Reproductive Slides 2023 (B&B) PDF

Embryonic Genes Jason Ryan, MD, MPH This PDF was created and uploaded by www.medicalstudyzone.com which is one the biggest free resources platform for medical students and healthcare professionals. You can access all medical Video Lectures, Books in PDF Format or kindle Edition, Paid Medical Apps a...

Embryonic Genes Jason Ryan, MD, MPH This PDF was created and uploaded by www.medicalstudyzone.com which is one the biggest free resources platform for medical students and healthcare professionals. You can access all medical Video Lectures, Books in PDF Format or kindle Edition, Paid Medical Apps and Softwares, Qbanks, Audio Lectures And Much More Absolutely for Free By visiting our Website https://medicalstudyzone.com all stuff are free with no cost at all. Furthermore You can also request a specific Book In PDF Format OR Medical Video Lectures. Embryonic Genes Sonic Hedgehog FGF Wnt-7a Homeobox (Hox) genes Patterning Development of body pattern Head, arms, legs Ed Uthman/Wikipedia Sonic Hedgehog Gene SHH Gene Makes Sonic Hedgehog protein Embryonic signaling protein Many embryonic roles: limbs, brain, eyes Key roles: CNS development Limb development Chris Dorward/Flikr Sonic Hedgehog Gene CNS Development Formation forebrain Signaling separates right and left brain Establishes midline Mutations: Holoprosencephaly Holo = “whole” Prosencephalon = forebrain Gaudete/Wikipedia Regional Brain Development OpenStax College Holoprosencephaly Failure of cleavage of prosencephalon Left/right hemispheres fail to separate Single-lobed brain No left/right hemispheres Facial abnormalities Cleft lip/palate Cyclopia  Mild Severe Cleft Lip Cyclopia Limb Development Limb “patterning” Limbs develop along three planes Ed Uthman/Wikipedia Limb Development Proximal to distal Humerus → radius → wrist Dorsal-ventral axis Dorsal: Extensors Ventral: Flexors Anterior-posterior axis Anterior: towards head Radius and thumb Ulna fingers Limb Development Dorsal Ventral Apical Ectodermal Ridge Critical for proximal to distal development Ectoderm overlying mesoderm Area of limb bud formation Removal: Limb stops growing AER Mesoderm Limb Growth Apical Ectodermal Ridge Influences underlying mesodermal growth “Progress zone” forms in mesoderm with growing cells Mesoderm also influences ectodermal ridge Key transcription factor: Fibroblast Growth Factor From expression of FGF gene Ridge removed, replaced with FGF: Normal growth FGF AER Mesoderm Limb Growth Dorsal-Ventral Development Flexors/extensors Depends on multiple genes Radial fringe (dorsal) Engrailed1 (ventral) SER2 (border) Wnt-7a Dorsal (extensors) AER Mesoderm Limb Growth Ventral (flexors) Dorsal-Ventral Development Wnt-7a key for dorsal development Activates LMX-1 gene in mesoderm “Dorsalizes” mesoderm Gene deletion: Two ventral sides to limb Mouse embryos: sole on both surfaces of paws Ventral side: Engrailed1 represses Wnt-7 Dorsal (extensors) AER Mesoderm Limb Growth Ventral (flexors) Wnt Genes Family of genes Originally described in Drosophila Winged integration gene Found in many species including humans Early embryo: regulators of dorsal-ventral axis Later embryogenesis: anteroposterior axis Hikasa H and Sokol S. Wnt Signaling in Vertebrate Axis Specification. Cold Spring Harb Perspect Biol. 2013 Jan (5(1) AP Development Anterior-Posterior Depends on zone of polarizing activity Posterior limb (near little finger) Influences AER Major signaling molecule: SHH Sonic Hedgehog protein Sisi Chen/Wikipedia Gaudete/Wikipedia Homeobox Genes HOX Genes Code for transcription factors Regulators of AP axis development Homeotic genes Homeosis = transformation of one structure into another Homeotic genes = lead to formation of body segments Mutation → abnormal body part formation All homeotic genes have same sequences ~180 bases Called the Homeobox (part of gene) Homeobox Genes HOX Genes Family of genes: HOXA1, HOXB1, HOXD1, etc. Rare mutations of some HOX genes described Most result in abnormal limb formations Fruit flies: legs grow from head instead of antenna! Polydactyly (extra fingers/toes) Syndactyly (fused fingers/toes) ikkyu2 /Wikipedia Pschemp/Wikipedia Embryonic Genes Summary Sonic Hedgehog Hemispheres of brain → holoprosencephaly Limb AP axis: zone of polarizing activity → AER FGF Limb proximal-distal axis → apical ectodermal ridge Wnt-7a Limb dorsal-ventral axis → “dorsalizes” limb Homeobox (Hox) genes Limb AP axis Mutation → abnormal digits/toes Embryogenesis Jason Ryan, MD, MPH Fertilization Haploid mature spermatozoon (1N, 1C) Haploid ovum (1N, 1C) Forms zygote (2N, 2C) Wikipedia/Public Domain DNA Synthesis Maternal/paternal DNA in “pronucleus” 2N, 2C → DNA synthesis → chromatids →2N, 4C Zygote divides into two cells (2N, 2C) Wikipedia/Public Domain Cleavage Fetal Development Two cell stage: first 1-2 days after fertilization Ttrue12/Wikipedia Morula Cells continue to divide Morula = ball of cells Blastulation Formation of blastula from morula Blastula contains fluid cavity called blastocoel Blastulation In humans, blastula called blastocyst Outer cells: trophoblast Polarized: one side different from other Watery fluid of blastocoel secreted by trophoblast cells Inner cell mass (apolar) Give rise to all tissues of body Embryonic stem cells derived from inner cell mass Blastocyst.png/Wikipedia Blastocyst Wikipedia/Public Domain Implantation Blastocyst implants in uterus about day 6-10 β-hCG secretion begins Ttrue12/Wikipedia Gastrulation Blastula → 3 layered structure called gastrula Three germ layers Ectoderm Mesoderm Endoderm Gastrulation Inner cell mass → bilaminar disc Two cell layers separated by basement membrane Epiblast and hypoblast Wikimedia Commons Primitive Streak Formed by invagination of epiblast cells Creates a visible line (“streak”) in blastocyst Presence indicates start of gastrulation Wikipedia/Public Domain Zephyris/Wikipedia Gastrulation Epiblast → three germ layers Ectoderm, endoderm, mesoderm Zephyris/Wikipedia Wikimedia Commons Germ Layers Jason Ryan, MD, MPH Gastrulation Formation of gastrula Contains three germ layers Ectoderm Mesoderm Endoderm Ectoderm Epidermis Nervous system Pixabay/Public Domain Quasar Jarosz/Wikimedia Nervous System Development Nervous System Development Notochord arises in mesoderm Adult remnant: nucleus pulposus of spine Induces overlying ectoderm → neural plate Neural plate folds → neural tube Debivort/Wikipedia Nervous System Development Neural tube: CNS CNS neurons, oligodendrocytes, astrocytes Retina Spinal cord Neural crest: PNS Cranial nerves Dorsal root ganglia Autonomic ganglia Schwann cells Meninges Microglia (phagocytes): Mesoderm Endoderm GI epithelium and derivatives Liver, gallbladder, pancreas Alveoli, epithelium of trachea/bronchi Airway cartilage from mesoderm Wikipedia/Public Domain Patrick J. Lynch/Creative Commons Mesoderm Muscle, bone, connective tissue Cardiovascular structures Kidneys Lymphatics Blood Wikimedia Commons Mesoderm Many congenital defects in mesoderm derivatives Congenital heart defects Limb deformities Renal defects Mesenchyme Embryonic connective tissue Not found in adults except for mesenchymal stem cells Mostly derives from mesoderm Cells surrounded by proteins and fluid Gives rise to most connective tissue Bones, cartilage, lymphatic and circulatory systems Mesenchymal tumors = sarcomas Embryonic Period First 8 weeks after fertilization Organogenesis occurs Most vulnerable period to teratogens Followed by fetal period Most adult structure established Organs/structures grow Embryonic Period Heart Development Week 4 Heart begins beating Week 6 Transvaginal ultrasound detects fetal heart movement Embryonic Period Limbs Week 4 Limbs form Week 8 Baby begins moving Embryonic Period Genitalia Week 10 Prior to week 10 genitalia look similar for males/females SRY gene (Y chromosome) → penis development Lack of SRY gene → clitoris development Ultrasound identification of sex Usually week 15 to 20 Pituitary Gland Anterior pituitary (adenohypophysis) From Rathke’s pouch of ectoderm Outpouching of upper mouth Posterior pituitary (neurohypophysis) From neural tube Wikipedia/Public Domain Adrenal Gland Cortex: Mesoderm Aldosterone, cortisol, androgens Medulla: Neural crest Epinephrine, norepinephrine OpenStax College/Wikipedia Errors in Morphogenesis Jason Ryan, MD, MPH Morphogenesis Process of embryo taking shape Errors in Morphogenesis Intrinsic Failure of embryo to develop Abnormal genes or other internal processes Agenesis, Aplasia, Hypoplasia, Malformation Extrinsic External force impacts normal development Disruption, Deformation Errors in Morphogenesis Intrinsic Errors Agenesis Missing organ caused by missing embryonic tissue Renal agenesis www.medicalgraphics.de Errors in Morphogenesis Intrinsic Errors Aplasia Missing organ due to growth failure of embryonic tissue Thymic aplasia (DiGeorge syndrome) Wikipedia/Public Domain Errors in Morphogenesis Intrinsic Errors Hypoplasia Incomplete organ development Microcephaly Marie Sogaard et al/Wikipedia Errors in Morphogenesis Intrinsic Errors Malformation Abnormal development of structure Neural tube defects Cleft lip or palate Congenital heart defects Errors in Morphogenesis Extrinsic Errors Disruption Normal tissue growth arrested due to external force Classic example: amniotic band syndrome Fetal structures entrapped by fibrous bands in utero Often involves limbs or digits Wikipedia/Public Domain Errors in Morphogenesis Extrinsic Errors Deformation External force leads to abnormal growth (not arrest) Deforms or misshapes structure Classic example: Potter’s syndrome Potter’s Syndrome Fetus exposed to absent or ↓ amniotic fluid Amniotic fluid = fetal urine Severe renal malfunction = ↓ amniotic fluid Loss of fetal cushioning to external forces Potter’s Syndrome External compression of the fetus Abnormal face/limb formation Alteration in lung liquid content Abnormal lung formation Also called Potter’s sequence Teratogens I Jason Ryan, MD, MPH Teratogens Substances that cause abnormal fetal development Common effects: Fetal loss Growth restriction Birth defects Impaired neurologic function Teratogens Many mechanisms: Cell death/apoptosis Disrupted metabolism Disrupted cell growth/proliferation Greatest risk of fetal exposure 1st trimester Embryonic period Formation of organs Teratogen Timing First two weeks “All or none” period Spontaneous abortion or no effect Weeks 2-8 Organogenesis Structural defects After week 8 Decreased growth Central nervous system dysfunction Usually no birth defects Teratogens Drugs Substances of abuse Alcohol, cocaine, smoking Radiation Chemicals (mercury) Maternal illness Diabetes Phenylketonuria (PKU) Infectious agents TORCH: Toxoplasmosis, Other, Rubella, CMV, Herpes Drug Testing Animals FDA requires all drugs be tested in animal models Often rodents (rats) Case reports Pixabay/Public Domain Drug Categories FDA labels drugs during pregnancy in categories Category A: no risk to fetus in human studies Category B: no risk to fetus in other studies Category C: risk cannot be ruled out Category D: positive evidence of risk Category X: contraindicated in pregnancy Drugs known to be teratogenic in animals and humans Risks clearly outweigh benefits ACE Inhibitors and ARBs Pregnancy class D 1st trimester: numerous congenital malformations 2nd/3rd trimester: Oligohydramnios Decreased fetal kidney function Fetal renal failure Can lead to Potter’s syndrome Pulmonary hypoplasia, limb/skeletal deformities www.medicalgraphics.de Seizure Drugs Women with epilepsy may require drugs in pregnancy All anti-seizure drugs may affect fetus Neural tube defects Congenital heart disease Cleft palate Short fingers Abnormal facial features Pixabay/Public Domain Seizure Drugs High risk drugs Valproic acid (↑↑ neural tube defects) Phenytoin Phenobarbital Carbamazepine Many anti-seizure drugs associated with ↓ folic acid ↓ folic acid → neural tube defects High dose folic acid supplementation Fetal Hydantoin Syndrome Associated with phenytoin use in pregnancy Growth deficiency Abnormal facial features Broad, short nose Wide-spaced eyes Malformed ears Microcephaly Classically cleft lip and cleft palate Chemotherapy Rarely women develop malignancy while pregnant Hodgkin lymphoma Ideally chemotherapy deferred After birth 2nd/3rd trimester Fetal malformations 15% with therapy in 1st trimester Chemotherapy Highest risk: alkylating agents and antimetabolites Adverse effects on fetus: Spontaneous abortion Missing digits Many other fetal abnormalities Aurélie & Sylvain Mulard/Wikipedia Isotretinoin Derivative of vitamin A Used to treat acne Pregnancy class X Spontaneous abortions (~20%) “Embryopathy”: 20-30% of live births Wikipedia/Public Domain Abnormal facial features (low ears, wide-spaced eyes) Congenital heart disease Hydrocephalus Birth control mandatory Vitamin A Excess Teratogenic in first trimester Spontaneous abortions Microcephaly Cardiac anomalies Occurs at doses several times RDA Vitamin A Methotrexate Inhibits folate metabolism Used as anti-inflammatory Pregnancy class X Used to induce abortion in ectopic pregnancy May cause neural tube defects Methotrexate Folate Methotrexate Aminopterin/methotrexate embryopathy Neural tube defects Abnormal skull/face shape Cleft palate Hydrocephalus Limb anomalies Methotrexate Folate Warfarin Anticoagulant Pregnancy class D Fetal hemorrhage, spontaneous abortion Behrang Amini, MD/PhD Optic atrophy (vision loss) Warfarin Embryopathy Bone and cartilage abnormalities Stippled epiphyses: small, round densities on X-ray Nasal hypoplasia Limb hypoplasia Methimazole Treatment for hyperthyroidism Pregnancy class D Wikipedia/Public Domain May cause fetal and neonatal hypothyroidism Aplasia cutis: absence of epidermis on scalp Solitary defect on scalp ~70% of cases Missing patch skin/hair Propylthiouracil (PTU) used in 1st trimester Lithium Used in psychiatric disorders Pregnancy class D Teratogenic effects primarily involve heart Ebstein’s anomaly most common Antibiotics Aminoglycosides Reports of permanent deafness in fetus Tetracycline Accumulate in fetal teeth and long bones May permanently discolor fetal teeth Fluoroquinolones Fetal cartilage damage Antibiotics Trimethoprim May disrupt folate metabolism in fetus → neural tube defects Sulfonamides Displace bilirubin from albumin Can cause kernicterus Thalidomide Pregnancy class X Rarely used for treatment of multiple myeloma Used in 1950s as sedative in pregnancy Limb deformities Amelia: absence of limb Micromelia: short limbs Phocomelia: abnormal limb Wikipedia/Public Domain Diethylstilbestrol Nonsteroidal estrogen Used to prevent miscarriage, premature birth Removed from US market 1971 Slightly increased risk of breast cancer for mothers Female babies: Reproductive tract abnormalities Pixabay/Public Domain Diethylstilbestrol Hypoplastic uterus Cervical hypoplasia Vaginal adenosis Metaplasia of cervical or endometrial epithelium in vagina Persistent Müllerian tissue after birth Vaginal clear cell adenocarcinoma High rate of infertility Teratogens II Jason Ryan, MD, MPH Teratogens Drugs Substances of abuse Alcohol, cocaine, smoking Radiation Chemicals (mercury) Maternal illness Diabetes Phenylketonuria (PKU) Infectious agents TORCH: Toxoplasmosis, Other, Rubella, CMV, Herpes Alcohol Neurotoxin Multiple mechanisms: Cell death, failure of cell migration May cause fetal alcohol syndrome (FAS) Characteristic facial features Congenital heart defects Skeletal anomalies Intellectual disability Pixabay/Public Domain Alcohol Facial Features Smooth philtrum Groove from base of nose to upper lip Short palpebral fissures Small opening of eyes Thin vermillion border Upper lip Teresa Kellerman/Wikipedia Alcohol Heart Defects Congenital heart defects Atrial septal defect Ventricular septal defect Tetralogy of Fallot Alcohol Growth/Skeletal Below average height, weight Limb defects Finger contractions RobinH Congenital hip dislocations Alcohol CNS Structural defects Microcephaly Small corpus callosum, cerebellum, basal ganglia Abnormal reflexes Hypotonia Cranial nerve deficits Intellectual impairment (reduced IQ) Alcohol First trimester Facial abnormalities Brain abnormalities Congenital heart disease Third trimester Mostly affects size of baby, brain growth Intellectual impairment: May occur without facial or brain anomalies Smoking Two toxins: Nicotine and carbon monoxide Impaired oxygen delivery to the fetus Nicotine-induced vasoconstriction → ↓ placental blood flow CO competes with O2 → ↓ oxyhemoglobin Pixabay/Public Domain Smoking IUGR/Low birthweight 20% cases associated with smoking Placental anomalies Pixabay/Public Domain Abruption Previa Premature rupture of membranes Preterm labor Well-documented association with SIDS Cocaine Vasoconstriction IUGR/low birthweight Placental abruption Preterm birth Miscarriage Valerie Everett/Flikr Mercury Methylmercury found in fish/seafood Wikipedia Not removed by cooking Highest levels: swordfish, shark, tilefish, Mackerel King Fetal brain highly sensitive to mercury Mother not usually affected CH3 - Hg Methylmercury Delayed milestones Rarely blindness, deafness, or cerebral palsy Stephen Ewen/Wikipedia X-rays No evidence of harm at small doses Nevit Dilmen/Wikipedia Threshold for harm not definitively determined Higher dosages 8-15 weeks may cause: Intellectual disability Microcephaly Growth restriction Lead shielding used to protect fetus Ted Eytan/Wikipedia Maternal Diabetes Multiple effects on fetus: Increased growth Blood sugar alterations Congenital heart disease CNS disorders Adverse effects related to severity of diabetes Maternal Diabetes Macrosomia (large baby) Baby born large for gestational age Weight >90th percentile is common Babies often >9lbs at birth Can lead to birth injury Shoulder dystocia (shoulders cannot pass through birth canal) Paul/Flikr Maternal Diabetes Neonatal Hypoglycemia Baby makes excess insulin (“hyperinsulinemic state”) Blood glucose levels below 40 mg/dL Transient: usually the first 24 hours of life Close glucose monitoring after delivery is essential Maternal Diabetes Congenital heart defects: 3-9% of babies Transposition of the great arteries (TGA) Ventricular septal defects (VSDs) Truncus arteriosus Tricuspid atresia Patent ductus arteriosus (PDA) Wikipedia/Public Domain Caudal Regression Syndrome Sacral Agenesis Classically associated with maternal diabetes Usually children of insulin-dependent mothers Incomplete development of sacrum May include sirenomelia “Mermaid syndrome” Fusion of legs Often includes a neural tube defect Caudal Regression Syndrome Sacral Agenesis Stanislav Kozlovskiy/Wikipedia H. Aslan et a. Prenatal diagnosis of Caudal Regression Syndrome: a case report. BMC Pregnancy and Childbirth. 1, 8. 2001. Phenylketonuria Phenylalanine Maternal PKU Occurs in women with PKU who consume phenylalanine High levels of phenylalanine acts as a teratogen Serum phenylalanine monitored in pregnancy Dietary restriction of phenylalanine essential Phenylketonuria Phenylalanine IUGR Microcephaly Intellectual disability Congenital heart defects Coarctation of the aorta Hypoplastic left heart syndrome Pharyngeal Arches Jason Ryan, MD, MPH Pharyngeal Apparatus Embryonic structure Key for development of head and neck Terminology Branchia: Greek word for gills “Branchial”: relating to gills Humans: similar embryonic structures Branchial or pharyngeal Pharyngeal Apparatus Three components Pharyngeal arches Pharyngeal clefts Pharyngeal pouches Pharyngeal Apparatus 24-28 Day Old Embryo Arch Cleft Wikipedia/Public Domain Pharyngeal Apparatus Loki austanfell/Wikipedia Pharyngeal Arches Core of mesenchyme (connective tissue) Gives rise to cartilage/bone and muscles Neural crest cells migrate to center Gives rise to cranial nerves Artery → forms aortic arches First Pharyngeal Arch Bones “Maxillary process” Maxilla Zygomatic bone “Mandibular process” Mandible Meckel’s cartilage → incus and malleus Maxilla and Mandible Zygomatic Bone Wikipedia/Public Domain First Pharyngeal Arch Muscles Muscles of mastication Temporalis, masseter, pterygoids Anterior digastric Mylohyoid Tensor tympani (ear)  Masseter Pterygoids Temporalis Mylohyoid Digastric Wikipedia/Public Domain First Pharyngeal Arch Trigeminal Nerve Trigeminal mandibular and maxillary divisions Sensory to face Motor: muscles of mastication Wikipedia/Public Domain First Pharyngeal Arch Aortic Arch Portion of maxillary artery Wikipedia/Public Domain Second Pharyngeal Arch Bones “Reichert’s cartilage” Stapes (ear) Styloid process of temporal bone Lesser horn of hyoid Styloid process Second Pharyngeal Arch Bones Second Pharyngeal Arch Muscles Stapedius (ear) Auricular muscles (ear) Stylohyoid Posterior digastric Muscles of facial expression Stylohyoid m. Second Pharyngeal Arch Nerve Facial nerve Wikipedia/Public Domain Second Pharyngeal Arch Artery Stapedial artery Embryonic vessel Usually involutes in development Hyoid artery Embryonic vessel Develops into small branch of internal carotid Third Pharyngeal Arch Cartilage/Bones Hyoid bone Body and greater horn Third Pharyngeal Arch Muscles Stylopharyngeus Third Pharyngeal Arch Nerve Glossopharyngeal nerve (IX) Wikipedia/Public Domain Third Pharyngeal Arch Artery Common carotid Proximal internal carotid Fourth and Sixth Arches Fifth arch does not persist in humans 4th/6th: both innervated by vagus nerve branches 4th: superior laryngeal 6th: recurrent laryngeal Jkwchui/Wikipedia Fourth and Sixth Arches Cartilage Both arches fuse to form larynx cartilage Thyroid Cricoid Arytenoid Corniculate Cuneiform Olek Remesz/Wikipedia Fourth and Sixth Arches Muscles Laryngeal muscles 4th Arch Cricothyroid Levator palatini Pharyngeal constrictors 6th Arch Intrinsic muscles of larynx (except cricothyroid) Olek Remesz/Wikipedia Fourth and Sixth Arches Arteries 4th Arch Left: aortic arch Right: proximal right subclavian artery 6th Arch (“pulmonary arch”) Left: proximal pulmonary artery Left: ductus arteriosus Right: proximal pulmonary artery Fourth and Sixth Arches Arteries Mikael Häggström/Wikipedia Pharyngeal Arches Aortic Arches Wikipedia/Public Domain Treacher Collins Syndrome First and second arch syndrome Failure of neural crest cell migration Underdeveloped facial bones Small mandible (mandibular hypoplasia) Small jaw (micrognathia) Absent/small ears Glossoptosis (retraction of tongue) May lead to difficulty breathing Underdeveloped lower jaw Obstruction of airway by tongue Leena Goel, Santosh Kumar Tongue Anterior two thirds: 1st and 2nd arches Lingual swellings and tuberculum impar Sensation: CN V (1st arch) Taste: CN VII (2nd arch) Posterior third: 3rd and 4th arches Gabymichel/Wikipedia Sensory: GP Nerve (IX) of 3rd arch Some posterior taste via CN X (4th arch) Motor: Hypoglossal (XII) One exception: palatoglossus (CN X) Wikipedia/Public Domain Cleft Lip and Palate Jason Ryan, MD, MPH Cleft Lip and Palate Cleft lip: most common craniofacial malformation Often occurs with cleft palate Multifactorial etiology Environmental, genetic James Heilman, MD /Wikipedia Cleft Lip Primary palate (front of palate) Formed by fusion of structures Nasal prominences fuse: form philtrum Maxillary prominences from 1st pharyngeal arch Fuse with medial nasal prominences to form 1° palate Failure of this process leads to cleft lip Nasal Maxillary Prominences Prominence Cleft Lip Wikipedia/Public Domain Cleft Lip Wikipedia/Public Domain Cleft Palate Secondary palate (back of palate) Lateral structures: palatal shelves (processes) Fusion to form 2° palate Failure leads to cleft palate Wikipedia/Public Domain Cleft Palate Wikipedia/Public Domain Pharyngeal Pouches and Clefts Jason Ryan, MD, MPH Pharyngeal Apparatus Three components Pharyngeal arches Pharyngeal clefts Pharyngeal pouches Pharyngeal Apparatus 24-28 Day Old Embryo Arch Cleft Wikipedia/Public Domain Pharyngeal Apparatus Loki austanfell/Wikipedia Pharyngeal Pouches Four pharyngeal pouches Composed of endoderm 1st Pharyngeal Pouch Forms many portions of inner ear Eustachian tube Middle ear cavity Contributes to tympanic membrane Chittka L, Brockmann/Wikipedia 2nd Pharyngeal Pouch Lining of palatine tonsils (back of throat) 2nd pouch forms buds Invaded by mesoderm Invaded by lymphatic tissue Wikipedia/Public Domain 3rd Pharyngeal Pouch Thymus (mediastinum) Left and right inferior parathyroid glands (neck) Forms two “wings” Dorsal (back): Parathyroid Ventral (front): Thymus Busca tu equilibrio/Wikipedia 4th Pharyngeal Pouch Superior parathyroid glands Ultimobranchial body Incorporates into thyroid gland Forms C-cells (calcitonin) Derived from neural crest cells Also forms two “wings” Dorsal (back): Parathyroid Ventral (front): Ultimobranchial body Busca tu equilibrio/Wikipedia DiGeorge Syndrome Thymic Aplasia Failure of 3rd/4th pharyngeal pouch to form Most cases: 22q11 chromosomal deletion Abnormal thymus, parathyroid function Classic triad: Loss of thymus (Loss of T-cells, recurrent infections) Loss of parathyroid glands (hypocalcemia, tetany) Congenital heart defects (“conotruncal”) Pharyngeal Clefts Four pharyngeal clefts Lined by ectoderm 1st cleft develops into external auditory meatus Also contributes to tympanic membrane 2nd through 4th clefts form cervical sinus Temporary cavity Obliterates in development Chittka L, Brockmann/Wikipedia Branchial Cleft Cyst Present as neck mass Location based on cleft of origin 2nd cleft cysts are most common Below angle of the mandible Anterior to sternocleidomastoid muscle Often noticed when become infected Fistula to skin may develop Wikipedia/Public Domain Branchial Cleft Cyst Often occur in children Mass does not move with swallowing Contrast with thyroglossal duct cyst Midline neck mass Moves with swallowing Wikipedia/Public Domain Genital Embryology Jason Ryan, MD, MPH Genital System Chromosomal sex determined at fertilization XX (female) or XY (male) Later development: Gonads (ovaries/testes) Internal genitalia External genitalia Wikipedia/Public Domain Gonads Testis/Ovaries Gonadal ridges form about 7 weeks Derived from mesenchyme (mostly mesoderm) Germ cells derived from epiblast Invade gonadal ridges Failure to reach ridges : gonads do not develop Male/female gonads initially identical “Indifferent gonad” Testis SRY gene (Y chromosome) Codes for testis determining factor Forms Sertoli and Leydig cells Leydig cells produce testosterone Wikipedia/Public Domain Testosterone → male development Medullary (testis) cords form Expand out of testis → connect to genital ducts Ovary Medullary cords regress Cortical cords develop → form clusters Surround germ cells Oogonia and follicular cells form primordial follicles Oocyte Wikipedia/Public Domain Wikipedia/Public Domain Genital Ducts Two pairs of genital ducts in embryo Mesonephric (wolffian) Paramesonephric (müllerian) Mesonephros: interim kidney 1st trimester Associated duct: mesonephric duct Paramesonephric duct: formed near mesonephric duct Genital Ducts Develop into internal genital tracts Male: epididymis, vas deferens, seminal vesicles Female: fallopian tubes, uterus, upper vagina Tsaitgaist/Wikipedia Miraceti/Wikipedia Genital Ducts Male Sertoli cells: Müllerian inhibitory factor (MIF) Suppress development of paramesonephric ducts Male remnant: appendix testis (tissue at upper testis) Leydig cells: Androgens Stimulate development of mesonephric ducts Testosterone Wikipedia/Public Domain Genital Ducts Male Mesonephric ducts elongate to form: Epididymis Ductus (vas) deferens Seminal vesicles Ejaculatory ducts Testosterone Wikipedia/Public Domain Genital Ducts Male Epididymis Duct behind testis Transport sperm from seminiferous tubules to vas deferens Ductus deferens (vas deferens) Transport sperm from epididymis to ejaculatory ducts Sunshineconnelly/Wikipedia Genital Ducts Male Seminal vesicles Glands behind bladder Secrete about 75% of fluid in semen Connect with ejaculatory ducts Ejaculatory ducts Collect sperm/fluid from seminal vesicles and vas deferens Pass through prostate Connect to urethra Male Genitalia Tsaitgaist/Wikipedia Genital Ducts Female Paramesonephric ducts form internal structures Only occurs in absence of MIF and androgens Fallopian tubes Uterus Upper 2/3 vagina Female Genitalia Miraceti/Wikipedia Gartner's Duct Wolffian/mesonephric remnant in females Found on vaginal walls May form cyst Genital Ducts Teixeira, J., Rueda, B.R., and Pru, J.K., Uterine Stem cells (September 30, 2008), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.16.1, Urogenital Sinus Cloaca divides Forms urogenital sinus and anal canal Urogenital sinus forms male/female structures  Pharyngeal Pouches Esophagus Foregut Celiac Trunk Yolk Sac (Vitelline Duct) SMA Midgut IMA Hindgut Cloaca Urogenital Sinus Males Upper portion: bladder Pelvic (middle) portion: prostate and prostatic urethra Phallic portion: penile urethra Females Upper portion: bladder Pelvic portion: Inferior vagina Connects with paramesonephric ducts Uterine Anomalies “Lateral fusion defects” most common Failed fusion of two sides of uterus May cause infertility, pregnancy loss Uterine Anomalies Most common: septate uterus Septum divides uterus Two endometrial cavities Defect in resorption of septum between Müllerian ducts Treatment: septoplasty Uterine Anomalies Bicornuate: Fundus is indented Partial fusion of the Müllerian ducts Unicornuate: Uterus connects to one ovary Other ovary not connected to uterus Uterine didelphys (double uterus) Müllerian ducts fail to fuse Hysterosalpingography Jemsweb/Wikipedia External Genitalia Begins with indifferent stage Four key structures Genital tubercle Urogenital sinus (from cloaca) Urogenital folds (from cloaca) Labioscrotal (genital) swellings External Genitalia Male Genital tubercle elongates → phallus Urogenital folds close → penile urethra Urogenital sinus → glands Prostate gland Bulbourethral glands (of Cowper) Labioscrotal swelling → scrotum Hypospadia Congenital anomaly of male urethra Ventral opening of urethra Failure of urethral folds to close Cryptorchidism in ~10% of patients Wikipedia/Public Domain Epispadia Urethral opening on dorsal side of penis Much less common than hypospadia Abnormal position/formation of genital tubercle Commonly occurs with bladder exstrophy External Genitalia Male Requires dihydrotestosterone Testosterone → DHT Enzyme: 5α-reductase 5α-reductase deficiency Ambiguous genitalia until puberty At puberty: ↑ testosterone External Genitalia Female Genital tubercle elongates → clitoris Urogenital folds (no fusion) → labia minora Urogenital sinus → glands Paraurethral glands (Skene) Bartholin glands Labioscrotal swelling → labia majora Requires estrogen >> androgen Spermatogenesis and Oogenesis Jason Ryan, MD, MPH Gametogenesis Development of haploid gametes Male and female sex cells Sperm Oocytes Wikipedia/Public Domain Primordial Germ Cells Common origins of spermatozoa and oocytes Derived from epiblast cells Migrate to reside among endoderm cells of yolk sac During 8th week: migrate to genital ridge Spermatogenesis Begins at puberty Sex cords in testes develop a lumen Become seminiferous tubules Spermatogenesis occurs in seminiferous tubules Meiosis Diploid cells give rise to haploid cells (gametes) Unique to “germ cells” Spermatocytes Oocytes Chromosome content of cells: 2n 2C (diploid) 2n 4C (diploid) 1n 2C (haploid) 1n 1C (haploid)  Meiosis Blue = Paternal Red = Maternal Meiosis I Meiosis II 2n 2C 2n 4C DNA Synthesis 1n 2C 1n 1C Spermatogonia 2n 2C cells Derived from primordial germ cells Precursors of spermatozoa Spermatogenesis 1° spermatocytes 2n, 4C cells from spermatogonia DNA synthesis completed Starting meiosis I 2° spermatocytes Meiosis I completed Starting meiosis II 1n, 2C cells Spermatogenesis Spermatids Haploid (1n 1C) Undergo spermiogenesis Form spermatozoa (sperm) Singular: spermatozoon Spermiogenesis Formation of spermatozoa Formation of acrosome Cap of sperm Contains enzymes to assist in fertilization Condensation of nucleus Formation of neck and tail Shedding of most of cytoplasm Sertoli Cells Line walls of seminiferous tubules Support and nourish developing spermatozoa Regulate spermatogenesis Stimulated by FSH Supported by Leydig cell testosterone (paracrine) Need FSH and LH for normal spermatogenesis Sertoli Cells Form blood-testis barrier Tight junctions between adjacent Sertoli cells Apical side (toward tubule): meiosis, spermiogenesis Basal side: spermatogonia cell division Isolates sperm; protection from autoimmune attack Uwe Gille/Wikipedia Seminiferous Tubules Spermatogonia Germ cells Behind blood-testis barrier Separated from tubule by Sertoli cells Sertoli cells Line tubules Support/regulate spermatogenesis Form blood testis barrier Leydig cells Found in interstitium (between tubules) Secrete testosterone Seminiferous Tubules OpenStax College/Wikipedia Oogenesis Primordial germ cells → oogonia (2n 2C) Oogonia divide in utero Oogonia → 1° oocytes (2n 4C) Maximum number formed by 5th month in utero About 7 million Surrounded by cells → primordial follicle Oogenesis Primary oocytes: diploid cells formed in utero Beginning meiosis I Arrested in prophase of meiosis I until puberty At puberty Menstrual cycles begin A few primary oocytes complete meiosis 1 each cycle Some form polar bodies → degenerate Some form 2° oocytes Oogenesis 2° oocytes (1n 2C) Meiosis II begins → arrests in metaphase No fertilization: oocyte degenerates Fertilization → completion of meiosis II Forms ovum (1n 1C) Placenta Jason Ryan, MD, MPH Placenta Nutrient and gas exchange between mother/fetus Wikipedia/Public Domain Decidual Reaction Endometrium reaction at implantation Decidua = altered uterine lining during pregnancy Decidua basalis Uterus at site of implantation Interacts with trophoblast Decidua capsularis Surrounds fetus Decidua parietalis Opposite wall of uterus Wikipedia/Public Domain Membranes Amnion Inner membrane that covers fetus Holds amniotic fluid Protects embryo Wikipedia/Public Domain Chorion Membrane that surrounds amnion/embryo Derived from trophoblast Supports fetus and amnion Wikimedia Commons Placental Terminology Basal plate Maternal side of placenta In contact with uterine wall Includes maternal decidua basalis Chorionic plate Fetal side of placenta Chorion at placenta Gives rise to chorionic villi Trophoblast Outer layer of blastocyst Develops into placenta Blastocyst.png/Wikipedia Trophoblast Proliferates into two cell layers Syncytiotrophoblast: outer layer Invades endometrium Finger-like projections: villi Form lacunae (spaces) for maternal blood Cytotrophoblast: inner layer Proliferates → cells migrate into syncytiotrophoblast Secretes proteolytic enzymes to aid invasion Chorionic villi: projections of both layers Contact with maternal blood Nutrient/gas exchange Trophoblast Wikipedia/Public Domain Chorionic Villi Outer layer: syncytiotrophoblast Inner layer: cytotrophoblast Contact area with maternal blood BruceBlaus/Wikipedia Chorionic Villi Fetal mesoderm invades villi Branches of umbilical artery/vein grow Eventually connects to umbilical cord Wikipedia/Public Domain Placental Circulation Maternal side Endometrial (spiral) art → villous space → endometrial vein Fetal side Umbilical arteries (deoxygenated blood) Umbilical arteries → chorionic arteries → capillaries Capillaries → umbilical vein (oxygenated blood) Placental Barrier No mixing of maternal/fetal blood Oxygen and carbon dioxide diffuse Facilitated transport of glucose Active transport of amino acids IgG antibodies (not IgM) Some other nutrients, drugs, infectious agents Umbilical Cord Connection between embryo and placenta Derives from fetus Contains umbilical arteries and veins Yolk sac Cavity (sac) formed in early embryogenesis Allantois Outpouching of hindgut Wikipedia/Public Domain GI Embryology Wikipedia/Public Domain  Pharyngeal Pouches Esophagus Foregut Celiac Trunk Yolk Sac SMA Midgut Allantois IMA Hindgut Cloaca Allantois Outpouching from wall of gut Walls form umbilical blood vessels Lumen occludes in development Becomes urachus Fibrous remnant of allantois Connects bladder to umbilicus Wikipedia/Public Domain Umbilical Cord Two umbilical arteries Deoxygenated fetal blood to placenta One umbilical vein Oxygenated fetal blood from placenta Johnlancer123/Wikipedia Single Umbilical Artery Abnormal variant Often identified on prenatal ultrasound Associated with fetal anomalies Aneuploidy Congenital malformations Patho/Wikipedia Umbilical Cord Wharton jelly Contains mucopolysaccharides Similar to vitreous humor Allantoic duct Johnlancer123/Wikipedia Connects fetal bladder to umbilical cord Obliterates in development Becomes urachus Duct sometimes seen in umbilical cord Urachus Remnant of allantois Connection between bladder and umbilical cord In adult: median umbilical ligament May cause adenocarcinoma of bladder Urachus Anomalies Patent urachus Urine discharge from umbilicus Vesicourachal diverticulum Diverticulum of bladder Urachal cyst Partial obliteration Fluid-filled cavity May become infected Immunology of Pregnancy Fetus: foreign antigens Half of genes from father HLA proteins differ from mother Protected from maternal immunity by placenta Several mechanisms Trophoblast cells do not express many MHC class I antigens Placenta secretions block immune response Twins Jason Ryan, MD, MPH Twins One pregnancy: two babies Dizygotic twins Two zygotes Two separate ova fertilized by two separate sperm Two siblings born from single pregnancy “Fraternal twins” Monozygotic twins One zygote divides in two One ova fertilized by one sperm “Identical twins” Trlkly/Wikipedia Twins Often one twin dies in utero Resorption of fetus/embryo Delivery of single baby More fetuses = shorter pregnancy Single fetus ~ 40 weeks Twins ~ 37 weeks Triplets ~ 33 weeks Dizygotic Twins Each baby has own amnion and chorion “Dichorionic diamniotic” Two separate placentas Common in mothers using IVF Wikipedia/Public Domain Monozygotic Twins May have a single shared placenta Variable number of amnions, chorions Depends on when zygote divides Kevin Dufendach/Wikipedia Monozygotic Twins Days 1-3 May have two placentas Dichorionic, diamniotic Days 4–8 Chorion already under development Monochorionic diamniotic Days 9-12 Chorion and amnion already under development Monochorionic monoamniotic Day 13+ Also monochorionic monoamniotic May result in conjoined twins 2-cell Stage Kevin Dufendach /Wikipedia Twin Pregnancies Increased risk of maternal/fetal complications Fetus Growth restriction Congenital anomalies Preterm delivery Maternal Gestational hypertension/preeclampsia Pregnancy Jason Ryan, MD, MPH Pregnancy Dating Embryonic age Age dated to fertilization Gestational age Age dated to last menstrual period Embryonic age plus two weeks Fertilization Occurs within 1 day of ovulation Usually occurs in the ampulla of fallopian tube Wikipedia/Public Domain Implantation Occurs about 6 days after ovulation Syncytiotrophoblast secretes hCG Ttrue12/Wikipedia HCG Human chorionic gonadotropin Similar structure to luteinizing hormone (LH) Two glycoprotein subunits (“heterodimeric glycoprotein”) α and β subunits LH and hCG: same α subunit Also same α subunit in FSH and TSH Binds LH receptors in corpus luteum HCG Human chorionic gonadotropin Maintains corpus luteum Corpus luteum continues progesterone release Prevents menstruation Maintains pregnancy for first 10 weeks Wikipedia/Public Domain HCG Human chorionic gonadotropin Used to detect pregnancy Usually antibody based tests (ELISA variants) Detect β subunit of hCG Wikipedia/Public Domain HCG Human chorionic gonadotropin Serum tests Most sensitive method for detecting hCG Can detect very low levels 1-2mIU/mL May be positive within 1 week of conception Urine tests hCG threshold 20 to 50mIU/mL May not be positive until 2 weeks or more Pixabay/Public Domain Syncytiotrophoblast Secretes hCG Begins progresterone synthesis about 10 weeks Placenta maintains pregnancy going forward Wikipedia/Public Domain Human placental lactogen Chorionic somatomammotropin Protein hormone Produced by syncytiotrophoblast Higher levels as placenta grows during pregnancy Blocks effects of insulin Raises blood glucose level (good for baby) Promotes breakdown of fatty acids by mother for fuel Promotes breakdown of proteins for fuel Diabetes in Pregnancy Pregnancy is an insulin-resistant state Decreased maternal response to insulin Diabetes mellitus Worsened by pregnancy Gestational diabetes Onset of diabetes during pregnancy Screening with serum glucose testing Glycosuria occurs in normal pregnancy Physiologic Changes Plasma Volume Total body volume expands Blood fills placenta Diverted from maternal circulation ↑ renin → salt/water retention Physiologic Changes Red Cell Mass Red cell mass expands Increased maternal EPO Dilutional anemia Rise in volume > rise in red cells Result: ↓ Hct Databese Center for Life Science (DBCLS) Physiologic Changes Hemodynamics Cardiac output rises Preload increased by rise in blood volume Afterload reduced due to fall in systemic vascular resistance Maternal heart rate rises slightly Physiologic Changes Hemodynamics Peripheral resistance falls Placenta is a low resistance system Also maternal vasodilation Blood pressure normally falls Parallel Series 1 1 1 = + Rtotal = R1 + R2 Rtotal R1 R2 Supine Hypotension Occurs in later stages of pregnancy Large baby compresses IVC when lying flat Decreased venous return (preload) Public Domain Fall in cardiac output Reflex tachycardia may produce symptoms Physiologic Changes Coagulation Pregnancy is a hypercoagulable state Probably evolved to protect against blood loss at delivery Many clotting factor levels change Increased fibrinogen Decreased protein S Fetus also obstructs venous return → DVTs common Physiologic Changes Pulmonary Ventilation increases More CO2 to exhale Also hormone-induced Mostly due to increased tidal volumes Respiratory rate minimally changed Labor Regular uterine contractions Progressive dilation of cervix Descent and expulsion of fetus Normally occurs at 40 weeks Preterm labor 90% women NOTE: Methotrexate used only in ectopic pregnancy Maternal-Fetal Disorders Jason Ryan, MD, MPH Ectopic Pregnancy Pregnancy outside the uterus 98% occur in fallopian tube Most commonly ampulla (mid portion) Wikipedia/Public Domain Ectopic Pregnancy Symptoms in 1st trimester Vaginal bleeding Abdominal pain (may mimic appendicitis) Abnormal ↑hCG based on dates Wikipedia/Public Domain Ectopic Pregnancy Diagnosis: ultrasound Treatment: Methotrexate Surgery James Heilman, MD/Wikipedia Ectopic Pregnancy Risk Factors Damage to fallopian tube Prior ectopic pregnancy Tubal disorders Tubal ligation (rarely pregnancy occurs) Tubal surgery (tumor) Pelvic inflammatory disease (Chlamydia, Neisseria) Ectopic Pregnancy Risk Factors Infertile women: higher incidence Kartagener syndrome (1° ciliary dyskinesia) Fallopian tubes: ciliated epithelium Spontaneous Abortion Miscarriage Pregnancy loss before 20 weeks After 20 weeks: stillbirth or fetal demise Presents as vaginal bleeding Often requires D&C to remove all tissue 50% cases due to fetal chromosomal abnormalities Spontaneous Abortion Risk Factors Maternal smoking, alcohol, cocaine Maternal infection (TORCH) Hypercoagulable states Lupus/antiphospholipid syndrome Amniotic Fluid Primary sources: fetal urine and lung secretions Major source for removal: fetal swallowing Oligohydramnios Decreased amniotic fluid Often a fetal kidney problem Polyhydramnios Excessive amniotic fluid Often a swallowing/GI problem Oligohydramnios Fetal renal abnormalities Bilateral renal agenesis Posterior urethral valves (males) Placental insufficiency Preeclampsia Maternal vascular diseases Premature rupture of membranes Image courtesy of Piotr Michał Jaworski Oligohydramnios Can lead to Potter’s sequence Loss of fetal cushioning to external forces Compression of the fetus Limb deformities Flat face Pulmonary hypoplasia Polyhydramnios Fetal swallowing malformations Esophageal/duodenal atresia Anencephaly Maternal diabetes Fetal hyperglycemia → polyuria Fetal anemia Leads to high fetal cardiac output Increased urine production Can occur in parvovirus infection Multiple gestations More fetal urine Low Birth Weight Less than 2500 grams (5.5lbs) Caused by: Premature delivery Intrauterine growth restriction (IUGR) Increased risk of: Pixabay/Public Domain Neonatal mortality Newborn complications Lower birth weight → greater risk complications Low Birth Weight Selected Risk Factors/Causes Congenital abnormalities of fetus Multiple gestation Maternal conditions Preeclampsia Abruptio placenta Alcohol Smoking Cocaine use Øyvind Holmstad/Wikipedia Low Birth Weight Newborn Problems Hypothermia Less white adipose tissue (insulation) Less brown adipose tissue (heat generation) Large ratio surface area to weight (lose heat easily) Hypoglycemia Loss of maternal glucose Insufficient fetal generation of glucose Hyperbilirubinemia ↑ unconjugated bilirubin May lead to newborn jaundice Nevit Dilmen/Wikipedia Low Birth Weight Newborn Problems Respiratory distress Neonatal RDS Deficiency of surfactant Transient tachypnea of the newborn Inadequate lung fluid clearance Pneumonia Respiratory failure Need for ventilator support Patrick J. Lynch Persistent Fetal Circulation In utero: high PVR Blood shunted right → left Via foramen ovale and ductus arteriosus At birth → oxygen to lungs → PVR falls Persistent high PVR → shunting → hypoxemia Abnormal development of pulmonary vasculature Small vessels Thickened walls Excessive vasoconstriction Immune Function Cellular immunity impaired ↓ T-cells and B-cells at birth Some babies have neutropenia Mgiganteus/Wikipedia Low Birth Weight Newborn Problems Databese Center for Life Science Polycythemia of the newborn Excessively elevated hematocrit at birth (>65) Newborns normally have increased red cell mass Fetus in a relatively hypoxic environment in utero Increased hemoglobin production Placental blood may transfer to baby at birth Usually asymptomatic Rarely may cause symptoms Hypoglycemia (excessive RBC glucose utilization) Hyperbilirubinemia Low Birth Weight Newborn Problems Necrotizing Enterocolitis Intestinal necrosis and obstruction Usually terminal ileum or colon Can lead to perforation Mikael Häggström/Public Domain Major risk factor is prematurity, low birth weight Low Birth Weight Newborn Problems Intraventricular Hemorrhage Hemorrhage into lateral ventricle Hypotonia Pixabay/Public Domain Loss of spontaneous movements Seizures, coma Germinal matrix problem Highly vascular area near ventricles Premature infants: poor autoregulation of blood flow here In full term infants, this area has decreased vascularity Low Birth Weight Long Term Outcomes SIDS Sudden infant death syndrome Leading cause infant mortality 1 month to 1 year in US Increased risk with preterm birth or low birth weight Increased risk of neurocognitive problems Cognition Social skills Behavioral and emotional skills SIDS Sudden Infant Death Syndrome Sudden death of infant < 1 year of age Unexplained by other causes Risk factors Stomach sleeping Maternal smoking during pregnancy Very young maternal age (100,000 ) early in pregnancy Ovarian theca lutein cysts Ovarian stimulation by hCG Often bilateral Complete Molar Pregnancy Clinical Features Hyperthyroidism Requires very high hCG hCG stimulation of TSH receptor Low TSH High T3/T4 Preeclampsia Partial Molar Pregnancy Clinical Features Uterine size May be normal (some villi drainage to fetus) May be small for gestational age (slow growth of fetus) Marked ↑hCG less common Molar Pregnancy Treatment Uterine suction curettage Rarely hysterectomy Chemotherapy: Methotrexate or Actinomycin D For high risk patients only Features suggesting high likelihood of choriocarcinoma Choriocarcinoma Rare malignant gestational neoplasm Can follow a normal pregnancy Complete molar pregnancy 15% develop locally invasive disease 5% develop metastatic disease Partial mole 90% Alternative: ampicillin-sulbactam RPOC Retained Products of Conception Placental/fetal tissue remaining in uterus May occur after delivery or miscarriage Uterine bleeding and pelvic pain Tissue becomes necrotic Prone to infection by flora from cervix/vagina Leads to acute endometritis Diagnosis by history and imaging Treatment: antibiotics +/- surgery Chronic Endometritis Intrauterine devices (IUDs) Pelvic Inflammatory Disease Ascending infection May involve uterus, fallopian tubes, ovaries Salpingitis, oophoritis, endometritis Chlamydia or gonorrhea Treatment: antibiotics Tuberculosis Hematogenous spread from lungs Biopsy: Acid- Fast Bacilli Chronic Endometritis Associated with infertility Indication for biopsy Biopsy hallmark: plasma cells White blood cells may be normal in endometrium Plasma cell indicates chronic inflammation Wikipedia/Public Domain Endometrial Polyps Hyperplastic growth of glands and stroma Most (95%) benign Project from endometrium (“exophytic mass”) Often asymptomatic May cause painless uterine bleeding Removed surgically Stop bleeding Prevent infection Small chance malignancy BruceBlaus/Wikipedia Endometrial Polyps Histology: Stroma Glands May see smooth muscle Associated with unopposed estrogen Common near menopause Ovarian estrogen production Chronic anovulation → lack of progesterone Tamoxifen Selective estrogen receptor modulator (SERM) Competitive antagonist of breast estrogen receptor Used in ER positive (ER+) breast cancer Estrogen agonist in other tissues (bone/uterus) Tamoxifen Partial agonist to endometrium Endometrial proliferation Hyperplasia Polyp formation (up to 36% of women) May cause endometrial cancer Endometriosis Jason Ryan, MD, MPH Endometriosis Endometrial tissue outside uterus Glands and stroma May occur anywhere Several common locations Ovary/Fallopian Tubes Uterosacral ligaments Rectovaginal septum Pelvic peritoneum BruceBlaus/Wikipedia Endometriosis Pathogenesis Exact etiology unknown, several theories Retrograde flow Movement of menstrual tissue through fallopian tubes Travels to ovaries, peritoneum Metastasis Spread through venous or lymphatic system Metaplasia Endometrium from coelomic epithelium in development Stem cells Progenitor cells develop into endometrial tissue Endometriosis Symptoms Ectopic endometrial tissue hormone-sensitive Growth from estrogen Atrophy from progesterone withdrawal Growth, bleeding, inflammation in ectopic sites Estradiol (17β-estradiol) Progesterone Endometriosis Classic Symptoms Dysmenorrhea Cyclic menstrual pelvic pain Dyspareunia Painful intercourse Ectopic tissue near vagina Infertility Many women unaware of disorder Ovarian/fallopian lesions → infertility ~40% infertile woman have endometriosis Endometriosis Other Symptoms Dyschezia Painful defecation Ectopic tissue near rectum Dysuria Painful urination Ectopic tissue near bladder BruceBlaus/Wikipedia Endometriosis Diagnosis Physical exam may be normal Vaginal tenderness Nodules in posterior fornix Upper vagina behind cervix Ovarian mass Endometriosis Diagnosis Normal uterus size Enlarged uterus: adenomyosis Retroverted uterus Uterus tipped backwards Detected on physical exam May be seen in normal women More common in women with endometriosis Endometriosis Diagnosis Definitive diagnosis: biopsy of lesion Often requires surgical exploration Classic ovarian finding: chocolate cyst Wikipedia/Public Domain Endometriosis Other Features Classically occurs in women of reproductive age Improves at menopause and in pregnancy Increased risk of ovarian epithelial cancer Wikipedia/Public Domain Endometriosis Treatment Definitive treatment: surgical removal Nonsteroidal anti-inflammatory drugs (NSAIDs) Reduce inflammation Wikimedia Commons Endometriosis Treatment Oral contraceptive pills (OCPs) First line therapy Suppress ovarian function Key component: progestins Suppress ovaries → cause anovulation Anti-estrogen → limit endometrial growth BruceBlaus/Wikipedia Leuprolide GnRH agonist Binds to receptors in pituitary Down-regulation of GnRH receptor Pituitary desensitization → ↓ LH/FSH ↓ estrogen production from ovaries Danazol Steroid Weak androgen and progesterone activity Inhibits LH surge → anovulation Suppresses ovarian function Rarely used due to side effects Danazol Danazol Adverse Effects Androgen effects Weight gain Edema Decreased breast size Danazol Acne and oily skin Increased hair growth Deepening of the voice Low estrogen effects: hot flashes Intracranial hypertension (pseudotumor cerebri) Headache, papilledema Adenomyosis Endometrial glands/stroma in myometrium Hyperplasia of basal endometrium into myometrium Diffusely enlarged uterus (“globular”) Two major symptoms: Heavy menstrual bleeding Painful menstruation Often co-exists with endometriosis Adenomyosis Less responsive to medical therapy Definitive treatment: hysterectomy Hic et nunc/Wikipedia Endometrial Cancer Jason Ryan, MD, MPH Leiomyoma Fibroid Benign tumor of myometrium (smooth muscle) Usually multiple tumors Occur in pre-menopausal women Growth stimulated by estrogen Usually resolve at menopause (↓ estrogen) Hic et nunc/Wikipedia Leiomyoma Fibroid Histology: Smooth muscle cell proliferation KGH/Wikipedia Leiomyoma Fibroid Usually asymptomatic Often detected as pelvic mass on exam Can be visualized with ultrasound May cause: Irregular bleeding (often heavier, longer menstrual flow) Infertility Pelvic pain Leiomyosarcoma Malignant smooth muscle tumor of uterus Arise de novo (not from fibroids) Occur in post-menopausal women Usually a single large mass Endometrial Hyperplasia Stimulation of endometrium by unopposed estrogen Absence of progesterone stimulation/withdrawal Usually occurs in peri/postmenopausal women Menstruation has slowed or stopped Anovulation → no progesterone from ovary Any estrogen source → hyperplasia Endometrial Hyperplasia Sources of Estrogen Obesity Increased conversion androgens → estrogens (estrone) Polycystic ovarian syndrome (PCOS) Obesity/anovulation Tamoxifen Estrogen agonist Hormone replacement therapy (estrogen only) Ovarian granulosa cell tumor Secrete estrogen May present with uterine bleeding and adnexal mass Endometrial Hyperplasia Clinical Features Presents as abnormal uterine bleeding Same presentation as endometrial carcinoma Same risk factors as endometrial carcinoma Diagnosis: endometrial biopsy Abundant, crowded glands Endometrial Hyperplasia Clinical Features obgymgmcri Endometrial Hyperplasia Risk for endometrial carcinoma Graded based on histology Simple, complex Presence of atypical cells Complex, atypical: high risk of cancer Endometrial Hyperplasia Treatment Low risk forms: Progestins Oppose estrogen effects Reverse hyperplasia Improve bleeding High risk forms: Hysterectomy Endometrial Carcinoma Most common gynecologic cancer Most common in post menopausal women Average age of diagnosis ~60 years old Menopause: anovulation → more estrogen exposure Classic presentation: abnormal uterine bleeding Endometrial Carcinoma Diagnosis: endometrial biopsy Often preceded by endometrial hyperplasia Often driven by unopposed estrogen Usually detected early Often treated with total abdominal hysterectomy Endometrial Carcinoma Pathophysiology Classified histologically Major types: Endometrioid and serous Endometrioid subtype (Type I) Estrogen-dependent hyperplasia Serous subtype (Type II) Estrogen independent Endometrial Carcinoma Endometrioid Subtype Due to estrogen-dependent hyperplasia Risk factors: more estrogen = more risk Resembles endometrium (“endometrioid”) Wikipedia Endometrial Carcinoma Serous Subtype Estrogen-independent tumors Pink, serous material on biopsy Arise from atrophic endometrium post-menopause Most frequently altered gene: p53 tumor suppressor Present in 90% tumors Poor prognosis (more aggressive type) Wikipedia HNPCC Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome Germline mutation in DNA mismatch repair genes Leads to colon cancer Also increased risk of endometrial cancer Most common non-colon malignancy Lifetime risk up to 70% (3% in general population) Ovarian Cysts Jason Ryan, MD, MPH Ovarian Cysts Often detected by ultrasound James Heilman, MD/Wikipedia Often “functional” From normal ovarian structure Follicle Corpus luteum Lyrl/Wikipedia Ovarian Follicle Egg surrounded by cells Two key cell types: theca and granulosa cells Granulosa Antrum Cells (fluid) Theca Cells Oocyte Hormone Synthesis Estrogens Theca cells Convert cholesterol into androstenedione (androgen) Stimulated by LH Granulosa cells Convert androstenedione into estradiol (estrogen) Stimulated by FSH Follicular Cysts Common cause of ovarian mass in young women Derive from an ovarian follicle (1st half cycle) Failure of ovarian follicle to rupture Or when follicle ruptures and reseals Lyrl/Wikipedia Follicular Cysts Lined by granulosa cells Filled with estrogen May continue to release estrogen May stimulate endometrial growth Classic symptoms: pain plus irregular bleeding Lyrl/Wikipedia PCOS Polycystic Ovarian Syndrome Multiple follicular cysts Amenorrhea Excess androgens Insulin resistance/diabetes Corpus Luteal Cyst Corpus luteum: large structure Forms 2nd half of menstrual cycle Failure to involute → cyst Lyrl/Wikipedia Ed Uthman Corpus Luteal Cyst May continue producing progesterone May delay menstruation Classic presentation Pain Missed period Adnexal mass Lyrl/Wikipedia Ed Uthman Cysts by Ultrasound Follicular Cyst Corpus Luteal Cyst Thin-walled Thick-walled No vascularity Ring of Fire vascularity James Heilman, MD/Wikipedia Case courtesy of Dr Matt A. Morgan, Radiopaedia.org, rID: 42531 Theca-lutein Cysts Usually bilateral, multiple cysts Luteinized theca cells with edema Hyperplasia of theca cells Benign Associated with high β-hCG levels Twins Molar pregnancy Usually regress Ovarian Epithelial Tumors Jason Ryan, MD, MPH Ovary Structures Oocytes (eggs) Germ cell tumors Supporting cells Theca/granulosa Fibroblasts Sex cord stromal tumors Surface epithelium Adenomas/Carcinomas Wikipedia/Public Domain Ovarian Surface Epithelium Simple cuboidal epithelium Single layer of cells Derived from coelomic epithelium Epithelial lining of intraembryonic celom Space that gives rise to thoracic and abdominal cavities Forms outer layer of male/female gonads Also forms lining of body wall, liver, lungs, GI tract Epithelial Cell Tumors Clinical Features Often a “silent” disease Classic presentation: adnexal mass Identified on pelvic exam or imaging Vague abdominal symptoms Bloating Early satiety Pelvic/abdominal pain Average age: 63 years old Epithelial Cell Tumors Clinical Features Rarely can present with acute symptoms Often in advanced disease Bowel obstruction Local spread through peritoneum Ascites Pleural effusion Malignant pleural effusion (pleural metastasis) Cancer cells in pleural fluid Venous thromboembolism Epithelial Cell Tumors Most common type of ovarian tumors Serous (40%) Secrete serum (water) Mucinous (25%) Secrete mucous Endometrioid (10%) Similar to endometrium Benign, malignant, or borderline Benign: adenoma Malignant: adenocarcinoma Serous Cystadenoma Often bilateral Cyst filled with watery fluid Thin wall of single cells lining cyst Nephron/Wikipedia Ed Uthman, MD/Wikipedia Serous Cystadenocarcinoma Most common malignant ovarian tumor Complex cysts with watery fluid Growth of epithelial layer Cells similar to fallopian tube cells KGH/Wikipedia Psammoma Bodies Images courtesy of Michael Blechner, MD Mucinous Tumors Mucinous cystadenoma Thin walled cyst filled with mucous Often larger than serous tumors Often “multiloculated”: many small cavities, recesses Mucinous cystadenocarcinoma Malignant variant of cystadenoma Pseudomyxoma Peritonei Mucinous spread to abdomen “Mucinous ascites” Diffuse gelatinous material in abdomen/pelvis Bowel obstruction may occur Seen in appendix cancer Endometrioid Tumors Contain tubular glands similar to endometrium Often occur in patients with endometriosis Good prognosis Often identified at early stage Sensitive to chemotherapy Wikipedia/Public Domain Brenner Tumor Rare subtype of epithelial ovarian tumor Contains bladder epithelial (transitional) cells Usually benign Often found incidentally “Coffee bean” nuclei seen on biopsy Nephron/Wikipedia Epithelial Cell Tumors Risk Factors More ovulation associated with more risk More Risk Less Risk Advanced age Pregnancy Early Menarche Breast Feeding Late Menopause Oral Contraceptive Pills Nulliparity Epithelial Cell Tumors Risk Factors Family history of ovarian cancer Infertility (any cause) Polycystic Ovarian Syndrome (PCOS) Endometriosis Tubal ligation: Protective (↓ risk) Possibly related to fallopian tube factors → cancer BRCA1 and BRCA2 BRCA1/BRCA2 genes → DNA repair proteins Gene mutation associated with breast/ovarian cancer Common among Ashkenazi Jews Non-Jewish population in US: 1 in 400 Ashkenazi Jewish population in US: 1 in 40 HNPCC Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome Germline mutation in DNA mismatch repair genes Leads to colon cancer Also increased risk of: Endometrial cancer (most common non-colon malignancy) Ovarian cancer (epithelial serous) CA-125 Cancer Antigen 125 Biomarker for epithelial ovarian cancer Poor performance for screening Useful in evaluating adnexal mass Useful in monitoring response to treatment Serial measurement for follow-up Ovarian Stromal Tumors Jason Ryan, MD, MPH Ovary Structures Oocytes (eggs) Germ cell tumors Supporting cells Theca/granulosa Fibroblasts Sex cord stromal tumors Surface epithelium Adenomas/Carcinomas Wikipedia/Public Domain Stromal Cell Tumors “Sex cord stromal tumors” Fibroblasts, theca cells, granulosa cells Often produce hormones Estradiol (17β-estradiol) Granulosa Cell Tumors Most common ovarian stromal tumor Tumors derived of granulosa-type cells May contain theca cells (“granulosa-theca cell tumor”) Secrete estrogens Usually unilateral May become malignant (“malignant potential”) Granulosa Cell Tumors Adult subtype (95% cases) Median age 50 to 54 years Symptoms from excess estrogen production Juvenile subtype Develop before puberty “Sexual precocity” from excess estrogen production Puberty at very early age (usually < 8 years old) Granulosa Cell Tumors Clinical Features Often present as large adnexal mass Estrogen symptoms Endometrial hyperplasia → uterine bleeding Often bleeding in postmenopausal woman Breast tenderness Associated with endometrial carcinoma Endometrial biopsy often performed Granulosa Cell Tumors Histology Pathognomonic finding: Call-Exner bodies Cells surrounding space filled with pink material Nephron/Wikipedia Fibroma Benign tumors of fibroblasts Solid, white tumor Usually unilateral Ed Uthman, MD/Wikipedia No hormone activity Occur in postmenopausal women Usually present as a pelvic/adnexal mass Two classic clinical associations Ascites Meigs syndrome Ascites and Meigs Syndrome Ascites occurs in 40% cases of ovarian fibroma Meigs syndrome Ovarian fibroma Ascites Pleural effusion Etiology unclear Probably related to capillary leak from tumor factors Removal of tumor resolves ascites and effusion Thecoma Usually co-exist with fibromas (“fibrothecoma”) Pure thecoma: rare May produce estrogens May lead to endometrial hyperplasia/bleeding Sertoli-Leydig Cell Tumor Tumor of Sertoli and Leydig cells Often occur in males as testicular tumors May occur in the ovary Tumor produces androgens Breast atrophy Amenorrhea Sterility (anovulation) Hirsutism Wikipedia/Public Domain Ovarian Germ Cell Tumors Jason Ryan, MD, MPH Ovary Structures Oocytes (eggs) Germ cell tumors Supporting cells Theca/granulosa Fibroblasts Sex cord stromal tumors Surface epithelium Adenomas/Carcinomas Wikipedia/Public Domain Ovarian Germ Cell Tumors Occur in young women Usually 10 to 30 years old Many secrete AFP or β-hCG Tumors of germ cell derivatives Germ layers (Teratoma) Germ cells (Dysgerminoma) Yolk sack (Yolk sac tumors) Placental tissue (Choriocarcinoma) Teratoma Most common overall germ cell tumor Cells from all three germ layers Ectoderm (skin, hair follicles) Endoderm (lung, GI) Mesoderm (muscle, cartilage) Benign form: Dermoid cyst Malignant form: Immature teratoma Rare monodermal forms Dermoid Cyst Mature Cystic Teratoma “Dermoid” = skin like Contain hair, squamous cells, sebaceous (oily) material Walls may contain calcification, tooth-like material Wikipedia/Public Domain Dermoid Cyst Mature Cystic Teratoma Usually asymptomatic, unilateral 10-20% bilateral Characteristic features on ultrasound Mikael Häggström/Wikipedia Dermoid Cyst Mature Cystic Teratoma Usually removed surgically to avoid complications: Torsion Rupture → tumor material in abdominal cavity → peritonitis Small risk (60 years) Phyllodes = Greek word “leaf like” Leaf-like growths of stroma covered by epithelial cells Phyllodes Tumor Nephron/Wikipedia Mammary Duct Ectasia Benign inflammatory condition Affects older women (~50 years old) Classically in multiparous women Distension (ectasia) of subareolar ducts (nipple) Due to chronic inflammation and fibrosis Presents as breast mass Dirty white, greenish or black nipple discharge Usually no pain, erythema Must be differentiated from breast cancer Mammary Duct Ectasia MD Specialclass Fat Necrosis Results from trauma Often biopsy, surgery Sports injury, seatbelt injury Prassa CBSR Many women do not recall a specific trauma Benign, inflammatory process Often mimics breast cancer May present as painless mass in breast Often asymptomatic Calcifications on mammogram Biopsy shows fat necrosis with inflammatory cells Lactational Mastitis Acute Mastitis Occurs in women during breast feeding Trauma to skin around nipple Breast erythema, tenderness Often fever, malaise Most commonly infection with S. Aureus Usual treatment: dicloxacillin or cephalexin Mother should continue nursing Can progress to abscess requiring drainage Periductal Mastitis Squamous Metaplasia of Lactiferous Ducts Inflammation of subareolar ducts More than 90% cases occur in female smokers Smoking toxic to subareolar ducts Smoking may cause relative vitamin A deficiency in ducts Pixabay/Public Domain Periductal Mastitis Squamous Metaplasia of Lactiferous Ducts Inflammation → squamous metaplasia Duct epithelium cuboidal → squamous Periareolar mass with redness, tenderness, warmth Often 2° infection requiring antibiotics Often requires incision/drainage Breast Disorders Summary Fibrocystic changes Cysts, fibrosis, apocrine metaplasia Benign Proliferative breast disorders Epithelial hyperplasia, sclerosis adenosis, papilloma Associated with increased risk Not usually precursors of cancer Stromal tumors Fibroadenoma Phyllodes tumor Breast Disorders Summary Mammary duct ectasia (white discharge) Fat necrosis (trauma) Mastitis (erythema, tenderness) Breast Carcinoma Jason Ryan, MD, MPH Breast Carcinoma Most common non-skin cancer in women 2nd most deadly cancer in women (lung) Mostly a disease of older postmenopausal women Rare before age 25 Incidence increases after age 30 Can occur in men (rare) Breast Carcinoma Risk Factors Female gender (99% of cases) Age (peak incidence 70-80 years) 1st degree relative with breast cancer Mother, sister, daughter Breast Carcinoma Risk Factors Increased estrogen exposure Early menarche/late menopause Obesity Breast feeding = protective Age at first live birth Young (35) = higher risk Breast Carcinoma Detection Palpable breast mass Mammography Detects micro-calcifications Occur in malignant lesions Also seen in fat necrosis and sclerosing adenosis Wikipedia/Public Domain Breast Carcinoma Major Types Ductal versus lobular Ductal = resemble duct cells Lobular = resemble lobules Both types from TDLU In situ versus invasive In situ = limited by basement membrane Terminal Duct Lobule Terminal Duct Lobular Unit Breast Carcinoma Major Types Almost all (95%) are adenocarcinomas Arise from epithelial cells of ducts/lobules At diagnosis >70% have invaded basement membrane Terminal Duct Lobule Terminal Duct Lobular Unit DCIS Ductal Carcinoma In Situ Malignant growth of epithelial cells of TDLU Fills ductal lumen Limited by intact basement membrane Cribriform DCIS KGH/Wikipedia DCIS Ductal Carcinoma In Situ Forms microcalcifications (LCIS does not) Usually detected by mammography Many subtypes based on histology Comedo DCIS Central necrosis Large tumor cells Pleomorphic nuclei High risk Difu Wu/Wikipedia Paget Disease Erythema at nipple due to underlying malignancy Occurs when DCIS extends to nipple May cause bloody nipple discharge Paget cells seen on biopsy Wikipedia/Public Domain Paget Disease Palpable mass in >50% cases ~50% have mass on mammogram Usually invasive carcinoma found Wikipedia/Public Domain LCIS Lobular Carcinoma In Situ Proliferation of cells in ducts/lobules Limited by intact basement membrane “Discohesive growth:” loose intercellular connections Loss of adhesion protein E-cadherin Round cells clumped together Difu Wu/Wikipedia LCIS Lobular Carcinoma In Situ Does not lead to micro-calcifications Usually an incidental finding on biopsy Often bilateral May be multi-focal LCIS Lobular Carcinoma In Situ Risk factor for invasive carcinoma Non-invasive lesion Risk of carcinoma in both breasts Management: surveillance +/- chemoprevention Common drug: Tamoxifen (SERM) Blocks endogenous estrogen effects Tamoxifen Invasive Ductal Carcinoma Most common type (~80%) invasive carcinoma Biopsy: duct cells with stroma Difu Wu/Wikipedia Invasive Ductal Carcinoma Most commonly in outer quadrant of breast More breast tissue Lateral Midline ~50% cases Inflammatory Carcinoma Erythema, swelling of breast (peau d'orange) Dimpling of skin Similar to orange rind Tumor invasion of skin (dermal) lymphatic vessels Mimics infection High grade Poor prognosis Invasive Lobular Carcinoma Cells grow in “single file” Lack of E-cadherin adhesion protein expression Can’t stick together in clumps Often bilateral with multiple lesions Ed Uthman/Wikipedia Breast Carcinoma Prognosis Axillary lymph node metastases Most important prognostic factor for invasive cancer Detected by biopsy Sentinel node biopsy often performed Wikipedia/Public Domain Predictive Markers Important for prognosis and therapy Estrogen receptor positivity (ER+) Progesterone receptor positivity (PR+) Human epidermal growth factor receptor-2 (HER2) Cell surface tyrosine kinase receptor Estradiol (17β-estradiol) Progesterone Predictive Markers ER+ and PR+ tumors May respond to Tamoxifen (SERM) HER2+ tumors May respond to Trastuzumab “Triple negative” tumors Highly aggressive More common in women under 40 Familial Breast Cancer Cause about 10% of breast cancers BRCA1 and BRCA2 gene mutation: Both gene mutations associated with breast cancer Cause of ~85% of single gene familial cases Genes code for DNA repair proteins Also associated with other malignancies BRCA1: Ovarian cancer BRCA2: Male breast cancer and pancreatic cancer BRCA1 and BRCA2 Germline gene mutation Autosomal dominant Incomplete penetrance Not all individuals with disease mutation develop disease Male Breast Cancer Incidence 1% compared to women Usually occurs 60 to 70 years of age Usually presents as subareolar mass +/- discharge Most breast tissue in males near nipple Key associations: Klinefelter syndrome (3 to 8% cases) BRCA2 gene mutations (4 to 14% cases) Penile Disorders Jason Ryan, MD, MPH Penis Anatomy Three cavernous bodies (“the corpora”) Corpus cavernosa: Two large spongy tissue beds Corpus spongiosum: Smaller spongy tissue bed Surrounds urethra Penis Anatomy Esseh/Wikipedia Wikipedia/Public Domain Penis Anatomy Tunica albuginea Latin: “tunica” = covering, “albuginea” = white White connective tissue surrounding corpus cavernosa Buck’s fascia Covers all three erectile structures Penis Anatomy Mcstrother/Wikipedia Penis Physiology Key structures: arterioles and corpora Flaccid penis: High tone of cavernosal arterioles ↓ inflow of blood Erection (tumescence) Smooth muscle relaxation ↑ blood flow Corpora swell (sinusoids) Compress veins/venules ↓ outflow High inflow/low outflow → ↑intracorporeal pressure Penis Physiology Detumescence Smooth muscle contraction Corpora shrink Venous outflow Peyronie Disease Abnormal tunica albuginea Acquired disorder Likely related to trauma in a susceptible individual Localized fibrosis of tunica albuginea Pain Nodule Abnormal curvature when erect Erectile dysfunction SugarMaple/Wikipedia Peyronie Disease Treatment: Pentoxifylline Phosphodiesterase inhibitor Reduces inflammation Prevents collagen deposition Injection or oral administration Penile Fracture Rupture of tunica albuginea Often associated with urethral damage Caused by blunt trauma Audible snap → pain, swelling, ecchymosis Mcstrother/Wikipedia Priapism Persistent erection Lasting more than 2-4 hours Not due to sexual activity Priapism Types Ischemic Most common type (95% of cases) Lack of outflow → tissue ischemia Non-ischemic “High flow” priapism Fistula between arteries and corpus cavernosum Often follows trauma Ischemic Priapism Etiology Failure of cavernosal outflow Two classic causes: Sickle cell and drugs Sickle cell anemia Veno-occlusion Drugs Block smooth muscle contraction Antipsychotics/antidepressants (trazadone, SSRIs) Alpha blockers (doxazosin, tamsulosin, terazosin, prazosin) Erectile dysfunction drugs Ischemic Priapism Treatment Urologic emergency Hypoxia, acidosis of penile blood occurs May cause permanent erectile dysfunction May leads to penile necrosis Treatments: Corporal aspiration Intracavernosal phenylephrine Surgery Condylomata Acuminata Anogenital Warts STD caused by papillomavirus (6, 11) Soft, tan, cauliflower-like lesions “Verrucous” = warts Also seen vulva, perianal area (rectal bleeding) Treatment: Chemical agents Surgical therapy Does not lead to cancer SOA-AIDS Amsterdam/Wikipedia Condylomata Acuminata Histology Peri-nuclear clear vacuolization (koilocytosis) KGH/Wikipedia Squamous Cell Carcinoma Rare penile malignancy Arises from squamous skin cells Occurs in the glans or shaft Occurs in older men (mean age ~60) Rare in US, Europe Common in Africa, Asia, South America Squamous Cell Carcinoma Risk Factors Uncircumcised penis Circumcision: reduced exposure to carcinogens HPV Infection HPV DNA in 30-50% of cases Types 16 and 18 Smoking Squamous Cell Carcinoma Pre-malignant (in situ) lesions In situ carcinoma (no basement membrane invasion) Bowen disease Gray-white plaque (leukoplakia) on shaft of penis Erythroplasia of Queyrat Dark red lesion on glans of penis Bowen disease of the glans Bowenoid papulosis Multiple, red-brown papules Erectile Dysfunction Inability to achieve/maintain an erection Usually psychological component Associated with many conditions Heart disease HTN Diabetes Obesity Certain medications Smoking Alcoholism and other forms of substance abuse Sleep apnea Phosphodiesterase 5 inhibitors Sildenafil, Vardenafil, Tadalafil PDE5 breaks down cGMP in smooth muscle cells Inhibition → more cGMP → relaxation Improved response to NO NO GMP GTP cGMP PDE5 RELAXATION Smooth Muscle Cell Phosphodiesterase 5 inhibitors Uses Erectile dysfunction (improved blood flow) Pulmonary hypertension (↓PVR) Benign prostatic hyperplasia (BPH) Only tadalafil has FDA approval Phosphodiesterase 5 inhibitors Side Effects Contraindicated in patients taking nitrates Life-threatening hypotension Cannot use with nitroglycerine, isosorbide Headache and flushing Priapism NO GMP GTP cGMP PDE5 RELAXATION Smooth Muscle Cell Phosphodiesterase 5 inhibitors Side Effects Vision problems Temporary blue vision (cyanopia) Only reported with sildenafil Drug cross-reacts with PDE-6 in retina Resolves in hours Scrotal Disorders Jason Ryan, MD, MPH Testicular torsion Testicle rotates in scrotum Twists spermatic cord Forms at deep inguinal ring Wikipedia/Public Domain Travels through inguinal canal Enters scrotum through superficial inguinal ring Ends at testes Carries arteries, veins, ductus deferens Testicular torsion Scrotal ligament Secures testis to scrotum Limits movement in scrotum Wikipedia/Public Domain Abnormal function may lead to torsion Allows testes to twist Testicular torsion Compression of thin-walled venous outflow Continued inflow through arteries (thick walled) Engorgement of testicle Hemorrhagic infarction Kalumet/Wikipedia Testicular torsion Neonatal form (rare) Occurs in first 30 days after birth Testes not yet attached to scrotum “Adult” form Boys 12-18 years old Often caused by anatomic defect Lack of attachment testicle to scrotum “Bell clapper deformity:” tunica vaginalis covers cord Increased mobility of testicle in scrotum Testicular torsion Clinical Features Painful, swollen testicle Absent cremaster reflex Stroking inner thigh Normal response: contraction of cremaster muscle Pulls ipsilateral scrotum/testis up Kalumet/Wikipedia Testicular torsion May lead to infertility Treatment: urgent surgery Detorsion (manual or surgical) Orchiopexy (fixation of testicle) Testicle removal (if nonviable) Must treat contralateral testis Kalumet/Wikipedia Varicocele Dilatation of pampiniform plexus of spermatic veins Wikipedia/Public Domain Varicocele Caused by obstruction to outflow of venous blood More common on left Left spermatic vein → left renal (long course) Compressed between aorta and superior mesenteric artery “Nutcracker effect” Right vein drains directly to IVC Associated with renal cell carcinoma Invades renal vein Varicocele Scrotal pain and swelling Dilated veins = “Bag of worms” More swelling with: Valsalva Standing Fisch12/Wikipedia Diagnosed by ultrasound Can cause infertility ↑ temperature Poor blood flow Schomynv /Wikipedia Varicocele Treatment Surgery (varicocelectomy) Isolate dilated/abnormal veins Redirect blood flow to normal veins Embolization Interventional radiology procedure Catheter inserted into dilated/abnormal veins Coil or sclerosants used to clot off veins Hydrocele Accumulation of fluid in tunica vaginalis Small, fluid-filled sac attached to testicle Scrotal swelling Transilluminates with light Differentiates from solid mass (i.e. tumor) Hydrocele Newborn form Incomplete closure of processus vaginalis “Communicating hydrocele” Peritoneal fluid collects in tunica vaginalis Usually resolve spontaneously by 1 year of age Adult form “Noncommunicating hydrocele” Often idiopathic May be 2° to infection, torsion, trauma May become bloody (“hematocele”) Hydrocele Spermatocele Large epididymal cyst Usually at head (top) of epididymis Wikipedia/Public Domain Usually asymptomatic Detected on physical exam Mass at top of testicle Separate from testis Can diagnosis with ultrasound KDS444 /Wikipedia Cryptorchidism “Hidden testes” Usually due to undescended testes Abdominal Inguinal canal Can be unilateral/bilateral Cryptorchidism Complications Low sperm counts ↑ temperature effects on Sertoli cells ↑ risk of germ cell tumors Inguinal hernias Testicular torsion Cryptorchidism Treatment Testes may descend on their own Usually occurs by 6 months of age Orchiopexy Surgical placement of the testis in scrotum Sperm counts usually become normal Testicular Tumors Jason Ryan, MD, MPH Testicular Malignancy Many similarities to ovarian malignancies Key difference: no common epithelial cancers Two main categories: Germ cell tumors Sex cord-stromal tumors Wikipedia/Public Domain Testicular Tumors Germ cell tumors Seminoma and Non-seminomas Embryonal carcinoma, Yolk Sac tumor Choriocarcinoma, teratoma Non-germ cell tumors Leydig cell tumor Sertoli cell tumor Lymphoma Mikael Häggström/Wikipedia Testicular Tumors Usually present as painless, testicular mass Do not transilluminate Often evaluated with ultrasound If cancer suspected: orchiectomy Usually not biopsied Risk of tumor seeding Into scrotum or spread to inguinal nodes Germ Cell Tumors Most common type (95%) of testicular malignancy Usually occur in young men 15-34 years old Key risk factors: Cryptorchidism Kleinfelter syndrome Malcolm Gin/Wikipedia Germ Cell Tumors Always malignant (capable of metastasis) Often a mix of subtypes Highly curable 5-year survival ~95% Seminoma Most common germ cell tumor Same characteristics as dysgerminoma in females Seminoma much more common Dysgerminoma: rare ovarian cancer Wikipedia/Public Domain Seminoma Homogenous mass Grey-white appearing No hemorrhage or necrosis May produce β-hCG Tumor marker in 15% cases Syncytiotrophoblast tissue in tumor Placental alkaline phosphatase Old marker Poor sensitivity Treatment Surgery +/- chemo/radiation Ed Uthman/Wikipedia Seminoma Histology: undifferentiated germ cells Nests of large cells with clear cytoplasm Central nuclei “Fried egg” appearance Nephron/Wikipedia Embryonal Carcinoma Non-seminoma Germ Cell Tumor Usually occurs as component of mixed tumor Pure embryonal carcinoma rare (2% testicular GCTs) Key distinctions from seminoma: Mass with hemorrhage and necrosis Painful May have syncytiotrophoblast tissue Secretes β-hCG Yolk Sac Tumor Endodermal Sinus Tumor Most common GCT children 60 years old Testicular mass may be presenting complaint Extragonadal GCT Extragonadal Germ Cell Tumors Occur in males and females Arise in midline locations Adults: Anterior mediastinum most common Children: Sacrococcygeal and intracranial most common Many types Seminomas/dysgerminomas Teratomas Failure of germ cell migration Prostate Jason Ryan, MD, MPH Prostate Round gland at base of bladder Anterior to rectum Palpation on digital rectal exam Encircles urethra Produces prostatic fluid Stimulated by androgens Wikipedia/Public Domain Acute Prostatitis Acute inflammation of the prostate Usually bacterial Older man Similar organisms to cystitis E. coli most common Also proteus, pseudomonas Sexually-active, younger men Neisseria gonorrhoeae Chlamydia trachomatis Image courtesy Wikipedia/Public Domain Acute Prostatitis Symptoms Fevers, chills, malaise Dysuria, frequency Cloudy urine Digital rectal exam: Prostate edematous/enlarged (“boggy”) Exquisitely tender Workup: Urine analysis (WBC) and culture