Adobe Systems Patofyziologie reprodukce – Ústav patologické fyziologie LF MU 1 Pathophysiology of reproduction II Julie Dobrovolná Obsah obrázku interiér, stůl, život, místnost Popis byl vytvořen automaticky 3 Pathophysiology of pregnancy 4 Fetoplacental unit: - consists of placenta, fetal adrenal gland and fetal liver. In this unit, the fetal adrenal gland is the primary source of dehydroepiandrosterone. It is further metabolized by the fetal liver and placenta to a wide range of estrogens. There are several diseases that can affect the fetal and maternal adrenal glands during pregnancy. Most often, it is steroid 21-hydroxylase deficiency, which leads to abnormalities in sexual development and may even endanger the life of the newborn. Pregnancy is marked by accretions in several endocrine systems, particularly the renin-angiotensin-aldosterone system and the hypothalamus-pituitary-adrenal system. Maternal abnormalities are associated with a significant risk of maternal morbidity and mortality. Fortunately, they are rare. 29-01a_1.jpg 00000941Sarah B9D5FA8B: 29-01b_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ 29-02_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ Implantation 5-12 days after conception Trophoblast grows and spreads Maternal blood freely circulating in lacunes Gastrulation Embryonic target consists of: Endoderm Mesoderm Ektoderm 29-03_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ Internal cellular mass and gastrulation 29-04ab_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ Extraembryonic membranes 29-05ab_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ Placental development 29-05cd_1.jpg 00000941Sarah B9D5FA8B: 29-05e_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ Embryo anatomy Yolk sac Where blood cells are produced Amnion Encompasses the fluid around embryo Allantois Bladder Chorion 29-06a_1.jpg 00000941Sarah B9D5FA8B: https://embryology.med.unsw.edu.au/embryology/index.php/ Characteristic features of feto-placental circulation • •Parallel arrangement of two arterial systems and corresponding chambers •Mixed venous return and preferential blood flow. •High resistance and low real circulation in lung circuit •Low resistance and high-flow circulation in placenta. •Shunt presence (3 shunts - Ductus venosus - Foramen ovale - Ductus arteriosus • https://embryology.med.unsw.edu.au/embryology/index.php/ 18-12 Source: http://www.colorado.edu/intphys/Class/IPHY3430-200/image/18-12.jpg https://embryology.med.unsw.edu.au/embryology/index.php/ Fetal blood flow I When oxygenated blood from the mother enters the right side of the heart it flows into the upper chamber (the right atrium). Most of the blood flows across to the left atrium through a shunt called the foramen ovale. From the left atrium, blood moves down into the lower chamber of the heart (the left ventricle). It's then pumped into the first part of the large artery coming from the heart (the ascending aorta). From the aorta, the oxygen-rich blood is sent to the brain and to the heart muscle itself. Blood is also sent to the lower body. 26_027 https://embryology.med.unsw.edu.au/embryology/index.php/ Fetal blood flow II 26_027 Blood returning to the heart from the fetal body contains carbon dioxide and waste products as it enters the right atrium. It flows down into the right ventricle, where it normally would be sent to the lungs to be oxygenated. Instead, it bypasses the lungs and flows through the ductus arteriosus into the descending aorta, which connects to the umbilical arteries. From there, blood flows back into the placenta. There the carbon dioxide and waste products are released into the mother's circulatory system. Oxygen and nutrients from the mother's blood are transferred across the placenta. Then the cycle starts again. https://embryology.med.unsw.edu.au/embryology/index.php/ Fetal blood flow III At birth, major changes take place. The umbilical cord is clamped and the baby no longer receives oxygen and nutrients from the mother. With the first breaths of air, the lungs start to expand, and the ductus arteriosus and the foramen ovale both close. The baby's circulation and blood flow through the heart now function like an adult's. 26_027 https://embryology.med.unsw.edu.au/embryology/index.php/ Pathophysiology of preterm birth 21 Obsah obrázku interiér, bílá, místnost, život Popis byl vytvořen automaticky Proprietary and confidential — do not distribute Preterm Labor •Preterm labor is defined as the onset of uterine contraction of adequate strength and frequency to cause progressive dilatation and effacement of cervix between 20 and 37 weeks of gestation1 •Preterm labor is one of the leading cause of perinatal morbidity and mortality2 • •Preterm delivery effects almost 23% pregnancies in developing countries like India3 1. Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF 2. BJOG. Volume 120, Issue 13 December 2013 Pages 1588–1598 3. International Journal of Basic and Applied Medical Sciences ISSN: 2277 : An Open Access, Online International Journal2015 Vol. 5 (3) September 2 Clinical Circumstances Associated with Preterm Birth •Spontaneous preterm labor with intact membranes •Preterm PROM •Indicated preterm delivery –Maternal (e.g. pre-eclampsia) –Fetal (e.g. SGA/fetal compromise) Risk Factors Clinic Factors in preterm Labor Maternal Low socioeconomic status Age <18 years or >40 years Low pregnancy weight Smoking Substance abuse Multiparity Past Obstetric History Previous history of preterm delivery Previous history of second trimester abortion Uterine Factors Uterine volume increased: Polyhydramnios, Multifetal gestation Uterine anomalies Trauma Infection 11 Proprietary and confidential — do not distribute Mechanism of Preterm Labor Causes Mechanism •Stress •Premature activation of physiological effectors Activation of maternal-fetal HPA-axis •CRH → Fetal adrenal androgens •Placental estrogen and progesterone •Inflammation and infection •Pro-inflammatory cytokines •Fetal inflammatory response syndrome •Ischemia or hemorrhage •Thrombin activation •Pathological Uterine distension •Increased gap junction along with contraction associated protiens and upregulation of prostaglandins and oxytocin receptors 12 Revisiting the use of Isoxsuprine in Preterm Labor – Indian Consensus Document by ISSRF Common Uterine Features of Term and Preterm Labor •Increased myometrial contractility •Cervical ripening (dilatation and effacement) •Decidual/membrane activation Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414 Term Labor Preterm Labor Common Pathway of Parturition •Anatomic, physiologic, biochemical, endocrinologic, immunologic, and clinical events in the mother and/or fetus in both term and preterm labor Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414 Synchronous and Asynchronous Activation of Labor Cervical Ripening Uterine Contractility Membrane- Decidual Activation Preterm PROM Preterm Contractions Cervical Insufficiency Common Terminal Pathway Normal Term Labor Physiologic Activation Preterm Labor Pathologic Activation What causes pathologic activation of the pathway ? The Preterm Parturition Syndrome •Frequent: 25 % (at presentation) •Sub-clinical •Fetal disease •FIRS •Host defense Intrauterine infection •12% of preterm labor • •20% of preterm PROM Clinical Chorioamnionitis Subclinical infection •Hematologic Abnormalities •Endocrine System •Cardiac Dysfunction •Pulmonary Injury •Renal Dysfunction •Brain Injury (PVL) Fetal inflammatory response syndrome Pathophysiology of premature birth II 37 Obsah obrázku snímek obrazovky Popis byl vytvořen automaticky Pathophysiology of premature birth III 38 Obsah obrázku text, mapa Popis byl vytvořen automaticky Low Birth Weight and Adverse Perinatal Outcomes •November 2019 DOI: 10.5772/intechopen.89049 Hypertensive disorders of pregnancy •They are divided into four categories : •1-gestational hypertension •2-chronic hypertension •3-chronic hypertension with superimposed preeclampsia •4- preeclampsia-eclampsia Pathophysiology of pre-eclampsia 40 Epidemiology •Hypertensive disorders of pregnancy complicate nearly 10 % of pregnancy and their incidence is increasing •Preeclampsia causes 50000 – 60000 deaths per year worldwide •In addition to causing significant maternal and fetal morbidity in hundreds of thousands of others •Some of these outcomes can be prevented or improved upon through implementation of the updated recommendations in clinical practice Preeclampsia •Preeclampsia is a multi-system progressive disorder characterized by the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, in the last half of pregnancy or postpartum •The disorder is caused by placental and maternal vascular dysfunction and always resolves after delivery •Although most affected pregnancies deliver at term or near term with good maternal and fetal outcomes, these pregnancies are at increased risk for maternal and/or fetal mortality or serious morbidity. •In addition, women with preeclampsia are at increased risk for future cardiovascular disease. No longer in use are the criteria of •Increase in blood pressure above baseline measurements of 30 mmHg systolic, 15 mmHg diastolic, or 20 mmHg mean arterial pressure. •Edema is a common finding in the gravid patient, occurring in approximately 50% of women. Lower extremity edema is the most typical form of edema. Severity Of Preeclampsia HELLP Syndrome •A particularly severe and serious form of preeclampsia is HELLP syndrome characterized by hemolysis, elevated liver enzymes, and low platelets. •Prompt recognition is vital to improving outcomes. •Due to the different number of assays used to measure liver enzymes, clinicians should be familiar with the upper limit values used in their own laboratory. •Criteria for HELLP syndrome are: •LDH > 600 IU/L (more than 2 times the upper limit of normal values) or •bilirubin > 1.2 mg/dL, •AST > 70 IU/L (more than 2 times the upper limit of normal values), and •platelets < 100,000/μL.(Sibai, 2004) •Proteinuria may or may not be present with HELLP syndrome Pathophysiology •The precise mechanism for the development of preeclampsia is unknown •The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. •A major component in the development of preeclampsia is the excessive placental production of antagonists to both vascular epithelial growth factors( VEGF) and transforming growth factorB ( TGF-B ) •These antagonists to VEGF and TGF-B disrupt endothelial and renal glomerular function resulting in edema , hypertension and proteinuria •In addition there appears to be a heritable component and oxidative stress and abnormal placental implantation can further increase the risk of developing the disease Aetiology of preeclampsia (Genetic predisposition) (Abnormal immunological response) (Deficient trophoplast invasion) (Hypoperfused placenta) (Circulating factors) (Vascular endothelial cell activation) Generalized vasospasm Activation of coagulation system Abnormal hemostasis Altered thromboxane- to-prostacyclin ratio Endothelial cell injury Abnormal hemodynamics Reduced uteroplacental blood flow (Clinical manifestations of the disease) Pathophysiology of pre-eclampsia - II Lina Bergman, Cerebral biomarkers in women with preeclampsia October 2017 DOI: 10.13140/RG.2.2.30083.81445 49 Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku text, mapa Popis byl vytvořen automaticky Aspirin in the prevention of preeclampsia: the conundrum of how, who and when. Shanmugalingam R, Hennessy A, Makris A. J Hum Hypertens. 2019 Jan;33(1):1-9. doi: 10.1038/s41371-018-0113-7. Context? 50 Adobe Systems 51 HEART KIDNEY VASA SKELETAL MUSCLE PANKREAS LIVER INFLAMMATION HYPERTROPHY OF ADIPOSE TISSUE CARDIOVASCULAR SYSTEM – BLOOD CLOTTING, FIBRINOLYSIS, ANTICOAGULATION INSULIN SENSITIVITY LEPTIN APN APELIN TNF-α PAI-1 AGT APN APELIN LEPTIN APN APELIN RBP-4? IL-6? TNF-α VISFATIN APN Adipokines ̶Terminology overlap with cytokines, also referred to as „adipocytokines“: ̶sensu stricto definition: „cytokines produced in WAT“ ̶sensu lato: „various substances, including cytokines and hormones, produced in WAT“ --------------------------------------------------------------------------------------------------- ------------------------------------ ̶ ̶ White adipose tissue (WAT) Adobe Systems Adipokines in development of trophoblast Graphic Tersigni C. Obstet Gynecol Survey 2011 Ramsay, J. E et al. BMJ 2006 Adipokines, obesity and female fertility Serum levels of leptin as function of % body fat Considine RV. N Engl J Med 1996 [USEMAP] [USEMAP] Serum leptin levels increase with increasing percent fat mass of the body, and decline during weight loss periods. Hammoud A. Fertil Steril 2008 Fedme Adipokines in male fertility Adobe Systems pata What else? Sugar? Adobe Systems Fetal programming? Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Francis D, Science 1999;286:1155–1158. Adobe Systems Fetal programming Fetal metabolic programming and epigenetic modifications: a systems biology approach Silvia Sookoian, Tomas Fernández Gianotti, Adriana L. Burgueño & Carlos J. Pirola Pediatric Research volume 73, pages531–542(2013) Diagram ilustrující vztahy mezi suboptimálními intrauterinními podmínkami, programováním endokrinních systémů během časného období po porodu a cirkulujícími koncentracemi hormonů a následným rozvojem metabolické dysfunkce. Endocrine systems in square boxes. Circulating hormones in ovals. Metabolic dysfunctions in ovoid boxes. (+) Positive effect; (−) negative effect. */^+ Hormones that appear twice on the diagram. Developmental plasticity Obsah obrázku text, mapa Popis byl vytvořen automaticky Ancient origins of human developmental plasticity. Crespi EJ, Denver RJ. Am J Hum Biol. 2005 Jan-Feb;17(1):44-54. Mismatchové paradigma metabolického onemocnění. Vyvíjející se organismus vnímá environmentální stimuly zprostředkované matkou, jako je podvýživa, a to jak během prenatálního, tak zčásti postnatální života. Vývojová plasticita v rámci odpovědi na tyto podněty modifikuje nastavenou trajektorii metabolismu definovanou zděděným fetálním genomem a epigenomem podle toho, zda je okolní prostředí vnímáno jako adekvátní (tmavé pozadí) nebo neadekvátní (světlé pozadí), což má za následek úpravu metabolického nastavení. Pokud následně okolní prostředí, ať už adekvátní či deprivované, odpovídá predikci, je riziko metabolického onemocnění později v životě nízké. Jestliže mezi predikovaným a aktuálním obdobím ovšem nastane nesouladem, zejména v tom smyslu, že aktuální prostředí je na živiny bohatší než prostředí predikované, riziko metabolického onemocnění se zvyšuje. new_logo_nephro Braam B et al. (2007) Technology Insight: innovative options for end-stage renal disease—from kidney refurbishment to artificial kidney Nat Clin Pract Nephrol 3: 564–572 doi:10.1038/ncpneph0600 Developmental plasticity in time About 40 percent overweight! Developmental plasticity? Obsah obrázku text Popis byl vytvořen automaticky Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage 1.Jung Wook Park1, 2.John K. Lee2, 3.Katherine M. Sheu3, 4.Liang Wang1, 5.Nikolas G. Balanis3, 6.Kim Nguyen4, 7.Bryan A. Smith1, 8.Chen Cheng5, 9.Brandon L. Tsai1, 10.Donghui Cheng1, 11.Jiaoti Huang6, 12.Siavash K. Kurdistani5,7,8,9, 13.Thomas G. Graeber3,7,8,9,10,*, 14.Owen N. Witte1,3,7,8,9,* See all authors and affiliations Science 05 Oct 2018: Hochberg Z et al. Endocrine Reviews 2011;32:159-224 ©2011 by Endocrine Society Environmental factors Programming Health Outcomes later in life ØIschemic heart disease ØDiabetes mellitus ØObesit ØHypertension ØCancer ØMental health problems Conflict with postnatal environment Epigenomic changes Permanent changes in gene expression Influence on phenotype later in life Ac CH3 CH3 Ac CH3 CH3 CH3 CH3 CH3 Ac Ac Ac CH3 Nutrition Maternal health Stress Lifestyle Placenta DOHAD – Developmental Origins of Health and Disease Epigenotypový model vývojového původu onemocnění. Environmentální faktory působící během časné fáze života mají následky, které se mohou manifestovat zvýšeným rizikem onemocnění později v životě. Období života, ve kterém mohou externí faktory ovlivňovat biologické procesy, sahají od početí přes neonatální období až do časného dětství. Má se za to, že dítě dostává od matky informace o stavu vnějšího prostředí, do kterého se narodí a modifikuje svůj metabolismus a veškeré fyziologické procesy včetně trajektorie růstu tak, aby postnatálně maximalizovalo svoje šance na přežití. Tyto adaptace se nicméně mohou stát škodlivými, jestliže podmínky, do kterých se dítě narodí, se významně odlišují od podmínek očekávaných během prenatálního období. Tyto adaptace zahrnují metabolické i endokrinní změny, které mohou vést k celoživotním změnám ve fungování a struktuře těla – koncept zvaný programování. Epigenetické znaky mohou být modulovány environmentálními faktory, jsou dědičné a jsou podkladem změn genové exprese, které mohou přispívat ke vzniku onemocnění později během života. Thank you for attention, Julie.dobrovolna@med.mc