic acid 0 Lactic acid goes to the liver and is used to synthesize glucose Cori cycle Adipose cells 0 BetaARs beta3 increase triglyceride lipase activity and release of FFA and glycerol lslets of Langerhans o AlphaARs decrease insulin secretion by B cells 0 BetaARs increase glucagon secretion by 0 cells Bronchial smooth muscles 0 Beta beta2 AR relaxation Heart 0 BetaBeta1AR increases force and rate of heart beating Pathophysiology Adrenal Chromaf n Tumors pheochromocytomas Usually benign 10 malignant Excess epi amp NE release Treat with ocmethyltyrosine competitive inhibitor of tyrosine hydroxylase Cholinergic Receptors Bind acetylcholine Nicotinic Type of Cholinergic Receptor Agonist nicotine Antagonist curare Located post synaptically at autonomic ganglia and at neuromuscular junctions somatic muscle gers Muscarinic Type of Cholinergic Receptor Agonist muscarine Antagonist atropine Located postsynaptically at parasympathetic neuroeffectorjunctions Myasthenia Gravis Autoimmune disease Antibodies against skeletal cholinergic nicotinic receptors Adrenal Steroid Hormones Embryology of Human Adrenal Cortex Derived from mesoderm Fetal zonean enlarged area next to medulla Produces dehydroepiandrosterone sulfate DHEA sulfate that is converted to estrogens in placenta Following birth adult adrenal cortex develops Adrenal Glands of Mammals amp Other Vertebrates Mammals o Cortex steroidogenic tissue medulla chromaf n tissue Most vertebrates o Steroidogenic and chromaf n tissues intermingled at various sites in body Teleosts and elasmobranchs sharks skates rays 0 Two types of tissues separated Microanatomy of Human Adrenal Cortex Connective tissue capsule Zona fasciculate and zona reticularis Histoloov of 3 Zones of Adrenal Cortex Zona reticularis Zona fasciculata Zona glomerulosa Adult Adrenal Cortex Zona Steroid class Primary control Glomerulosa Mineralocorticoids Angiotensin II Fasciculata Glucorticoids androgens small amounts ACTH Reticularis Glucorticoids androgens ACTH Adrenal Functional Unit Blood ows from cortex to medulla Stressors increase ACTH and thus cortisol Cortisol activates PNMT which converts NE to Epi Cortisol and epinephrine important hormones in stress response Source of Cholesterol in Synthesis of Adrenal Steroids Most obtained from plasma Receptormediated endocytosis of LDL low density lipoprotein Cholesterol stored as ester Model for Cholesterol Homeostasis STARsteroidogenic acute regulatory proteintransports cholesterol from outer to inner mitochondrial membrane where side chain cleavage enzyme is located Conversion of Cholesterol to Pregnenolone Cholesterolpregnenolone Occurs in mitochondriainner membrane Done by cytochrome P450scc 2 maior pathwavs Delta4 Pathwav and 17dhvdroxvlase pathwav SER Prednenolone A4 pathway 1 I d hydroxylase pathway 3 Bhydmxyster0id 7uhydroxylase P450017 dehydr ogelnasel A 5A4 isomerase l3l3l3lDl I 7dOIHPregnenolone P g n 399 1I dhydroxy progesterone i i And rogens ttdeoxycortisone It deoxycortisol I I Corticosterone Aldosterone Relative Importance of 17dhydroxylase pathway Important in humans but less important in reptiles birds and some mammals o Humans make more cortisol than corticosterone Zona glomerulosa in humans lacks 17ozhydroxylase and this is why aldosterone is secreted in this zona Adrenal Mineralocorticoids Aldosterone primary mineralocorticoid in mammals 11deoxycorticosterone and 11deoxycortisol weaker mineralocorticoids Secreted by zona glomerulosa Adrenal Glucocorticoids In humans cortisol is most important glucocorticoid o Corticosterone is mostly converted to aldosterone In many species including amphibians lizards birds and some mammals corticosterone is most important glucocorticoid Post secretory Metabolism of Adrenal Cortical Steroids Conversion of Active Cortisol to Inactive Cortisone Cortisol shuttle bw cortisol and cortisone llBhydroxsteroid dehydrogenase HSD in target cells Two HSD isoforms 0 HSDII only stimulates conversion of cortisol to cortisone Glucocorticoid and Mineralocorticoid Receptors Mineralocorticoid receptors typel 0 High and nearly equal af nity for aldosterone and cortisol Glucocorticoid receptors type2 0 Greater af nity for cortisol than for aldosterone Free cortisol available to bind to typel and type 2 receptors is 100x as abundant as free aldosterone However the enzyme llBHSDII colocalizes with the mineralocorticoid receptor and by converting cortisol to cortisone cannot bind to receptor makes the receptor available to bind to aldosterone HSDII conversion of Cortisol to Cortisone Protects Mineralocorticoid Receptor Concentration of cortisol in blood much greater than that of aldosterone However access to mineralocorticoid receptor protected by llBHSDII enzyme Adrenal Androgens Dehydroepiandrosterone DHEA and androstenedione Relatively weak androgens Precursors to T and E in nonadrenal tissues Important at puberty Mostly produced in zona reticularis ExtraAdrenal Svnthesis of T and E from Adrenal Androqens DHEAs Physiological Effects of Glucocorticoids Major Effects of Excess Cortisol in Intermediary Metabolism Liver cells 0 Increases gluconeogenesis and thus blood glucose Muscle cells 0 Increases proteolysis o Decreases protein synthesis Fat cells 0 Increases lipolysis o Decreases lipogenesis Additional Effects of Cortisol Catabolism of collagen and mucoproteins causing atrophy of skin Inhibits catecholamineomethyltransferase COMT and increases halflife of Epi and NE 0 Stress in absence of cortisol causes vascular collapse and death Deposition of body fat on trunk back and face 0 Deposition of fat on neck and back of neck Suppresses in ammation and immune function 0 Avoid wasting resources 0 Long periods of stresssuppression of immune systemmore prone to virusesbacteria o Glucocorticoids suppress immune systemgood for short term in ammation preventionreduces pain without solving problem AntiIn ammatory Actions of Cortisol Cortisol inhibits NFkB nuclear factor kappa light chain enhancer of activated B cells a transcription factor that enhances the production of in ammatory mediators By inhibiting NFkB cortisol inhibits synthesis of prostaglandins thromboxanes leukotrienes NO Il1 TNFa and other cytokines that play a key role in in ammation Glucocorticoid inhibits transcription factors Developmental Effects of Cortisol Stimulates o Differentiation of pulmonary epithelial cells that produce surfactant 0 Mammary gland development Inhibits actions of 125 OH2 vit D3 Initiates synthesis of surfactant needed during pregnancy for lung expansion Respiratory distress in preterm delivery Surfactantsreduce surface tension consist of phospholipids and some protein Treat premature infant with cortisol to manufacture surfactant Pharmacological Uses of Dexamethasone and Prednisone powerful synthetic glucocorticoids Dexamethasoneabout 10X stronger than prednisone Decrease in ammation and pain Suppress overactive immune system in allergies and autoimmune diseases 0 Treatment for severe asthma and allergies Adrenal insuf ciency if synthetic glucocorticoids are quickly stopped which can result in death Dangers Associated with Use of Dexamethasone and Prednisone Susceptibility to infection Increases appetite and weight gain Fluid buildup due to Na2 retention Hypertension Hyperglycemia Mood changes After treatment ends depressed ACTH causes adrenal steroid insuf ciency o Happens if synthetic glucocorticoids are withdrawn too quickly Physiological Effects of Mineralocorticoids Effects of Aldosterone Increases Na retention Increases K and H excretion Acts on kidneys intestine sweat glands salivary glands Stimulates reuptake of Na Effects of Aldosterone on Renal Distal Tubule Presence of aldosterone favors reuptake of Na 0 Sodium goes through concentration gradient into the blood 0 Favors loss of K and H into the urine from lumen Mechanisms of Aldosterone Action on Kidnev Protein synthesissodium pump hypothesis Metabolic hypothesisgenerate ATP Permease hypothesis Regulation of Adrenal Corticoid Function Glucocorticoid Synthesis Regulation Increased ACTH stimulates glucocorticoid synthesis Diurnal rhythm in ACTH release and cortisol synthesis maximum ACTH and cortisol levels an hour after awakening CRH stimulates ACTH AVP also stimulate release of ACTH by increasing responsiveness of corticotropes to CRH Aldosterone Regulation Reninangiotensin system 0 ATII stimulates aldosterone synthesis Other regulators o ACTH stimulates aldosterone synthesis 0 Excess plasma K stimulates aldosterone synthesis 0 Atrial naturietic factor ANF inhibits aldosterone synthesis Aldosterone lowers K levels in blood so if K levels rise then there is not enough aldosterone 0 Body can respond to excess K by stimulating more aldosterone Renal luxtaglomerular Apparatus Juxtaglomerular cells that release renin o Stimulated by fall in blood pressureD releases renin IG cells of Kidney Located on the afferent arteriole leading into the glomerulus of the kidney nephron Monitor blood pressure Release renin when blood pressure falls below normal Macula Densa Cells of Kidnev Located in distal tubule and abut against JG cells of different arteriole Possess chemo receptors that monitor Na in ltrate Stimulate JG cells to release renin when there is decrease in NaCl in distal tubule Renin Release Factors stimulating release 0 Increased adosterone 0 Low blood pressure low blood volume 0 Sympathetic nervous system via beta1 ARs 0 Low Na in ltrate of distal convoluted tubule Factors inhibiting release 0 ANF and brain naturietic factor BNF Synthesis of ATII Angiotensinogen renin substrate from liverD angiotensin I 10AA l angiotensin II 8 AA Renin converts angiotensinogen to ATI Angiotensin converting enzyme ACE converts ATI to ATII ACE inhibitors are used to treat hypertension Angiotensin II Actions Stimulates adosterone synthesis in adrenal cortex Vasoconstriction of vascular beds Stimulates ADH release ATII Stimulation of Aldosterone Synthesis in Cells of Zona Glomerulosa Generates P3 and DAG P3 increase Ca and activates Ca camoduin dependent kinase II CAM kinase II CAM kinase li activates STAR protein that transfers cholesterol into mitochondria Calcium stimulates P450c11AS enzyme necessary for adosterone synthesis Effect of fall in Blood Pressure on Renin Release Fall in blood pressure stimulates renin release into blood Converts to ATII ACE cuts off 2 amino acids8 AA left ATII causes vasoconstriction Goes to adrenal cortex and stimulates adosterone synthesis ANF Atrial Naturietic Factor Polypeptide produced by specialized cardiac muscle cells of atria Increased blood volume stretches atria causes ANF release 4 Wavs ANF lowers Blood Volume and BP ANF inhibits o Aldosterone synthesis 0 Renin release 0 ATII vasoconstriction actions 0 ADH release and actions Congenital Adrenal Hyperplasia CAH Masculinization of female fetuses due to excess adrenal androgens Defect in 21hydroxylase 90 of cases 3 B hydroxysteroid dehydrogenase ampor Bhydroxylase Cushing s disease Elevated cortisol Pituitary adenoma most common cause excess ACTH Symptoms 0 Weight gain 0 High blood sugar 0 Redistribution of body fat Trunkal obesity Moon face Buffalo hump 0 Thin fragile skin 0 Purple red stretch marks Treatment 0 Surgery to remove tumor from pituitary o Transsphenoidal surgery Hvooaldosteronism Characteristics amp Consequences Characteristics 0 Low blood Na hyponaturemia 0 High blood K hyperkalemia 0 High blood H low pH Consequences 0 Low blood pressure hypotension o Abnormal cardiac rhythms o Acidosis o Paralysis Treatment of Hypoaldosteronism lncrease sodium intake Correction of acidosis Fludrocortisone acetate synthetic mineralocorticoid treatment to control blood Keve Hyperaldosteronism Characteristics amp Consequences Characteristics 0 High blood Na hypernaturemia 0 Low blood K hypokalemia 0 Low blood H high pH Consequences 0 High blood pressure hypertension 0 Increased blood volume 0 Abnormal cardiac rhythms o alkalosis Treatment of vaeraldosteronism give spironolactone aldosterone antagonist Addison s Disease de ciency in both glucocorticoids and mineralocorticoids destruction of adrenal glands o autoimmune disorder 70 of cases 0 bilateral tubercular destruction Role of Adrenal Hormones in Stress Response Hans Selye Terminology Stressor stress and stress Response Don t get stressed out Stressor anything that disrupts homeostasis eg lack of food Stress state resulting because of stressor eg low blood glucose Stress response means of reestablishing homeostasis eg glucagon release Non Speci city of Stress Resoonse Different stressors but same stress response Stress response determined by magnitude of imba stressnot by nature of its cause 0 Eg epinephrine released in both ght response and in ight response 0 Being attacked by a lion vs being in a class taking examsame response Exam Day Stress Response Circulating levels of stress hormones adrenaline and cortisol Pronounced increase up to exam after exam levels fall off Adaptive responsegreater blood ow to brain more 02 to vital organs Glucocorticoids increase blood glucose levels and suppress other function Logic of Short Term Stress Response Increased 0 Availability of energy 0 Blood ow to vital organs 0 Oxygen uptake 0 Memory and sensory functions Inhibition o Digestion 0 Growth 0 Immune function 0 Reproduction 0 Pain perception Being nervousshort term stressnot preparing body to receive food by digestiondate Harmful Effects of Long Term Stress Resoonses Muscle breakdown hyperglycemia quotsteroid diabetesquot Hypertension Reduced growth psychosocial dwar sm Impaired disease resistance and cancer Accelerated neural degeneration during aging Peptic ulcers Mech of Stress Induced Inhibition of Reproduction Hypothalamus increased CRH and Bendorphin inhibit GnRH release Pituitary increased glucocorticoids decrease sensitivity of gonadotropes to GnRH causing less LH and FSH release Gonads increased glucocorticoids and PRL decrease sensitivity to LH and FSH Practice Quiz 1 B cortisol 2 3 False 4 ANF 5 D aldosterone 6 C spironolactone Endocrinology of Sexual Differentiation and Development Nature of Sex Chromosomal Gonadal Hormonal Morphological Behavioral Sex Determination The Greeks believed that it was the level of male excitement during intercourse that determined whether the child would be male or femalemore excitationD boy SRY Sex Determining Region Y Gene on short arm on chromosome Codes for SRY a transcription factor Directs development of a testis in mammals SOX9 a target of SRY upregulated in Sertoli cells Gonadal Differentiation Primordial germ cells of extra gonadal origin migrate to urogenital ridges Initially male amp female gonads cannot be identi ed by their histology but in time germ cells come to reside in medullary area in males and cortical area in females General Pattern of Sex Determination amp Differentiation in mammals In mammals testes develop earlier than ovaries during embryonic development In humans testes develop in males at 67 weeks and ovaries develop in females around 1316 weeks Mammalian Sex Differentiation Alfred lost Chromosomal sexD gonadal sexD hormonal sexD morphological sexD behavioral sex Chromosomal sexD behavioral sex Sequential Events Determine Genetic Gonadal and PhenotVbic Sex Development of internal urogenital systeminvolves series of ductstransports gametes in adults Testicular Hormones Important in Sexual Differentiation and Develoopment Testosterone key hormone produced by Leydig cells Mullerian inhibitory hormone MIH a glycoprotein produced by Sertoli cells 0 Alternative names antiMullerian hormone AMH MIH a member of transforming growth factorB family of growth factors Testosterone A Prohormone for Dihvdrotestosterone and Estradiol 3 pathways for testosterone o Differentiation of male external genitalia 5areductase o Differentiation of male internal genital ducts and 2 sex characteristics testosterone to nucleus 0 Differentiation of a male hypothalamus aromalase Ovarian Hormones Estradiol E most important Embryonic ovaries release very little if any T and no MIH Formation of Male and Female Reproductive Ducts from Indifferent Stage In males degenerationregression of the Mullerian ducts o Males will lose Mullerian ducts MIH will go to the ducts and destroy them Wolf an ducts will degenerate bc ovary does not make T o Wolf an ducts need T so they will persist Mullerian ducts persist in females bc there is no MIH to destroy it Hormonal Differentiation of Ducts Males o Wolf an ducts persist and develop due to T stimulation 0 Mullerian ducts regress due to MIH presence Females o Wolf an ducts degenerate due to absence of T o Mullerian ducts persist due to absence of MIH Summary of Male Gonadal Development Role of Hormones in Duct Differentiation Ovaryno T or MIH TestisT and MIH Differentiation of External Genitalia Enlargement in masculine direction In female absence of stimulation Both structures originate from same place Role of Hormones in Differentiation of External Ganglia Males DHT stimulates penis and scrotum to develop Females lack of DHT causes clitoris and labia to develop Normal Development of External Genitalia Proceeds Along a Single Masculine to Female Continuum Pseudohermaphrodites Individuals born with ambiguous external genitalia Not a true hermaphrodite which would require an ovary and a testis to be present in the same individual 0 True hermaphroditeindividual has function of gonads of both sexes at any point in life cycle 0 Has ovary and testis Sex Difference in Pattern of Gonadotropin Release Females cyclic pattern of gonadotropin release Males noncyclic pattern 0 Brain exposed to T or its metabolite E early in development during a quotcritical periodquot when brain is sensitive to steroid exposure Sex Differences in Behavior Female lardosis o Elevates tail and back side and remains immobile o If male is sexually active they will mate Effects of Castration and Testosterone Treatment in Neonatal Rat on Subsequent Male and Female Behavior Castration of male early in development during critical period 0 Remove source of testosterone o Feminized maIe resuIts female behavior Testosterone during critical period in females 0 Provide testosterone early in development 0 Masculinized female results D maIe behavior Organization vs Activational Effects of Hormones Organizational organize or prime neural substrates for permanent long term developmental changes 0 Eg T or its metabolite E required to organize male rat brain for subsequent adult sexual behavior Activational activate neural substrates for relatively short term changes in behavior 0 T activates male sexual behavior when maIe becomes adult Sex Difference in DOCI Urinarv PostureOrganizational Effect ofT FuII squatfemale Full leg elevationadult male Juvenile malestand forward Aromatization Hypothesis Conversion of T to E within target cells necessary for differentiation of some aspects of male phenotype Illustration of Aromatization Hypothesis Diagram of male testes Afetobrotection hvbothesis Female embryos protected bc circulating E tightly bound to ocfetoprotein AF and cannot enter target cells Females thus protected from the potential masculinizing and defeminizing effects of E exposure early in development Binding of E in Blood to AFP Ovary is shown E can t leave the protein in the blood and enter target cells to interact w estrogen receptor If female ovary makes estradiol and it is released in blood it binds to 0 fetoprotein Vandenbergh 2003 Reading Assignment Mice Embryos Effects of Intrauterine position 8 embryos Different ratios of malesfemales Positional effect OMO maIes next to it Hormone Levels and Intrauterine Position Fetus o Testosterone in 2M females gt than in OM females Adults 0 2M and OM females did not differ in testosterone Used Csection Intrauterine Position and Anogenital Distances Greater in average for males than females The 2M females had much longer distance than other females 2M females responded to increased androgens Behavior amp Intrauterine Position Adult OM females more sexually attractive to males than 2M females Adult 2M females more aggressive than OM females Fitness Consequences of Intrauterine Position Sex Differences in Brain Structures Sexually Dimorphic Nucleus of Preoptic Area SDNPOA Larger in male rats than female rats SDNPOA a hormonally controlled sexual dimorphism in rodents Males do not make androgen receptor Requires aromatization ofT to E Males w testicular feminization mutation TFMlack androgen receptorhave normal SDNPOA Treatment with fadrazole an aromatase inhibitor blocks enlargement of SDN POA in males Secondary Sexual Characters in Humans Beard growth in males Breast development in females Pitch of Human Voice Adult males on average have lower pitched voices than adult females Due to exposure to androgens during puberty Males castrated before puberty have a high pitched voice similar to females Castratihigh pitched voice Sex Differences in Length of Vocal Cords amp Thus Pitch of Voice Group Length of Vocal Cords mm inversely related to pitch Pre puberty both sexes 78 Post puberty females 812 Post puberty males 1216 Castrati 78 Role of Hormones in Human Sexual Behavior Males libido sex drive dependent on androgens requires threshold level Females hormonal basis of sex drive not understood but some evidence androgens may play a role Puberty Period of gonad maturation and beginning of reproductive activity Timing of puberty 0 Human females reach puberty sooner than males 0 Blood estradiol levels in females 0 Males don t have increase in T until 12 years old First Sign of Puberty increase in nocturnal pulsatile secretion of GnRH LH and T levels in a pubertal 14 year old boy Environmental Factors Affecting Timing of Puberty Critical weight or of fat in females 0 Obese early puberty elevated leptin 0 Lean delayed puberty eg ballet dancers Missing Link vaothesis of Pubertv Component of brainpituitarygonad axis missing or nonfunctional prior to pube y Brain key component Activation of dormant hypothalamic GnRHsecreting neurons required to start pube y Kissoebtin Activation of GnRH Neurons KisspeptinKISSl gene product Binds to GPCR 54 Stimulates GnRH neurons to release GnRH Hormonal Changes in Females Increased estrogens from ovarian follicles o Mammary gland development 0 Increased fat deposition 0 Growth vagina oviduct uterus bony pelvis Increased adrenal androgens 0 Growth long bones pubic and axillary armpit hair 0 Development of sebaceous glands and acne o Slight lowering of voice in some females Hormonal Changes in Males Increased T synthesis in testes o Spermatogenesis o Skeletal and muscle growth 0 Male pattern of pubic hair and hair on axilla face Menopause Period of reproductive senescence in females Completed one year after last menstrual period Depletion of ovarian follicles and changes in hypothalamus Effects of Lower Estrogen After Menopause Increased FSH and LH Thinner vaginal wall and less lubrication Glandular tissue of breast regresses quothot ashesquotsudden ushing perspiration inc GnRH Osteoporosis Pathophysiology Congenital Adrenal Hyperplasia CAH Masculinization excess adrenal DHEA and androstenedione synthesis 21hydroxylase de ciency most important cause 21Hydroxylase De ciency 17dhydroxylase pathway Normal and Abnormal Differentiation of The External Genitalia external view Male and female and indifferent 5dReductase Deficiencv Genetic defect causing lack of enzyme Leads to DHT de ciency Abnormal male external genitalia by birth Males incorrectly assigned as females at birth in villages in Dominican RepubHc o Called guevedoces 0 Mistake discovered at puberty when individuals exhibit masculine traits Role ofT and DHT in Male Sexual Differentiation 5ocreductase deficiency Prostate Sensitive to action of DHT Wolf an Duct Finasteride An Inhibitor of 5ocreductase Propecia 1mg Proscar 5mg Testicular Feminization Mutation TFM Androgen lnsensitivity Syndrome AIS Androgen receptor de ciency found in humans chimps rats mice Defective gene X chromosome Results in female phenotype 0 Neither Mullerian nor Wolf an ducts o Breasts develop at puberty due to unopposed action of estrogens formed extragonadally from T Individuals with Complete Androden lnsensitivitv Svndrome CAIS Individuals are highly successful nevertheless XY sex determining region Y They have testes technically male Hypogonadotropic hypogonadism Primary gonads Secondary pituitary Tertiary hypothalamus Alcohol and Levdid Cell Failure in Males Decreased LH binding to Leydig cells Increased conversion ofT to E in fat cells Hormones and Male Reproductive Physiology Gross and Microscopic Anatomy of Human Testis Seminiferous tubule Vas deferens Histological Section of Human Testis Sertoli cells Leydig cells Spermatoqenesis Stem celi renewal gt Sperrnatagoniia Proliferation Primary spermatocyies Secondary spermatocytes Spermaiids 39 Ii Ll iquot quot 394 ii If iii Spermiation mwermatozoans Importance of Leydig and Sertoli Cells Leydig cells 0 Produce androgens Sertoli Cells 0 Produce inhibin and androgenbinding protein ABP o ABP same as sex hormone binding globulin SHBG in plasma Only cells in males with FSH receptors Androgens Source Relative Blood Levels and Blood Tranport Source 0 Leydig cells of testes 95 o Adrenal cortex 5 Blood levels 0 TgtDHEAgtandrostenedionegtDHT Blood transport 0 Sex hormone binding globulin SHBG o Albumin Importance of DHT In many tissues more potent than T Development of masculine genitalia prior to birth Prostate gland o PSA prostate speci c antigen Libido Vasodilation in penile erection Estrogens T converted to E within cells by aromatase Low levels of circulating E normally masked by higher levels ofT Pattern of Androgen Secretion GnRH pulse every 90 min in humans LHFSH relatively constant compared to females T levels 20 higher at night and early morning Some species have seasonal cycles ofT synthesis in males Negative Feedback Control of LH and FSH Release Sperm maturationD Sertoli cells Follicular maturation D granulosa cell FSH Actions on Sertoli Cells Increased synthesis of androgen binding protein ABP in Sertoli cells Increased of Sertoli cells Summary of FSH and LH Action on Sertoli and Leydig Cells Pituitary LH and FSH binds to receptor and activates cAMP pathway Effect of PRL on LH Receptors in Leydig Cells PRL required to maintain the of LH receptors Inhibition of PRL release causes a decline in LH receptors PRL treatment prevents the loss of LH receptors Anabolic Effects of Androgens Increased amino acid uptake and protein synthesis T more effective than DHT in skeletal muscle Anabolic steroids used to prevent muscle loss in bedridden patients Hormonal Control of Spermatogenesis Both FSH and T required for initiation of normal spermatogenesis Sperm formation once established can be maintained with high doses ofT or with suf cient LH to stimulate T production T support of spermatogenesis mediated indirectly by way of Sertoli cells 0 Developing human sperm cells lack androgen receptors Role of Andr0gens on Ebibhvseal Growth Estrogens rather than androgens responsible for acceleration of growth at puberty and maturation of epiphyseal plates in males Conversion of testosterone to estrogens via action of aromatase enzyme required Males lacking E ER andor aromatase have nonfused epiphyses and unusual height Pathophysioogy Hypersexuality 0 Treat with cyproterone acetate or medroxyprogesterone acetate Depo Provera Hyposexuality 0 Treat with transdermal patches or gels to deliver T Erectile De ciency Syndrome EDS Normal Erectile Mechanism DHle increased NO synthetase increased NOD increased cGMPl inc vasodilation and erection Treatment of EDS Inhibition of PDE5 increases cGMP levels and time of action PDE5 inhibitors Viagra sildena l citrate Levitra Vardena l Cialis Tadalana l Prolactin and Sexual Function High PRL levels inhibit sexual behavior and function PRL inhibits GnRH release and thus FSH and LH release Postorgasm elevations in PRL induces sexual satiety and refractoriness MSH and Sexual Function MSH stimulates sexual behavior via melanocortin4 receptor MCR4 MSH induces erection in rats MCR4 agonist causes erections in normal men Hormones amp Female Reproductive Physiology Reproductive Organs of Human Female Corpus luteum Myometrium Endometrium Primate Ovarian Follicular Cycle Follicular cells Oocyte Oocyte I Corpus Luteum N Follicular cells Of Pregnancy 3 Zona pellucida Primordial u Follicle Primary Follicle f7quot 7 Zona granulosa Luteolysis Theca interna Granulosa N Corpus Secondary lutein cells AIbicans Folllcle Antrum formation 7 Mature Corpus Luieum Prearltral Follicle Theca inlerna Theca Theca externa lutein cells 39 G l S r 39 ranuosace x Corpus MGtraafignlprI a l a ure 0 Ice Hemorrhaglcum Ovulatory ll Follicle 1 F iquot 39 A Antrum Blood Corona radiate y Cumullus oophorus Ovulated ovum 39 OVARIAN CYCLE Copyright 2007 Pearson Prentice Hall Inc Follicular Development at Various Stages of a Woman s Life Prepubertal years reproductive yearsljmenopause Biosvnthesis and Metabolism of Estradiol Cholesterolljpregnenoloneljprogesterone Testosteroneestradiol via aromatase Roles of FSH and lnhibin in Control of Ovarian Function Sperm maturation on Sertoli cell Follicular maturation in Granulosa cell Menstrual Cycles Ovarian cycle found in most primates De ned by recurring periods of menstruation Not de ned by behavioral events Some cyclic activity in sexual behavior although females may mate throughout cycle as in humans Three Phases of Human Menstrual Cycle Menstrual phase Follicular phase Luteal phase Human Menstrual Cycle Latin for menses month 28 day cycle Reproductive potential481 eggs lifetime Cvcle of Uterine Endometrial Growth Durinq NonFertile and Fertile Cvcles Nonfertile cycleFollicular phase and luteal phase Fertile cycleovulation and implantation 3 Phases of Human Menstrual Cycle Menstrual phase Follicular phase Luteal phase Menstrual Phase menses Day 0 start 15 days duration Low E and P Corpus luteum of previous cycle regressed Follicular Phase Estrogenic Proliferative Lasts 1016 days Increased FSH Increased E E peaks on day 12 or 13 LH surge after 24h after E peak Ovulation 9 h after LH surge Positive Feedback of Ovulation Control GnRH to pituitary LHFSH to gonads 2 Cell 2 Gonadotropin Hypothesis of Estrogen Synthesis Thecal cell Granulosa cell Theca and Granulosa Cell Cooperation in Estrogen Synthesis Pregnenolone LDL Luteal Phase Prooestational Secretorv Lasts 14 days Increased LH stimulates corpus luteum development and P E synthesis P peaks 8 days after corpus luteum formation High P inhibits GnRH release thickens cervical mucus stimulates uterine gland secretions and slightly raises basal body temperature Creates environment suitable for implantation Progesterone synthesized by remains of follicle after ovulation Estradiol thins and loosens cervical mucus so sperm can move in and fertilize 999 Life Span of Human Corpus Luteum Corpus luteum begins to degenerate 4 days before menstruation unless female becomes pregnant Programmed cell death Endometrial Changes during a Typical Menstrual Cycle Buildup of uterus Supportive secretory components of uterus is maintained by levels of estradiol otherwise it will degenerate Corpus luteum degeneratesdecline in synthesis of progesterone and estradiol Importance of Environmental Factors in Female Reproductive Physiology Light most universal factor in many vertebrates Olfaction important role of pheromones especially in rodents Dormitory Effect in Humans Evidence of a Human Pheromone Martha McClintock Compared menstrual cycles of pairs of female roommates to random pairs of females Female roommates more synchronous menstrual cycle In addition females spending more time with males had shorter cycles Con dence Intervals gtO99 ln Days for Median Difference in Onset Date of Menses Group Difference in Onset Date days Female roommates 3ltmedianlt7 Female random pairs 5ltmedianlt15 Does not necessarily prove that there is a pheromone Evidence of a Human Pheromone Regulating Affecting Menstrual Cycle Ovulatory pheromone Follicular pheromone 2 cycles Bruce Effect in Rodents Pregnancy failure in female mice exposed to a male or its odor other than the male that inseminated them 0 Foreign male Effect not seen in females exposed to castrated adult males or to juvenile males pheromone production requires T Adaptive as males often kill newborn litters they did not sire Vandenbergh Effect Sexually immature female mice exposed to adult males or their urine reach sexual maturity sooner than the control group females Sexually immature female mice exposed to adult females or their urine reach sexual maturity later than control females Pathophysiology Amenorrhea Absence of monthly menstrual ow Primary failure to start Secondary loss due to pregnancy lactation menopause Causes hyperprolactinemia anorexia nervosa Hirsutism and Virilization Excess hair growth and masculinizing effect due to excess androgens CAH Cyproterone acetate treatment Osteoporosis Due to Menopause Loss of bone density due to lack of estrogen 750k bone fracturesyear due to osteoporosis causing 58k deaths Treat with estrogens Ca supplements and other drugs Bene ts and Risks of Hormone Replacement Therapy HRT Bene ts 0 Lessen symptoms of menopause 0 Reduce risk of heart disease stroke Alzheimer s disease and other neurodegenerative conditions of aging Risks 0 Increased risk of certain cancers blood clots and stroke SERMs Synthetic molecules w target sitespeci c estrogenic or antiestrogenic activity Tamoxifen and raloxifene are SERMS Selective estrogen receptor modulators Estrus Latin oestrus for in a frenzy or possessed by gad y Period when females sexually receptive to males Regulated by hormones associated w ovarian cycle and timed to maximize probability of fertilization Common in female vertebrates including lower primates such as marmosets Human females and female rhesus monkeys do not have estrous cycles per se Spontaneous Ovulators Ovulate predictably in absence of copulatory stimuli Examples mice rats guinea pigs sheep primates Seasonal factors regulate when reproductive activity occurs so as to produce young at optimal time lnduced Ovulators Ovulation only occurs when induced by mating Mating stimuli cause GnRH and LH release Examples cats ferrets camels Opportunistic reproductive strategy often found in solitary species Practice Quiz B false D PRL B granulosa B progesterone B 8 days C B false P P FWN Endocrinology of Pregnancy Parturition and Lactation Events Leading to Pregnancy Maternal Recognition of Pregnancy in Mammals Marsupials recognition not needed bc life span of corpus luteum in nonpregnant and pregnant females is the same Placental mammals recognition needed as luteal phase of cycle must be prolonged in pregnancy 0 Human females HcG extends life of corpus luteum 0 Female sheep conceptus inhibits PGF20lt release by uterus and this extends life of corpus luteum Maintenance of Human Pregnancy Placentadependent species Require P from placenta bc corpus luteum regresses before term Human Chorionic Gonadotropin HcG Secreted by synchtiotropoblast after attachment to endometrium Home pregnancy test EIA Levels peak in 3rd month and then decline Placental Function Steroid synthesis begins 5 weeks after pregnancy Stimulated by hCG P and E secreted Removal of corpus luteum leads to miscarriage before 7th week but not after this time Fetal Placental Unit and Steroid Synthesis Relationship bw fetal adrenal gland and placenta of mother Fetal adrenal cortex DehydroepiandrosteroneDHEA Forms estradiol in the fetal placental unit Cant convert pregnenolone to progesterone Progesterone Inhibits release of gonadotropins via negative feedback Stimulates decidual cells necessary for early embryo nutrition Inhibits contraction of gravid uterus helps prevent abortions Stimulates mammary gland growth and development Estroden Actions Enlarges uterus breasts and their ducts and genitalia Stimulates fat deposition Relaxes sacroiliac ligaments and pubic symphysis Human Chorionic Somatomammotropin HcS actions Synthesized by placenta Levels rise late in pregnancy Increases blood glucose levels in mother Primes mammary glands for later milk production Prolactin Action Synthesized by both pituitary and placenta Increases milk secretion but only after P levels decline Relaxin Actions in Humans Polypeptide hormone similar to insulin in structure Secreted by placenta and corpus luteum Levels peak during implantation Increases formation of new blood vessels in endometrium Induces differentiation of uterine stroma decidualization thsiolodical Roles of Relaxin in the Rodent Relaxes cervix Hormonal Control of Parturition Increased estradiol to progesterone ratio EP P blocking hypothesis P blocks oxytocin OT and prostaglandin PGF 2d induced smooth muscle contraction OT stimulates PGF 20c synthesis and smooth muscle contraction Pitocin a synthetic OT used to initiate labor Hormonal Regulation of Mammary gland Growth and Development Glucocorticoids necessary 0 Estrogens and progesterone Prolactin and placental lactogen
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