Boards and Beyond: Reproductive A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 9-20-2017
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Table of Contents Embryonic Genes Embryogenesis Germ Layers Errors in Morphogenesis
1 4 6 9
TORCH Infections Vaginal Cancer Cervical Cancer Endometrial Disorders
57 61 63 66
Teratogens I Teratogens II Pharyngeal Arches Cleft Lip and Palate Pharyngeal Pouches/Clefts Reproductive Embryology Spermatogenesis/Oogenesis Placenta Twins Pregnancy Maternal-Fetal Disorders
11 16 20 24 25 27 31 34 38 40 44
Endometriosis Endometrial Cancer Ovarian Cysts Ovarian Epithelial Tumors Ovarian Stromal Tumors Ovarian Germ Cell Tumors Breast Tissue Breast Disorders Breast Carcinoma Penile Disorders Scrotal Disorders
69 72 75 77 80 82 85 88 92 97 101
HTN in Pregnancy Placental Complications Gestational Tumors
48 51 54
Testicular Cancer Prostate Sex Chromosome Disorders Hypogonadism
104 108 111 116
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Embryonic Genes •
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Sonic Hedgehog FGF Wnt-7a Homeobox (Hox) genes
Embryonic Genes Jason Ryan, MD, MPH
Sonic Hedgehog Gene
Patterning •
SHH Gene •
Development of body pattern •
Head, arms, legs
Sonic Hedgehog Gene •
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Formation forebrain
Holo = “whole”
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Prosencephalon = forebrain
Key roles:
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Signaling separates right and left brain Establishes midline Mutations: Holoprosencephaly •
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CNS development
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Limb development
Holoprosencephaly
CNS Development •
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Makes Sonic Hedgehog protein Embryonicsignalingprotein Many embryonic roles: limbs, brain, eyes
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Failure of cleavage of prosencephalon
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Left/right hemispheres fail to separate Single-lobedbrain
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Facial abnormalities
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No left/right hemispheres
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Cleft lip/palate
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Cyclopia
Limb Development •
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Limb Development
Limb “patterning” Limbs develop along three planes
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Proximal to distal
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Dorsal-ventral axis
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Limb Development
Humerus radius wrist
Dorsal: Extensors Ventral: Flexors
Anterior-posterior axis •
Anterior: towards head
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Radius and thumb
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Ulna fingers
Apical Ectodermal Ridge
Dorsal
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Ventral
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Critical forproximal to distaldevelopment Ectodermoverlying mesoderm Area of limb bud formation
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Removal: Limb stops growing
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AER Mesoderm Limb Growth
Apical Ectodermal Ridge •
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Influences underlying mesodermal growth •
“Progress zone” forms in mesoderm with growing cells
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Mesoderm also influences ectodermal ridge
Key transcription factor:Fibroblast Growth Factor •
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Dorsal-Ventral Development
From expression of FGF gene
Ridge removed, replaced with FGF: Normal growth
•
Flexors/extensors
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Depends on multiple genes •
Radial fringe (dorsal)
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Engrailed1 (ventral)
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SER2 (border)
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Wnt-7a
Dorsal (extensors) AER
FGF
Mesoderm Limb Growth
AER Mesoderm
Ventral (flexors)
Limb Growth
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Dorsal-Ventral Development •
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Wnt Genes
Wnt-7a key for dorsaldevelopment •
Activates LMX-1 gene in mesoderm
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“Dorsalizes” mesoderm
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Gene deletion: Two ventral sides to limb
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Mouse embryos: sole on both surfaces of paws
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Family of genes
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Originally described in Drosophila
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Found in many species including humans
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Ventral side: Engrailed1 represses Wnt-7
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Winged integration gene
Early embryo: regulators ofdorsal-ventral axis Later embryogenesis:anteroposterior axis
Dorsal (extensors) AER Mesoderm Limb Growth Hikasa H and Sokol S. Wnt Signaling in Vertebrate Axis Specification. Cold Spring Harb Perspect Biol. 2013 Jan (5(1)
Ventral (flexors)
AP Development
Homeobox Genes
Anterior-Posterior
HOXGenes
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Depends onzone of polarizing activity Posterior limb (near little finger) Influences AER
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Major signaling molecule:SHH
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Sonic Hedgehog protein •
Code for transcription factors Regulators of AP axis development Homeotic genes •
Homeosis = transformation of one structure into another
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Homeotic genes = lead to formation of body segments
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Mutation abnormal body part formation
All homeotic genes have same sequences ~180 bases •
Called the Homeobox (part of gene)
Homeobox Genes
Embryonic Genes
HOXGenes
Summary
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Family of genes: HOXA1, HOXB1, HOXD1, etc.
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Rare mutations of some HOX genes described •
Most result in abnormal limb formations
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Fruit flies: legs grow from head instead of antenna!
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Polydactyly (extra fingers/toes)
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Syndactyly (fused fingers/toes)
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Sonic Hedgehog •
Hemispheres of brain holoprosencephaly
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Limb AP axis: zone of polarizing activity AER
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FGF
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Wnt-7a
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Homeobox (Hox) genes
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Limb proximal-distal axis apical epidermal ridge
Limb dorsal-ventral axis
“dorsalizes” limb
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Limb AP axis
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Mutation abnormal digits/toes
Fertilization •
Haploid maturespermatozoon(1N, 1C)
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Haploidovum (1N, 1C)
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Formszygote(2N, 2C)
Embryogenesis Jason Ryan, MD, MPH
DNA Synthesis •
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Maternal/paternal DNA in“pronucleus” 2N, 2C DNA synthesis chromatids2N, 4C
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Zygote divides into two cells (2N, 2C)
Fetal Development •
Morula
Two cell stage: first1-2 days after fertilization
Blastulation
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Cells continue to divide
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Formation ofblastulafrom morula
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Morula = ball of cells
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Blastula contains fluid cavity called blastocoel
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Blastulation
Implantation
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In humans, blastula called blastocyst
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Outer cells: trophoblast
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Polarized: one side different from other
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Watery fluid of blastocoel secreted by trophoblast cells
Inner cell mass (apolar) •
Give rise to all tissues of body
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Embryonic stem cells derived from inner cell mass
Gastrulation •
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Gastrulation •
Blastula 3 layered structure called gastrula Threegerm layers •
Ectoderm
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Mesoderm
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Endoderm
Primitive Streak •
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Blastocyst implants in uterus aboutday 6-10 β-hCG secretionbegins
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Inner cell mass bilaminar disc Two cell layers separated by basement membrane
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Epiblast andhypoblast
Gastrulation
Formed by invagination of epiblast cells
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Creates a visible line(“streak”) in blastocyst Presence indicatesstart of gastrulation
Epiblast three germ layers •
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Ectoderm, endoderm, mesoderm
Gastrulation •
Formation ofgastrula
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Contains threegerm layers •
Ectoderm
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Mesoderm
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Germ Layers
Endoderm
Jason Ryan, MD, MPH
Nervous System Development
Ectoderm •
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Epidermis Nervous system
Nervous System Development •
Notochord arises inmesoderm •
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Nervous System Development •
Adult remnant: nucleus pulposus of spine
Inducesoverlying ectoderm neural plate Neural plate folds neural tube •
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Neural tube: CNS •
CNS neurons, oligodendrocytes, astrocytes
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Retina
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Spinal cord
Neural crest: PNS •
Cranial nerves
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Dorsal root ganglia
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Autonomic ganglia
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Schwann cells
Microglia (phagocytes): Mesoderm Meninges: Mesoderm
Endoderm •
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Mesoderm
GI epitheliumand derivatives
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Liver,gallbladder, pancreas Alveoli, epithelium of trachea/bronchi •
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Airway cartilage from mesoderm
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Mesoderm •
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Manycongenital defects in mesoderm derivatives Congenital heart defects Limb deformities
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Renal defects
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Muscle, bone, connective tissue Cardiovascular structures Kidneys Lymphatics Blood
Mesenchyme •
Embryonic connective tissue •
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Cells surrounded by proteins and fluid Gives rise to mostconnective tissue
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Mesenchymal tumors = sarcomas
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Bones, cartilage, lymphatic and circulatory systems
Embryonic Period
Embryonic Period •
Not found in adults except for mesenchymal stem cells
Mostly derives from mesoderm
Heart Development
First 8 weeks after fertilization
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Week 4
Organogenesisoccurs Must vulnerable period toteratogens Followed by fetal period
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Week 6
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Most adult structure established
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Organs/structures grow
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Heart begins beating
Transvaginal ultrasound detects fetal heart movement
Embryonic Period
Embryonic Period
Limbs
Genitalia
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Week 4 •
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Limbs form
Week 8 •
Baby begins moving •
Week 10 •
Prior to week 10 genitalia look similar for males/females
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SRY gene (Y chromosome)
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Lack of SRY gene clitoris development
penis development
Ultrasound identification of gender Usually week 15 to 20 •
Pituitary Gland •
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Adrenal Gland •
Anterior pituitary (adenohypophysis) •
From Rathke’s pouch of ectoderm
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Outpouching of upper mouth
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Posteriorpituitary (neurohypophysis) •
Cortex:Mesoderm
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From neural tube
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Aldosterone, cortisol, androgens
Medulla: Neural crest Epinephrine, norepinephrine
Morphogenesis •
Process of embryo taking shape
Errors in Morphogenesis Jason Ryan, MD, MPH
Errors in Morphogenesis
Errors in Morphogenesis •
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Intrinsic Errors •
Intrinsic •
Failure of embryo to develop
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Abnormal genes or other internal processes
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Agenesis, Aplasia, Hypoplasia, Malformation
Agenesis •
Missing organ caused by missing embryonic tissue
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Renal agenesis
Extrinsic •
External force impacts normal development
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Disruption, Deformation
Errors in Morphogenesis
Errors in Morphogenesis
Intrinsic Errors
Intrinsic Errors
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Aplasia
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Hypoplasia
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Missing organ due to growth failure of embryonic tissue
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Incomplete organ development
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Thymic aplasia (DiGeorge syndrome)
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Microcephaly
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Errors in Morphogenesis
Errors in Morphogenesis
Intrinsic Errors
Extrinsic Errors
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Malformation
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Disruption
Abnormal developmentof structure Neural tube defects Cleft lip or palate
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Classic example:amniotic band syndrome
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Congenital heart defects
Errors in Morphogenesis
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Deformation •
External force leads to abnormal growth (not arrest)
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Deforms or misshapes structure
Potter’s Syndrome External compression of the fetus
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Alteration in lung liquid content
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Also called Potter’s sequence
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Often involves limbs or digits
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Fetus exposed to absent or↓ amniotic fluid Amniotic fluid = fetal urine Severerenal malfunction = ↓ amniotic fluid
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Loss of fetal cushioning to external forces
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Classic example:Potter’ssyndrome
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Fetal structures entrapped by fibrous bands in utero
Potter’s Syndrome
Extrinsic Errors •
Normal tissue growth arrested due to external force
Abnormal face/limb formation
Abnormal lung formation
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Teratogens •
Substances that causeabnormal fetal development
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Common effects: •
Fetal loss
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Growth restriction
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Teratogens I
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Birth defects Impaired neurologic function
Jason Ryan, MD, MPH
Teratogens •
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Teratogen Timing •
Many mechanisms: •
Cell death/apoptosis
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Disrupted metabolism
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Disrupted cell growth/proliferation
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Greatest risk of fetal exposure1st trimester •
Embryonic period
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Formation of organs
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Teratogens •
Drugs
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Substances of abuse •
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Radiation Chemicals (mercury) Maternal illness Diabetes
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Phenylketonuria (PKU)
Infectious agents •
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“All or none” period
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Spontaneous abortion or no effect
Weeks 2-8 •
Organogenesis
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Structural defects
After week 8 •
Decreased growth
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Central nervous system dysfunction
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Usually no birth defects
Drug Testing
Alcohol, cocaine, smoking
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First two weeks
TORCH: Toxoplasmosis, Other, Rubella, CMV, Herpes
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Animals •
FDA requires all drugs be tested in animal models
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Often rodents (rats)
Case reports
Drug Categories •
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ACE Inhibitors and ARBs
FDA labels drugs during pregnancy in categories
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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
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Drugs known to be teratogenic in animals and humans
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Risks clearly outweigh benefits
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Seizure Drugs •
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Women with epilepsy may require drugs in pregnancy All anti-seizure drugs may affect fetus
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Fetal renal failure Can lead to Potter’s syndrome
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Pulmonary hypoplasia, limb/skeletal deformities
High risk drugs •
Valproic acid (↑↑ neural tube defects)
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Neural tube defects
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Phenytoin
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Congenital heart disease
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Phenobarbital
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Cleft palate
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Carbamazepine
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Short fingers
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Abnormal facial features
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Fetal Hydantoin Syndrome •
Decreased fetal kidney function
Seizure Drugs
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1st trimester: numerous congenital malformations 2nd/3rd trimester: Oligohydramnios •
Category D: positive evidence of risk Category X: contraindicated in pregnancy •
Pregnancy class D
Many anti-seizure drugs associated with ↓ folic acid
↓ folic acid neural tube defects High dose folic acid supplementation
Chemotherapy
Associatedwithphenytoinuse in pregnancy Growth deficiency Abnormal facial features
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Rarely women develop malignancy while pregnant
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Ideally chemotherapy deferred
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Hodgkin lymphoma
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Broad, short nose
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After birth
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Wide-spaced eyes
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2nd/3rd trimester
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Malformed ears
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Microcephaly
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Classicallycleft lip and cleft palate
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Fetal malformations 15% with therapy inst1trimester
Chemotherapy
Isotretinoin
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Highest risk: alkylating agentsand antimetabolites
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Adverse effects on fetus:
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Spontaneous abortion
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Missing digits
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Many other fetal abnormalities
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Vitamin A Excess •
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Used to treat acne Pregnancy class X Spontaneous abortions (~20%)
“Embryopathy”:20-30% of live births •
Abnormal facial features (low ears, wide-spaced eyes)
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Congenital heart disease
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Hydrocephalus
Birth control mandatory
Methotrexate •
Teratogenic in first trimester Spontaneous abortions
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Microcephaly Cardiac anomalies
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Occurs at doses several times RDA
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Derivative of vitamin A
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Inhibits folate metabolism Used as anti-inflammatory
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Pregnancy class X
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May cause neural tube defects
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Methotrexate
Vitamin A
Aminopterin/methotrexate •
Neural tube defects
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Abnormal skull/face shape
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Cleft palate
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Hydrocephalus
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Limb anomalies
Methotrexate
Folate
Warfarin
Methotrexate •
Used to induce abortion in ectopic pregnancy
embryopathy
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Warfarin Embryopathy
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Folate
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Anticoagulant Pregnancy class D Fetal hemorrhage, spontaneous abortion Optic atrophy (vision loss)
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Bone and cartilage abnormalities
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Stippled epiphyses: small, round densities on X-ray
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Nasal hypoplasia
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Limb hypoplasia
Methimazole •
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Treatment for hyperthyroidism
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Pregnancy class D May cause fetal and neonatal hypothyroidism Aplasia cutis: absence of epidermis on scalp •
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Lithium •
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st trimester Propylthiouracil (PTU) used in 1
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Antibiotics •
Aminoglycosides •
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Reports of permanent deafness in fetus •
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May disrupt folate metabolism in fetus neural tube defects
Sulfonamides
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Accumulate in fetal teeth and long bones
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Displace bili rubin from albumin
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May permanently discolor fetal teeth
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Can cause kernicterus
Fluoroquinolones Fetal cartilage damage
Thalidomide •
Trimethoprim •
Tetracycline
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Pregnancy class D Teratogenic effects primarily involve heart Ebstein’sanomaly most common
Solitary defect on scalp ~70% of cases Missing patch skin/hair
Antibiotics •
Used in psychiatric disorders
Diethylstilbestrol
Pregnancy class X
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Rarely used for treatment of multiple myeloma Used in 1950s as sedative in pregnancy Limb deformities •
Amelia: absence of li mb
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Micromelia: short limbs
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Phocomelia: abnormal limb
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Female babies: Reproductive tract abnormalities
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Nonsteroidal estrogen Used to prevent miscarriage, premature birth Removed from US market 1971 Slightly increased risk of breast cancer for mothers
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Diethylstilbestrol •
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Hypoplasticuterus Cervicalhypoplasia Vaginal adenosis •
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Metaplasia of cervical or endometrial epithelium in vagina Persistent Müllerian tissue after birth
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Vaginal clear cell adenocarcinoma
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High rate of infertility
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Teratogens •
Drugs
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Substances of abuse
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Radiation
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Teratogens II
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Jason Ryan, MD, MPH •
Chemicals(mercury) Maternal illness •
Diabetes
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Phenylketonuria (PKU)
Infectious agents •
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Facial Features •
Neurotoxin •
Multiple mechanisms: Cell death, failure of cell migration
Characteristic facial features
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Congenital heart defects
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Skeletal anomalies
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Intellectual disability
Smooth philtrum •
May causefetal alcohol syndrome (FAS) •
TORCH: Toxoplasmosis, Other, Rubella, CMV, Herpes
Alcohol
Alcohol •
Alcohol, cocaine, smoking
Groove from base of nose to upper lip
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Short palpebral fissures
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Thin vermillion border
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Small opening of eyes
Upper lip
Alcohol
Alcohol
Heart Defects
Growth/Skeletal
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Congenital heart defects •
Atrial septal defect
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Ventricular septal defect
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Tetralogy of Fallot
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Below average height, weight
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Limb defects •
Finger contractions
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Congenital hip dislocations
Alcohol
Alcohol
CNS •
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Structuraldefects
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First trimester
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Microcephaly
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Facial abnormalities
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Small corpus callosum, cerebellum, basal ganglia
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Brain abnormalities
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Congenital heart disease
Abnormal reflexes •
Hypotonia Cranial nerve deficits
Third trimester Mostly affects size of baby, brain gr owth •
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Intellectual impairment (reduced IQ)
Intellectual impairment: •
Smoking •
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Smoking •
Two toxins:Nicotine and carbon monoxide Impaired oxygen delivery to the fetus
Nicotine-induced vasoconstriction
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CO competes with O2 ↓ oxyhemoglobin
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Cocaine
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Miscarriage
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20% cases associated with smoking
Placental anomalies •
Abruption
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Previa
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Premature rupture of membranes
Preterm labor Well-documented association withSIDS
Mercury
Vasoconstriction IUGR/low birthweight Placental abruption Preterm birth
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IUGR/Low birthweight •
↓ placental blood flow
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May occur without facial or brain anomalies
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Methylmercury found infish/seafood •
Not removed by cooking
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Highest levels: swordfish, shark, tilefish, Mackerel King
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Fetal brain highly sensitive to mercury
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Delayed milestones
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Rarely blindness, deafness, or cerebral palsy
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Mother not usually affected
CH3 - Hg Methylmercury
X-rays •
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No evidence of harm at small doses
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Threshold for harm not definitively determined Higher dosages 8-15 weeks may cause: •
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Maternal Diabetes
Intellectual disability Microcephaly Growth restriction
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Increased growth
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Blood sugar alterations
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Congenital heart disease
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CNS disorders
Adverse effects related to severity of diabetes
Lead shieldingused to protect fetus
Maternal Diabetes •
Multiple effects on fetus:
Maternal Diabetes •
Macrosomia(large baby)
Neonatal Hypoglycemia
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Baby born large for gestational age
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Baby makes excess insulin (“hyperinsulinemic state”)
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Weight >90th percentile is common
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Blood glucose levels below 40 mg/dL
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Babies often >9lbs at birth
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Transient: usually the first 24 hours of life
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Close glucose monitoring after delivery is essential
Can lead to birth injury •
Shoulder dystocia (shoulders cannot pass through birth canal)
Caudal Regression Syndrome
Maternal Diabetes
Sacral Agenesis
Congenital heart defects: 3-9% of babies
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Classically associated with maternal diabetes
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Incomplete development ofsacrum
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Transposition of the great arteries (TGA) Ventricular septal defects (VSDs) Truncus arteriosus
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May includesirenomelia
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Tricuspid atresia
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Patent ductus arteriosus (PDA)
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Usually children of insulin-dependent mothers
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“Mermaid syndrome”
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Fusion of legs
Often includes a neural tube defect
Phenylketonuria •
Maternal PKU •
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Phenylketonuria Phenylalanine •
Occurs in women with PKU who consume phenylalanine
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High levels of phenylalanine acts as a teratogen Serum phenylalanine monitored in pregnancy
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Dietary restriction of phenylalanine essential
IUGR Microcephaly
Intellectual disability (mental retardation) Congenital heart defects •
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Phenylalanine
Coarctation of the aorta Hypoplastic left heart syndrome
Pharyngeal Apparatus •
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Embryonic structure Key for development ofhead and neck
Pharyngeal Arches Jason Ryan, MD, MPH
Terminology •
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Pharyngeal Apparatus •
Branchia: Greek word for gills
“Branchial”: relating to gills Humans: similar embryonic structures Branchial or pharyngeal
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Gives rise tocartilage/boneand muscles
Neural crest cells migrate to center •
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Pharyngealpouches
Bones
Core ofmesenchyme(connective tissue) •
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First Pharyngeal Arch
Pharyngeal Arches •
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Three components Pharyngealarches Pharyngealclefts
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Gives rise tocranial nerves
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Artery forms aortic arches
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“Maxillaryprocess” •
Maxilla
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Zygomatic bone
“Mandibularprocess” •
Mandible
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incus and malleus Meckel’s cartilage
First Pharyngeal Arch
First Pharyngeal Arch
Muscles
Trigeminal Nerve
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Muscles of mastication •
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Temporalis, masseter, pterygoids
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Anterior digastric
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Mylohyoid
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Tensor tympani (ear)
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Trigeminalmandibular and maxillary divisions Sensory to face Motor: muscles of mastication
First Pharyngeal Arch
Second Pharyngeal Arch
Aortic Arch
Bones
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Portion ofmaxillary artery
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“Reichert’scartilage” Stapes (ear) Styloid process of temporal bone Lesser horn of hyoid
Second Pharyngeal Arch
Second Pharyngeal Arch
Muscles
Nerve
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Stapedius (ear)
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Auricular muscles (ear) Stylohyoid Posteriordigastric
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Muscles of facial expression
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Facial nerve
Second Pharyngeal Arch
Third Pharyngeal Arch
Artery
Cartilage/Bones
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Stapedialartery •
Embryonic vessel
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Usually involutes in development
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Hyoid bone •
Body and greater horn
Hyoid artery •
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Embryonic vessel Develops into small branch of internal carotid
Third Pharyngeal Arch
Third Pharyngeal Arch
Muscles
Nerve
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Stylopharyngeus
Third Pharyngeal Arch
Glossopharyngeal nerve (IX)
Fourth and Sixth Arches
Artery •
Common carotid
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Fifth arch does not persist in humans
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Proximal internal carotid
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4th/6th: both innervated byvagus nervebranches
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4th: superior laryngeal
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6th: recurrent laryngeal
Fourth and Sixth Arches
Fourth and Sixth Arches
Cartilage
Muscles
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Both arches fuse to formlarynx cartilage •
Thyroid
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Cricoid
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Arytenoid
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Corniculate
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Cuneiform
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Cricothyroid
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Levator palatini Pharyngeal constrictors
6th Arch •
Intrinsic muscles of larynx
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(except cricothyroid)
Pharyngeal Arches
th
4 Arch •
Left: aortic arch
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Right: proximal right subclavian artery
6th Arch (“pulmonaryarch”) •
Left: proximal pulmonary artery
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Left: ductus arteriosus
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Right: proximal pulmonary artery
TreacherCollins Syndrome •
4th Arch
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Arteries
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Laryngeal muscles
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Fourth and Sixth Arches •
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Tongue
First archsyndrome
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Failure of neural crest cell migration Underdeveloped facial bones
Anterior two thirds: 1st and 2nd arches •
Lingual swellings and tuberculum impar
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Sensation: CN V (1st arch)
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Taste: CN VII (2nd arch)
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Small mandible (mandibular hypoplasia)
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Small jaw (micrognathia)
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Absent/small ears
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Sensory: GP Nerve (IX) of 3rd arch
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Glossoptosis (retraction of tongue)
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Some posterior taste via CN X (4th arch)
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May lead to difficulty breathing
Posterior third: 3rd and 4th arches
Motor:
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Underdeveloped lower jaw
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Hypoglossal (XII)
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Obstruction of airway by tongue
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One exception: palatoglossus (CN X)
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Cleft Lip and Palate •
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Cleft lip: most common craniofacial malformation Often occurs with cleft palate Multifactorialetiology •
Environmental, genetic
Cleft Lip and Palate Jason Ryan, MD, MPH
Cleft Palate
Cleft Lip •
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Primary palate (front of palate) Formed by fusion of structures Nasal prominences fuse: form philtrum
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st pharyngeal arch Maxillary prominences from 1
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Fuse with medial nasal prominences to form 1° palate Failure of this process leads to cleft lip Maxillary Prominence
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Secondary palate (back of palate) Lateralstructures:palatal shelves (processes) Fusion to form 2° palate
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Failure leads to cleft palate
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Nasal Prominences
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Pharyngeal Apparatus •
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Pharyngeal Pouches and Clefts
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Three components Pharyngealarches Pharyngealclefts Pharyngealpouches
Jason Ryan, MD, MPH
1st Pharyngeal Pouch
Pharyngeal Pouches •
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Four pharyngeal pouches Composed ofendoderm
2nd Pharyngeal Pouch •
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Forms many portions ofinner ear Eustachian tube Middle ear cavity
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Contributes to tympanic membrane
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3nd Pharyngeal Pouch
Lining ofpalatine tonsils(back of throat)
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2nd pouch forms buds Invaded by mesoderm Invaded by lymphatic tissue
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Thymus(mediastinum) Left and right inferior parathyroid glands(neck) Forms two“wings” •
Dorsal (back): Thymus
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Ventral (front): Parathyroid
DiGeorge Syndrome
4th Pharyngeal Pouch
Thymic Aplasia
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Superior parathyroid glands
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Ultimobranchial body
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Incorporates into thyroid gland
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Forms C-cells (calcitonin)
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Also forms two“wings” •
Dorsal (back): Parathyroid
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Ventral (front): Ultimobranchial body
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Also contributes to tympanic membrane
2nd through 4th clefts form cervical sinus •
Temporary cavity
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Obliterates in development
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Branchial Cleft Cyst •
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Often occur in children Mass does not move with swallowing Contrast withthyroglossal duct cyst •
Midline neck mass
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Moves with swallowing
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Loss of thymus (Loss of T-cells, recurrent infections) Loss of parathyroid glands (hypocalcemia, tetany)
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Congenital heart defects (“conotruncal”)
Branchial Cleft Cyst
Four pharyngeal clefts Lined byectoderm 1st cleft develops into external auditory meatus •
Most cases: 22q11 chromosomaldeletion Abnormal thymus, parathyroid function Classic triad: •
Pharyngeal Clefts •
Failure of 3rd/4th pharyngeal pouch to form
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Present asneckmass •
Location based on cleft of srcin
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2nd cleft cysts are most common
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Below angle of the mandible
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Anterior to sternocleidomastoid muscle
Often noticed when become infected Fistula to skin may develop
Genital System •
Chromosomal sex determined at fertilization
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Later development:
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Genital Embryology
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XX (female) or XY (male)
Gonads (ovaries/testes) Internal genitalia External genitalia
Jason Ryan, MD, MPH
Gonads
Testis
Testis/Ovaries •
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Gonadal ridgesform about 7 weeks Derived frommesenchyme(mostly mesoderm) Germ cells derived from epiblast
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Invade gonadal ridges
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Failure to reach ridges : gonads do not develop Male/female gonads initially identical •
“Indifferent gonad”
Ovary •
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SRY gene(Y chromosome) Codes for testis determining factor Forms Sertoli and Leydig cells
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Leydig cells produce testosterone
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Testosterone male development
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Medullary (testis) cords form
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Expand out of testis connect to genital ducts
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Genital Ducts
Medullary cords regress
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Cortical cords develop form clusters Surround germ cells Oogonia and follicular cells form primordial follicles
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Two pairs of genital ducts in embryo •
Mesonephric (wolffian)
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Paramesonephric (müllerian)
Mesonephros: interim kidney 1st trimester •
Associated duct: mesonephric duct
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Paramesonephric duct: formed near mesonpehric duct
Genital Ducts
Genital Ducts •
Male
Develop into internal genital tracts
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Sertoli cells: Müllerian inhibitory factor (MIF)
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Male: epididymis, vas deferens, seminal vesicles
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Suppress development of paramesonephric ducts
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Female: fallopian tubes, uterus, upper vagina
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Male remnant: appendix testis (tissue at upper testis)
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Leydig cells: Androgens •
Stimulate development of mesonephric ducts
Testosterone
Genital Ducts
Genital Ducts
Male
Male
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Mesonephric ducts elongate to form: •
Epididymis
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Ductus (vas) deferens
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Seminal vesicles
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Ejaculatory ducts
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Epididymis •
Duct behind testis
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Transport sperm from seminiferous tubules to vas deferens
Ductus deferens (vas deferens) •
Transport sperm from epididymis to ejaculatory ducts
Testosterone
Genital Ducts
Genital Ducts
Male
Female
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Seminal vesicles •
Glands behind bladder
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Secrete about 75% of fluid in semen
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Connect with ejaculatory ducts Collect sperm/fluid from seminal vesicles and vas deferens
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Pass through prostate
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Connect to urethra
Paramesonephric ductsform internal structures
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Fallopian tubes
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Uterus
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Upper 2/3 vagina
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Ejaculatory ducts •
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28
Only occurs in absence of MIF and androgens
Gartner's Duct •
Wolffian/mesonephric remnantin females
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Found on vaginal walls
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May form cyst
Urogenital Sinus
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Upper portion: bladder
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Pelvic (middle) portion: prostate and prostatic urethra
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Phallic portion: penile urethra
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Urogenital sinus forms male/female structures
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Forms urogenital sinus and anal canal
“Lateral fusion defects” most common •
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Failed fusion of two sides of uterus
May cause infertility, pregnancy loss
Females •
Upper portion: bladder
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Pelvic portion: Inferior vagina
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Connects with paramesonephric ducts
Uterine Anomalies •
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Uterine Anomalies
Males •
Cloacadivides •
Urogenital Sinus •
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Uterine Anomalies
Most common:septate uterus •
Septum divides uterus
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Two endometrial cavities
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Defect in resorption of septum between Müllerian ducts
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Bicornuate: Fundus is indented
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Unicornuate: Uterus connects to one ovary
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Uterine didelphys (double uterus)
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Treatment: septoplasty
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29
Partial fusion of the Müllerian ducts
Other ovary not connected to uterus
Müllerian ducts fail to fuse
External Genitalia
External Genitalia Male
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Begins with indifferent stage
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Genital tubercle elongates phallus
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Four key structures
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Urogenital folds close penile urethra
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Urogenital sinus glands
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Genital tubercle
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Urogenital sinus (from cloaca)
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Urogenital folds (from cloaca) Labioscrotal (genital) swellings
Hypospadia •
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Congenital anomaly of male urethra Ventral opening of urethra Failure of urethral folds to close
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Cryptorchidism in ~10% of patients
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Prostate gland Bulbourethral glands (of Cowper)
Labioscrotal swelling scrotum
Epispadia •
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Urethral opening on dorsal side of penis Much less common than hypospadia Abnormal position/formation of genital tubercle
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Commonly occurs withbladder extrophy
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External Genitalia
External Genitalia
Male
Female
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Requiresdihydrotestosterone •
Testosterone DHT
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Enzyme: 5α-reductase
5α-reductase deficiency •
Ambiguous genitalia until puberty
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At puberty: ↑ testosterone
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Genital tubercle elongates clitoris
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Urogenital folds (no fusion) labia minora
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Urogenital sinus glands
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Paraurethral glands (Skene)
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Bartholin glands
Labioscrotalswelling labia majora Requires estrogen >> androgen
30
Gametogenesis •
Spermatogenesis and Oogenesis
Development of haploid gametes •
Male and female sex cells
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Sperm
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Oocytes
Jason Ryan, MD, MPH
Primordial Germ Cells •
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Common srcins of spermatozoa and oocytes Derived from epiblast cells Migrate to reside among endoderm cells of yolk sac
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During 8th week: migrate togenital ridge
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Spermatogenesis •
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Meiosis •
Diploid cells give rise to haploid cells (gametes)
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Unique to “germcells”
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Spermatocytes
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Oocytes
Begins at puberty •
Sex cords in testes develop a lumen
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Become seminiferous tubules
Spermatogenesis occurs inseminiferous tubules
Meiosis Blue = Paternal Red = Maternal
Meiosis I
Chromosome content of cells: •
2n 2C (diploid)
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2n 4C (diploid)
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1n 2C (haploid)
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1n 1C (haploid)
Meiosis II
2n 4C
2n 2C DNA Synthesis
1n 2C 1n 1C
31
Spermatogonia •
2n 2C cells
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Derived from primordial germ cells
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Precursors of spermatozoa
Spermatogenesis •
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1° spermatocytes •
2n, 4C cells from spermatogonia
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DNA synthesis completed
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Starting meiosis I
2° Meiosis spermatocytes I completed •
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Haploid (1n 1C)
Undergo spermiogenesis •
Form spermatozoa (sperm)
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Singular: spermatozoon
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Sertoli Cells •
Line walls of seminiferous tubules
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Support and nourish developing spermatozoa
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Regulate spermatogenesis Stimulated by FSH Supported by Leydig cell testosterone (paracrine)
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Need FSH and LHfor normal spermatogenesis
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1n, 2C cells
Formation of spermatozoa
Spermatids •
Starting meiosis II
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Spermiogenesis
Spermatogenesis •
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Formation ofacrosome •
Cap of sperm
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Contains enzymes to assist in fertilization
Condensation of nucleus Formation of neck and tail Shedding of most of cytoplasm
Sertoli Cells •
32
Formblood-testis barrier •
Tight junctions between adjacent Sertoli cells
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Apical side (toward tubule): meiosis, spermiogenesis
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Basal side: spermatogonia cell division
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Isolates sperm; protection from autoimmune attack
Seminiferous Tubules •
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Oogenesis
Spermatogonia •
Germ cells
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Behind blood-testis barrier
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Separated from tubule by Sertoli cells
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Primordial germ cells oogonia (2n 2C)
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Oogonia divide in utero
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Oogonia 1° oocytes (2n 4C) Maximum number formed by 5th month in utero
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Surrounded by cells primordialfollicle
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Sertoli cells Line tubules
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Support/regulate spermatogenesis
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Form blood testis barrier
Leydig cells •
Found in interstitium (between tubules)
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Secrete testosterone
Oogenesis •
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About 7 million
Oogenesis •
Primary oocytes: diploid cells formed in utero •
Beginning meiosis I
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Arrested in prophase of meiosis I until puberty
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At puberty •
Menstrual cycles begin
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A few primary oocytes complete meiosis 1 each cycle
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Some form polar bodies degenerate
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Some form 2° oocytes
2° oocytes (1n 2C)
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33
Meiosis II begins
arrests in metaphase
No fertilization: oocyte degenerates Fertilization completion of meiosis II Forms ovum (1n 1C)
Placenta •
Nutrient and gas exchange between mother/fetus
Placenta Jason Ryan, MD, MPH
Decidual Reaction •
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Endometrium reaction at implantation Decidua= altered uterine lining during pregnancy Decidua basalis •
Uterus at site of implantation
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Interacts with trophoblast
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Decidua capsularis •
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Membranes
Surrounds fetus
Decidua parietalis •
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Inner membrane that covers fetus
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Holds amniotic fluid
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Protects embryo
Chorion •
Membrane that surrounds amnion/embryo
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Derived from trophoblast
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Supports fetus and amnion
Opposite wall of uterus
Placental Terminology •
Amnion
Trophoblast
Basal plate •
Maternal side of placenta
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In contact with uterine wall
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Includes maternal decidua basalis
Chorionicplate •
Fetal side of placenta
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Chorion at placenta
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Gives rise to chorionic villi
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Outer layer of blastocyst
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Develops into placenta
Trophoblast
Chorionic Villi
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Proliferates into two cell layers
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Outer layer:syncytiotrophoblast
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Syncytiotrophoblast: outer layer
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Innerlayer: cytotrophoblast
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Contact area with maternal blood
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Invades endometrium
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Finger-like projections: vil li
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Form lacunae (spaces) for maternal blood
Cytotrophoblast: inner layer •
Proliferates cells migrate into syncytiotrophoblast
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Secretes proteolytic enzymes to aid invasion
Chorionic villi: projections of both layers •
Contact with maternal blood
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Nutrient/gas exchange
Chorionic Villi •
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Fetal mesoderm invades villi Branches of umbilical artery/vein grow
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Eventually connects to umbilical cord
Placental Circulation •
Maternal side •
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Placental Barrier
Endometrial (spiral) art villous space endometrial vein
Fetal side •
Umbilical arteries (deoxygenated blood)
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Umbilical arteries
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Capillaries umbilical vein (oxygenated blood)
chorionic arteries capillaries
Umbilical Cord
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No mixing of maternal/fetal blood
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Connection between embryo and placenta
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Oxygen and carbon dioxide diffuse
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Derives from fetus
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Facilitated transport of glucose Active transport of amino acids IgG antibodies (not IgM)
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Some other nutrients, drugs, infectious agents
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Contains umbilical arteries and veins Yolk sac
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Allantois
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Cavity (sac) formed in early embryogenesis
Outpouching of hindgut
Pharyngeal Pouches
Allantois Esophagus
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Outpouching from wall of gut
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Walls formumbilical blood vessels
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Celiac
Foregut
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Trunk
Yolk Sac
Lumen occludes in development Becomes urachus •
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SMA
Fibrous remnant of allantois Connects bladder to umbilicus
Midgut
Allantois IMA
Hindgut
Cloaca
Umbilical Cord •
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Two umbilical arteries •
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Single Umbilical Artery
Deoxygenated fetal blood to placenta
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One umbilical vein •
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Oxygenated fetal blood from placenta
Umbilical Cord •
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Contains mucopolysaccharides
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Similar to vitreous humor
Connects fetal bladder to umbilical cord
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Obliterates in development
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Becomes urachus
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Duct sometimes seen in umbilical cord
Aneuploidy
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Congenital malformations
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Remnant of allantois
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Connection between bladder and umbilical cord
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Allantoic duct •
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Urachus
Wharton jelly •
Abnormal variant Often identified on prenatal ultrasound Associated withfetal anomalies
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36
In adult: median umbilical ligament May cause adenocarcinomaof bladder
Urachus Anomalies •
Patent urachus •
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Urine discharge from umbilicus
Vesicourachal diverticulum •
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Immunology of Pregnancy
Diverticulum of bladder
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Urachal cyst •
Partial obliteration
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Fluid-filled cavity
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May become infected
37
Fetus: foreign antigens •
Half of genes from father
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HLA proteins differ from mother
Protected from maternal immunity by placenta Several mechanisms •
Trophoblast cells do not express many MHC class I antigens
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Placenta secretions block immune response
Twins •
One pregnancy: two babies
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Dizygotic twins •
Two zygotes
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Two separate ova fertilized by two separate sperm
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Twins
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Jason Ryan, MD, MPH
Twins •
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Resorption of fetus/embryo
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Delivery of single baby
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More fetuses = shorter pregnancy •
Single fetus ~ 40 weeks
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Twins ~ 37 weeks
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Triplets ~ 33 weeks
Monozygotic Twins •
May have a single shared placenta
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Variable number of amnions, chorions
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Depends on when zygote divides
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One zygote divides in two
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One ova fertilized by one sperm
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“Identical twins”
Dizygotic Twins
Often one twin dies in utero •
Two siblings born from single pregnancy “Fraternal twins”
Monozygotic twins
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Each baby has own amnion and chorion “Dichorionicdiamniotic”
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Two separate placentas
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Common in mothers using IVF
Monozygotic Twins •
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Days 1-3 •
May have two placentas
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Dichorionic, diamniotic
Days 4–8 •
Chorion already under development
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Monochorionic diamniotic
Days 9-12 •
Chorion and amnion already under development
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Monochorionic monoamniotic
Day 13+ •
Also monochorionic monoamniotic
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May results inconjoined twins
Twin Pregnancies •
Increased risk of maternal/fetal complications
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Fetus •
Growth restriction
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Congenital anomalies
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Preterm delivery
Maternal •
Gestational hypertension/preeclampsia
39
Pregnancy Dating •
Embryonicage
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Gestational age
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Pregnancy
Age dated to fertilization
Age dated to last menstrual period Embryonic age plus two weeks
Jason Ryan, MD, MPH
Fertilization •
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Implantation •
Occurs within 1 day of ovulation Usually occurs in the ampulla of fallopian tube
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Occurs about 6 days after ovulation Syncytiotrophoblast secretes hCG
HCG
HCG
Human chorionic gonadotropin
Human chorionic gonadotropin
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Similar structure toluteinizing hormone (LH) •
Two glycoprotein subunits (“heterodimeric glycoprotein”)
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α and β subunits
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LH and hCG: same α subunit
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Also same α subunit in FSH and TSH
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Maintains corpus luteum
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Corpus luteum continuesprogesterone release
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Binds LH receptors in corpus luteum
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Prevents menstruation Maintains pregnancy for first 10 weeks
HCG
HCG
Human chorionic gonadotropin
Human chorionic gonadotropin
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Used to detect pregnancy
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Usually antibody based tests (ELISA variants) Detect β subunit of hCG •
Serum tests •
Most sensitive method for detecting hCG
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Can detect very low levels 1-2mIU/mL
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May be positive within 1 week of conception
Urine tests 20 to hCG threshold •
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Human placental lactogen
Syncytiotrophoblast •
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Secretes hCG Begins progresterone synthesis about 10 weeks
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Placenta maintains pregnancy going forward
50mIU/mL
May not be positive until 2 weeks or more
Chorionic somatomammotropin •
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Protein hormone Producedby syncytiotrophoblast
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Higher levels as placenta grows during pregnancy
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Blocks effects of insulin •
Raises blood glucose level (good for baby)
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Promotes breakdown of fatty acids by mother for fuel
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Promotes breakdown of proteins for fuel
Physiologic Changes
Diabetes in Pregnancy
Plasma Volume
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Pregnancy is aninsulin-resistant state
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Total body volume expands
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Decreased maternal response to insulin
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Blood fills placenta
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Diabetes mellitus
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Worsened by pregnancy
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Gestational diabetes
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Screening with serum glucose testing
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Onset of diabetes during pregnancy
Glycosuria occurs in normal pregnancy
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Diverted from maternal circulation ↑ renin salt/water retention
Physiologic Changes
Physiologic Changes
Red Cell Mass
Hemodynamics
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Red cell mass expands
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Increased maternal EPO
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Dilutional anemia •
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Rise in volume > rise in red cells
Preload increased by rise in blood volume
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Afterload reduced due to fall in systemic vascular resistance
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Maternal heart rate rises slightly
Supine Hypotension
Hemodynamics
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Result: ↓ Hct
Physiologic Changes •
Cardiac output rises
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Peripheral resistancefalls •
Placenta is a low resistance system
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Also maternal vasodilation
Blood pressure normally falls
Parallel 1 =
Rtotal
1 R1
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Occurs in later stages of pregnancy Large baby compresses IVC when lying flat Decreased venous return (preload)
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Fall in cardiac output
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Reflex tachycardia may produce symptoms
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Series 1 +
R2
Rtotal = R1 + R 2
Physiologic Changes
Physiologic Changes
Coagulation
Pulmonary
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Pregnancy is a hypercoagulable state
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Ventilation increases
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Probably evolved to protect against blood loss at delivery
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More CO2 to exhale
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Many clotting factor levels change
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Also hormone-induced
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Increased fibrinogen
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Decreased protein S
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Fetus also obstructs venous return DVTs common
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Mostly due to increased tidal volumes Respiratory rate minimally changed
Labor
Terbutaline/Ritodrine
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Regular uterine contractions
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Progressive dilation of cervix
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Descent and expulsion of fetus Normally occurs at 40 weeks
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Preterm labor <37 weeks
Apgar Score •
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β-2 agonists ↑ cAMP Relax uterine (smooth) muscle Inhibit contractions
Pregnancy Termination •
Used to access newborn immediately after birth 10 point scoreat 1 and 5 minutes after birth Value of 0, 1, or 2 for five categories: •
Heart rate
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Respiratory effort
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Muscle tone
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Reflex irritability
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Skin color (pink, blue)
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5-min score ≤3 associated with neurologic damage •
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Cerebral palsy
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Mifepristone •
Anti-progesterone
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Blocks progesterone effects on uterus
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Prevents implantation
Misoprostol •
Synthetic prostaglandin E1 analog
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Induces uterine contractions
Combination: Medical abortion in >90% women NOTE: Methotrexate used only in ectopic pregnancy
Ectopic Pregnancy
Maternal-Fetal Disorders
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Pregnancy outside the uterus
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98% occur in fallopian tube
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Most commonlyampulla(mid portion)
Jason Ryan, MD, MPH
Ectopic Pregnancy •
st
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Symptoms in 1 trimester Vaginal bleeding Abdominal pain (may mimic appendicitis)
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Abnormal↑hCG based on dates
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Ectopic Pregnancy •
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Diagnosis: ultrasound Treatment: •
Methotrexate
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Surgery
Ectopic Pregnancy
Ectopic Pregnancy
Risk Factors
Risk Factors
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Damage to fallopian tube
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Infertile women: higher incidence
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Prior ectopic pregnancy
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Kartagener syndrome (1° ciliary dyskinesia)
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Tubal disorders •
Tubal ligation (rarely pregnancy occurs)
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Tubal surgery (tumor)
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Pelvic inflammatory disease (Chlamydia, Neisseria)
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Fallopian tubes: ciliated epithelium
Spontaneous Abortion
Spontaneous Abortion
Miscarriage
Risk Factors
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Pregnancy loss before 20 weeks •
After 20 weeks: stillbirth or fetal demise
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Presents as vaginal bleeding
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Often requires D&C to remove all tissue
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50% cases due tofetal chromosomal abnormalities
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Decreased amniotic fluid
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Often a fetal kidney problem
Maternal infection (TORCH)
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Polyhydramnios •
Excessive amniotic fluid
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Often a swallowing/GI problem
Hypercoagulable states Lupus/antiphospholipid
syndrome
Oligohydramnios
Primary sources:fetal urineand lung secretions Major source for removal:fetal swallowing Oligohydramnios •
Maternalsmoking, alcohol, cocaine
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Amniotic Fluid •
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Fetalrenal abnormalities •
Bilateral renal agenesis
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Posterior urethral valves (males)
Placental insufficiency •
Preeclampsia
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Maternal vascular diseases
Premature rupture of membranes
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Oligohydramnios •
Polyhydramnios
Can lead toPotter’ssequence
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Fetal swallowing malformations
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Loss of fetal cushioning to external forces
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Esophageal/duodenal atresia
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Compression of the fetus
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Anencephaly
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Limb deformities
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Flat face
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Pulmonary hypoplasia
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Maternal diabetes
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Fetal anemia
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Leads to high fetal cardiac output
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Increased urine production
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Can occur in parvovirus infection
Multiple gestations •
45
Fetal hyperglycemia polyuria
More fetal urine
Low Birth Weight
Low Birth Weight
Selected Risk Factors/Causes
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Less than 2500 grams (5.5lbs)
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Congenital abnormalities of fetus
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Caused by:
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Multiple gestation
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Maternal conditions
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Premature delivery
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Intrauterine growth restriction (IUGR)
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Increased risk of:
Preeclampsia
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Neonatal mortality
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Abruptio placenta Alcohol
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Newborn complications
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Smoking
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Cocaine use
Lower birth weight greater risk complications
Low Birth Weight
Low Birth Weight
Newborn Problems
Newborn Problems
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Hypothermia •
Less white adipose tissue (insulation)
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Less brown adipose tissue (heat generation)
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Large ratio surface area to weight (lose heat easily)
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Respiratory distress Neonatal RDS
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Transient tachypnea of the newborn
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Pneumonia
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Respiratory failure
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Need for ventilator support
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Hypoglycemia •
Loss of maternal glucose
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Insufficient fetal generation of glucose
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Hyperbilirubinemia •
↑ unconjugated bilirubin
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May lead to newborn jaundice
Persistent Fetal Circulation In utero: high PVR
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Blood shunted right left
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Via foramen ovale and ductus arteriosus
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At birth oxygen to lungs PVR falls Persistent high PVR shunting hypoxemia
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Abnormal development of pulmonary vasculature
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Small vessels
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Thickened walls
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Excessive vasoconstriction
Inadequate lung fluid clearance
Immune Function
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Deficiency of surfactant
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46
Cellular immunity impaired
↓ T-cells and B-cells at birth Some babies have neutropenia
Low Birth Weight
Low Birth Weight
Newborn Problems
Newborn Problems
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Polycythemia of the newborn
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Necrotizing Enterocolitis
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Excessively elevated hematocrit at birth (>65)
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Intestinal necrosis and obstruction
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Newborns normally have increased red cell mass
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Fetus in a relatively hypoxic environment in utero
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Increased hemoglobin production Placental blood may transfer to baby at birth
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Usually terminal ileum or colon Can lead to perforation Major risk factor is prematurity, low birth weight
Usually asymptomatic Rarely may cause symptoms •
Hypoglycemia (excessive RBC glucose utilization)
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Hyperbilirubinemia
Low Birth Weight
Low Birth Weight
Newborn Problems
Long Term Outcomes
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Intraventricular Hemorrhage Hemorrhage i nto lateral ventricle
Hypotonia 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
•
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 (<20)
•
Bed sharing (infant/parent)
•
Prematurity/low birth weight
47
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
Hypertension in Pregnancy •
Pre-existing hypertension
•
Gestational hypertension
•
Hypertension in Pregnancy
•
•
Jason Ryan, MD, MPH
Gestational Hypertension •
•
•
α-methyldopa
•
Labetalol (β1β2α1 blocker)
•
Nifedipine (calcium channel blocker)
Elevated BP that develops during pregnancy
Preeclampsia-eclampsia •
Hypertension in pregnancy
•
Proteinuria
•
End-organ damage
Preeclampsia •
Elevated BP after 20 weeks No proteinuria or evidence of preeclampsia Safe drugs in pregnancy •
Elevated BP prior to pregnancy
•
Multi-system disorder of pregnancy Hypertension Proteinuria
•
End-organ dysfunction
•
Preeclampsia
Preeclampsia
Pathogenesis
Pathogenesis
•
Disorder of theplacenta •
Normally trophoblast invades/transforms spiral arteries
•
Abnormal invasion/transformation preeclampsia
•
Placental under-perfusion Leads to release of circulating substances Diffuse maternal endothelial dysfunction Vasospasm and coagulation
•
Resolves with delivery (placental removal)
•
•
•
•
•
•
•
48
Extravillous trophoblast fails to penetrate myometrium Spiral arteries do not develop normally Remain narrow placental hypoperfusion Placentalbiopsy: fibrinoid necrosis of vessels
Preeclampsia Clinical Features • •
•
Preeclampsia HTN Proteinuria
3rd trimester
Usually occurs New onset hypertension •
In mother with no known HTN
•
First pregnancy
Clinical Features
Edema
•
Often presents withedema
•
Endothelial dysfunction
•
•
Proteinuria low oncotic pressure Increased salt/water retention
Proteinuria or end-organ damage •
Renal failure (vasospasm of renal vessels)
•
CNS (headache, visual changes, confusion)
•
Liver failure
Preeclampsia
Preeclampsia
Clinical Features
Risk Factors
•
•
Often involves the liver Edema of the liver Ischemia/necrosis
•
Elevated liver enzymes common
•
•
•
Prior preeclampsia First pregnancy Familyhistory
•
Multiple gestations
•
Preeclampsia
Preeclampsia
Risk Factors
Complications
•
Maternal conditions (prior to pregnancy)
•
Placental insufficiency
•
Diabetes
•
Growth restriction
•
Hypertension
•
Oligohydramnios
•
Obesity
•
Chronic kidney disease
•
Lupus/Antiphospholipid syndrome
•
49
Placental abruption
Preeclampsia
Eclampsia
Complications •
Pulmonary edema
•
Seizures in a mother with preeclampsia
•
Heart failure
•
Generalized, tonic-clonic seizures
•
•
Liver hematoma with/without rupture Liver failure
•
Disseminated intravascular coagulation Stroke
•
Dialysis (advanced renal failure)
•
•
•
•
•
Eclampsia •
•
•
Anticonvulsive of choice:magnesium sulfate •
Most effective drug
•
Often given forprevention in preeclampsia
Microangiopathic hemolytic anemia Schistocytes
•
Elevated bilirubin
•
Low haptoglobin
•
Variant of preeclampsia Hemolysis Elevated Liver enzymes
•
Low Platelet count
•
Complication of preeclampsia (severe form)
•
Coagulation activation and liver infarction
•
Definitive treatment:d elivery of baby
•
Exact etiology of seizures unclear Related to blood flow/endothelial dysfunction
HELLP Syndrome
HELLP Syndrome •
May lead to coma/death Often complicated by DIC, respiratory failure
•
Thrombocytopenia
•
Treatment:delivery of baby
(consumption)
50
Placental Abruption Abruptio Placentae •
Placental Complications
•
Placental detachmentprior to delivery of baby •
Normally implanted placenta
•
Partial or complete early separation
Blood loss from maternal vessels •
•
•
•
Jason Ryan, MD, MPH
Rupture of maternal vessels indecidua basalis
Blood separates decidua from uterus Loss of gas and nutrient exchange Life-threatening to mother and fetus
Placental Abruption
Placental Abruption
Clinical Presentation
Complications
•
•
Occurs in 3 trimester Abrupt onset of painful vaginal bleeding •
Posterior abruption may have minimal/no bleeding
•
Abdominal or back pain Uterine contractions
•
Often diagnosed clinically
•
Ultrasound not reliable
•
•
rd
•
Maternal shock Fetal distress/demise
•
Disseminated intravascular coagulation (DIC)
Placental Abruption
Cortical Necrosis
Risk Factors
•
Ischemic necrosis of renal cortex
•
Previous abruption
•
Rare cause of acute renal failure
•
Maternal
•
Related to ischemia and DIC Can lead to permanent renal failure Often associated withplacental abruption
•
Clinical presentation
•
•
•
Acute renal failure
•
Anuria
•
Hematuria (may be gr oss)
•
Flank pain
•
•
•
•
51
hypertension/preeclampsia
Smoking Cocaine Abnormal uterus •
Bicornuate uterus
•
Prior C-section
Trauma (motor vehicle accident)
Placenta Previa •
Previa = “going before” •
•
•
Placenta Previa
Placenta before baby
Placenta attached to lower uterus Over or close tocervicalos
•
May cause painlessbleeding during pregnancy
•
May lead to preterm birth
•
•
May require C-section delivery Risk factors •
Prior placenta previa Prior C-section
•
Multiple prior pregnancies
•
Velamentous Umbilical Cord •
•
Normal umbilical cord: inserts into central placenta Velamentous cord:inserts into fetal membranes Attaches to chorion
•
Fetal vessels travel with membranes to placenta
•
Vessels exposed
•
No protection fromWharton’sjelly
•
Risk of rupture/bleeding
•
Vasa Previa •
Abnormal Attachment
•
Fetal blood vessels in membranes near cervical os Rupture of membranes at birth bleeding
•
Usually requires C-section delivery
Abnormal Attachment
•
Normal placenta attaches to decidua
•
Caused bydefective uterine decidualization
•
Abnormal decidua abnormal attachment
•
Most important risk factor:prior C-section
•
Other risk factors:
•
•
Placenta attaches directly to myometrium Three forms •
Placenta accreta (most common)
•
Placenta increta
•
Placenta percreta
•
•
52
Especially withplacenta previa
Prior uterine surgery or D&C
Abnormal Attachment
Abnormal Attachment •
•
•
Placenta attached to myometrium
•
No penetration into myometrium
•
•
•
•
•
Undetected: placenta fails to detach after birth
Placenta percreta •
Placenta penetrates through myometrium
•
Invades uterine serosa (outer layer)
•
Can attach to bladder/rectum
•
Part/all of placenta remains attached to uterus
•
Breaks into pieces
•
Massive bleeding
•
Maternal hemorrhage Shock, DIC, ARDS Delivery usually by C-section
•
Often requires hysterectomy
•
•
Postpartum Hemorrhage •
Uterine atony(most common cause)
Coagulopathy
•
Uterus contracts after delivery constricts spiral arteries
•
Blood loss may consumes clotting f actors
•
Lack of contraction = atony
•
Some obstetric conditions may cause D IC
•
Often treated with oxytocin
•
Abruption, amniotic fluid embolism, preeclampsia
•
Also treated with uterine massage
•
Trauma •
Lacerations from delivery
•
Especially if instruments used
•
Surgical incisions
Amniotic Fluid Embolism •
Usually diagnosed onroutine ultrasound
•
Placenta penetrates myometrium
Postpartum Hemorrhage •
•
Placenta increta •
•
Clinical Presentation
Placenta accreta
Retained tissue •
Placenta expelled by uterine contractions
•
Retained tissue bleeding
Amniotic Fluid Embolism
During labor or shortly after Amniotic fluid, fetal cells, fetal debris Enter maternal circulation Inflammatory reaction Often fatal
•
Phase I (respiratory/shock)
•
Phase II (hemorrhagic phase)
•
•
53
Key features: respiratory distress, ↓O 2, hypotension
•
Massive hemorrhage
•
DIC
•
Key feature: bleeding
Seizures also often occur
GTD Gestational Trophoblastic Disease •
Rare variant of pregnancy
•
Neoplasms of trophoblast (placenta)
•
Gestational Tumors
•
Usually benign (molar pregnancy) Rarely malignant
Jason Ryan, MD, MPH
Hydatidiform Mole
Complete Mole
Molar Pregnancy •
•
Most common form of GTD Hydatid = fluid filled cyst Mola = Greek for“false pregnancy”
•
Growth oftrophoblast tissue
•
•
•
•
•
Fertilization of“empty”egg •
All chromosomes of paternal srcin
•
No maternal chromosomes
Swollen chorionic villi Villi form clusters - “clustersof grapes” Ultrasound:“snowstormappearance”
Complete Mole
Complete Mole
•
Cells usually 46,XX karyotype
•
No f etal tissue
•
Haploid sperm that duplicates
•
Maternal chromosomes needed for fetal tissue
•
23 X 46 XX
•
46,YY does not occur
•
lethal
•
Rarely 46,XY moles occur
•
p57-negativeon immunostaining
•
•
Empty egg fertilized by two sperm
•
Cyclin dependent kinase
•
Only expressed by maternal chromosomes (imprinted)
54
No fetus to drain villi = massively swollen villi Most common form of molar pregnancy
Complete Molar Pregnancy
Partial Mole •
Less common form
•
Some fetal tissue(maternal chromosomes)
•
•
•
•
Clinical Features
69,XXX 69,XXY
•
Rarely 69,XYY
•
Size/date discrepancyof uterus •
•
Cells usually triploid •
Initially may appear to be normal pregnancy •
Fertilization of normal egg by two sperm Some villi drainage = less swollen villi •
•
Uterus too big for stage of pregnancy
Painless uterine bleeding •
•
Positive pregnancy test; uterine enlargement
Separation of molar villi from decidua
These findings often lead to ultrasound
p57-positive (maternal genetic material)
Complete Molar Pregnancy
Complete Molar Pregnancy
Clinical Features
Clinical Features
•
•
•
•
•
Hyperemesis gravidarum
Severe nausea and vomiting with weight loss
Maternal serum hCG
Hyperthyroidism •
Requires very high hCG
•
hCG stimulation of TSH receptor
•
Higher than normal for gestational age
•
Low TSH
•
May be very high (>100,000 ) early in pregnancy
•
High T3/T4
•
Ovarian theca lutein cysts •
Ovarian stimulation by hCG
•
Often bilateral
Preeclampsia
Partial Molar Pregnancy
Molar Pregnancy
Clinical Features
Treatment
•
•
Uterine size •
May be normal (some villi drainage to fetus)
•
May be small for gestational age (slow growth of fetus)
Marked ↑hCG less common
55
•
Uterine suction curettage
•
Rarely hysterectomy
•
Chemotherapy:Methotrexate or Actinomycin D •
For high risk patients only
•
Features suggesting high likelihood of choriocarcinoma
Choriocarcinoma
Choriocarcinoma
•
Rare malignant gestational neoplasm
•
Must monitor hCG level after molar pregnancy
•
Can follow anormal pregnancy
•
Should fall after treatment
•
Completemolarpregnancy
•
Plateau: indication of persistent disease
•
•
•
15% develop locally invasive disease 5% develop metastatic disease
Partial mole •
<5% develop any invasive disease
Choriocarcinoma
Choriocarcinoma •
•
Syncytiotrophoblast and cytotrophoblast cells No formation of villi Early spread with extensive metastases
•
Hematogenous spread
•
80% of casemetastasize to lungs
•
Clinical Features •
•
Vaginal bleeding Cough, hemoptysis ElevatedhCG level
•
Possible ovarian cysts, hyperthyroidism (hCG)
•
Non-Gestational Choriocarcinoma
Choriocarcinoma Treatment •
Highly sensitive to chemotherapy
•
Rare germ cell tumor
•
Methotrexate or Actinomycin D
•
May arise in theovary or testes
•
Most patients cured
•
•
•
•
56
Germ cells differentiate into trophoblasts Histologically same as gestational choriocarcinoma Produces β-hCG More difficult to treat/cure
TORCH Infections •
Maternal infections fetal abnormalities
•
TORCH •
Toxoplasmosis
•
Other (syphilis, varicella-zoster, parvovirus B19)
•
TORCH Infections
•
Rubella CMV
•
Herpes
Jason Ryan, MD, MPH
Toxoplasma gondii
TORCH Infection •
Toxoplasmosis •
•
Maternal illness during pregnancy Infection fetus Miscarriage
•
Protozoa Commonly lives in cats (felines) Oocysts shed in stool
•
Stillbirth
•
Infection from ingested oocysts (soil)
•
Fetal abnormalities at birth
•
Also meat from contaminated animal
•
•
Toxoplasma gondii
Toxoplasma gondii
Toxoplasmosis
Toxoplasmosis
•
Maternal 1° infection (immunocompetent mother) •
80 to 90% of infections asymptomatic
•
Lymphadenopathy
•
Fever, chills, sweats
•
Latent infection usually does not infect fetus
•
Diagnosis •
IgM antibodies in first week
•
IgG antibodies peak 6 to 8 weeks, fall over next two years
57
•
Most newborns appear normal
•
Classic triad in fetus: •
Hydrocephalus
•
Chorioretinitis (inflammation of choroid in eye)
•
Intracranial calcifications (often seen on prenatal US imaging)
Syphilis
Congenital Syphilis
Treponema pallidum
Early Findings
•
Spirochete (bacteria)
•
Maculopapular rash
•
Transmitted by sexual contact
•
Runny nose
•
Maternal symptoms
•
Abnormal long-bones
•
•
•
Primary syphilis: Chancre
•
•
Secondary syphilis: Maculopapular rash (palms/soles)
Findings in baby can be early or late •
Varicella Zoster Virus
Late Findings
•
•
Ears/nose •
Saddle nose (no nasal bridge)
•
Hearing loss/deafness
•
Teeth •
Hutchinson teeth (notched, peg-shaped teeth)
•
Mulberry molars (maldevelopment of the molars)
•
Legs
•
Caused by scarring and gumma formation
•
•
•
Herpes virus (DNA) Maternal infection •
Primary: Chickenpox
•
Reactivation: Herpes Zoster (shingles)
Maternal 1° first trimester disease fetal infection
Saber shins (bowed legs)
Varicella Zoster Virus •
Many, many abnormalities reported
Early (<2ys); Late (>2yrs)
Congenital Syphilis •
More common in legs
Parvovirus B19
Newborn signs and symptoms •
Scars in a dermatomal pattern
•
Microcephaly, hydrocephalus, seizures
•
Ocular abnormalities (cataracts, nystagmus)
•
Limb atrophy and hypoplasia
•
Non-enveloped, single-stranded DNA virus
•
Found in respiratory secretions of infected persons
•
Classic infection: Fifth disease in children
•
Adults often develop arthritis
•
Infects red cell progenitors
•
Long term: learning disabilities,mental retardation
•
58
“Slapped cheek” appearance of face Hands, wrists, knees, and ankles
•
Mild ANEMIA in normal individuals
•
Severe in chronic anemia (sickle cell)
Parvovirus B19 •
•
Parvovirus B19
Fetus especially vulnerable to B19
•
Shortened RBC half-life
•
Fluid accumulation in fetus
•
Expanding RBC volume
•
Ascites, pleural, etc.
•
Immature im mune system
•
Often diagnosed on ultrasound
•
“Immune hydrops” from Rh mismatch
•
Many non-immune causes including B19
Miscarriage, fetal death
Rubella •
Congenital Rubella Syndrome
•
RNA virus Found in nasal/throat secretions of infected persons Maternal infection viarespiratory droplets
•
Mild, self-limited illness
•
Hydrops fetalis
•
•
Maculopapular rash
•
Lymphadenopathy
•
Joint pain
•
•
Sensorineural deafness Cataracts Cardiac malformations
•
Blueberry muffin baby
•
•
Blueberry Muffin Baby
Classically a patent ductus arteriosus (PDA)
CMV
•
Purpuric skin lesions
•
Herpes virus (DNA)
•
Extramedullary
•
Several modes of maternal infection:
•
hematopoiesis
•
In utero hematopoiesis occurs outside bone marrow
•
Sexual contact
•
Normally stops prior to birth
•
Close contact of infected individual (family member, daycare)
•
Persists in rubella infection
•
Blood/tissue exposure (transfusion, organ transplant)
May also be seen in congenital toxoplasmosis, CMV
•
1° CMV infection asymptomatic 90% cases May cause mild febrile illness “Mononucleosis-like”
•
Nonspecific symptoms
•
Rhinitis, pharyngitis, headache, myalgia, arthralgia
•
•
59
CMV •
Most infected newborns are asymptomatic
•
Major consequence:sensorineural hearing loss
CMV •
•
Small for gestational age, microcephaly
•
Most common consequence of congenital CMV
•
Hepatosplenomegaly
•
Many babies diagnosed based only on failed hearing screen
•
Blueberry muffin baby
•
Seizures
•
Most common ID cause of congenital sensorineural deafness
•
Herpes Simplex •
•
Other potential findings
•
Intracranial calcifications
•
Usually periventricular
Herpes Simplex •
HSV 2 (DNA virus) Genital HSV fetus at birth via genital tract lesions •
Classic neuroimaging finding:
NOT transplacental
60
•
Vesicles: skin, near eyes, in mouth May spread to CNS
•
May disseminate to multiple organs
Vaginal Malignancies •
Vaginal carcinoma
•
Clear cell carcinoma
•
Embryonal rhabdomyosarcoma (infants)
Vaginal Cancer Jason Ryan, MD, MPH
Vaginal Carcinoma •
•
Very rare Usually squamous cell carcinoma Almost always involvesHPV
•
Same risk factors as cervical cancer
•
Rarely a primary tumor of vagina
•
Most commonly: extension of cervical carcinoma
•
Lymphatic Drainage •
•
Clear Cell Carcinoma
Upper vagina •
From Mullerian duct
•
Iliac nodes
Lower vagina •
From urogenital sinus
•
Inguinal nodes
Diethylstilbestrol
•
Rare malignancy of cervix or vagina
•
Abnormal uterus, cervix
•
Associated with maternald iethylstilbestrol (DES)
•
Vaginal adenosis
•
•
Nonsteroidal estrogen
•
Used to prevent miscarriage, premature birth
•
Removed from US market 1971
•
•
Female babies: Reproductive tract abnormalities
61
Vaginal clear cell adenocarcinoma High rate ofinfertility
Sarcoma botryoides
Vaginal Adenosis
Embryonal Rhabdomyosarcoma
•
Upper vagina: Mullerian duct
•
Rare vaginal tumor of young children
•
Lower vagina: Urogenital sinus
•
May also develop in boys
•
Adenosis •
•
•
•
•
Mullerian tissue in outer cervix/vagina •
Columnar epithelium in vagina Lack of normal squamous epithelium
•
Immature muscle cells
Desmin •
Occurs in children < 5 years old Clear,grape-likemass growing from vagina •
•
Scrotal or inguinal enlargement
Derives from embryonal rhabdomyoblasts •
Embryonal Rhabdomyosarcoma
•
“Paratesticular tumors”
•
Associated with in utero DES exposure May lead to clear cell carcinoma
Sarcoma botryoides •
•
•
Musclefilament Part of Z-disks in sarcomeres Marker of rhabdomyosarcoma
•
99% of rhabdomyosarcomas positive for desmin
•
Botryoid = appearance of bunch of grape
May invade peritoneum obstruct bladder Treatment: surgery and chemotherapy
62
Cervical Cancer •
3rd most common gynecologic cancer in US
•
Human papilloma virusdetected in 99.7% cases
•
Identifiable in precursor stage viaPap smear
Cervical Cancer Jason Ryan, MD, MPH
Cervical Cancer
Cervical Neoplasia •
•
Risk Factors •
Epithelial neoplasia Occurs in thesquamocolumnar junction •
Junction between squamous and columnar epithelium
•
Endocervix: columnar epithelium
•
Ectocervix: squamous epithelium
•
Transformation zone
•
Extends outward
•
•
Human Papillomavirus infection Immunodeficiency state
•
Cigarettesmoking
•
Sexual intercourse at a young age
•
Multiple sexual partners
•
•
95% cancers arise here
Human Papillomavirus
Cannot clear HPV
Affects secretions in endocervical glands
HPV Cancer Risk
•
Non-enveloped
•
Persistent infection over years can lead to cancer
•
Double stranded, circular DNA virus
•
Malignancies associated with HPV infection:
•
•
•
Multiple subtypes: 1, 2, 6, 11, 16, 18 Most common sexually transmitted infection Clinical disease depends on subtype: •
Cutaneous warts
•
Genital warts
•
Cancer
•
•
Cervical
•
Anal, Penile
•
Oropharyngeal squamous cell cancers (mouth, throat)
Usually types 16 and 18 •
63
High risk sub types for cancer
HPV Cancer Risk •
•
HPV Virology
High prevalence HPV among sexually active women •
Most will clear infection
•
Some will have infection persist
•
Two key oncogenes: E6 and E7
•
E6 gene
Vaccine available (capsid proteins) •
•
•
Codes for protein that inhibits p53 suppressor gene
•
p53 protein: controls cell cycle G1 to S phase progression
•
Some target types 16/18 Others also target 11/6 (genital warts)
•
Inhibited p53
uncontrolled growth
E7 gene product •
Codes for protein that inhibits RB suppressor gene
•
Rb protein inactivates E2F transcription factor
•
Inhibited Rb E2F activation uncontrolled growth
G1-S Checkpoint
P53 Protein DNA Damage
Active
Cdk Inhibition Growth Arrest
P53
P53
Unstable Protein RapidBreakdown
Stable
Cyclin
P
P
P
Cdks E2F
P21
E2F
Inactive
P53
Cell Growth P21 gene
Cervical Neoplasia •
Progresses slowly through stages to carcinoma
•
Classifiedas “cervical intraepithelialneoplasia”
•
•
Cervical Carcinoma
Often regresses
•
Not always treated
High risk of progression
•
Usually require treatment
•
Almost always in women with HPV infection
•
•
CIN2 and CIN 3: High grade lesions •
Most commonlysquamous cell carcinoma •
CIN1: Low grade lesion •
•
64
2nd most common adenocarcinoma (endocervix srcin)
Usually occurs in 40s/50s Usually in a woman who do not get screened
Cervical Carcinoma
Cervical Carcinoma •
Usually asymptomatic
•
May present as vaginal bleeding
•
•
Irregular/heavy menses
•
Post-coital bleeding
Diagnosis •
•
•
Can invade locally: bladder, rectum
Pap Smear •
•
Secondary preventionof cervical neoplasia Screening test for cervical dysplasia and carcinoma Used to detect Koilocytes
•
Epithelial cell infected by HPV
•
Large, darkened nuclei
•
Best at detecting squamous cell carcinoma
•
65
Colposcopy •
Use of a colposcope
•
Illuminated, magnified view of cervix
Biopsy Usually done after abnormal Pap smear
Uterus •
Myometrium:Smooth muscle
•
Endometrium: Mucosal surface •
Endometrial Disorders
Glands and stroma
Jason Ryan, MD, MPH
Endometrium •
•
Growth and shedding during menstrual cycle Estrogen= stimulates growth Progesterone= stimulates secretory activity
•
Progesterone withdrawal = menstruation
•
Endometrium •
•
Dysfunctional Uterine Bleeding
Proliferative phase •
Estrogen driven
•
↑ glands and stroma
Secretory phase •
Progesterone driven
•
↓ proliferation
•
Secretory vacuoles appear
•
Prominent spiral arterioles
Anovulatory Cycle
•
Abnormal menstrual bleeding
•
Menstrual cycle without ovulation
•
Not due to a structural cause
•
No ovulation no corpus luteum formation
•
•
•
“Functional”
•
Absence of luteal phase of ovary
•
Uterus, endometrium: normal structure
•
No switch to progesterone secretion
Very common gynecologic problem Most common cause:anovulatory cycle
•
•
•
66
Excessive endometrial growth from estrogen “Unopposed growth”from lack of progesterone Irregular bleeding
Anovulatory Cycle •
Common atmenarche •
•
Underdeveloped hypothalamus-pituitary-ovary axis
Common approachingmenopause •
•
•
Endometritis •
Inflammation of the endometrium
•
Acute or pregnancy-related
•
Chronic or non-pregnancy related
Loss of ovulation Continued estrogen production
Also may result from other disorders •
Thyroid disease
•
Obesity
Acute Endometritis
Acute Endometritis
Pregnancy-Related Endometritis
Pregnancy-Related Endometritis
•
•
Occurspost-partum Bacterialinfection after delivery or miscarriage Key risk factor: cesarean section delivery
•
Prophylactic antibiotics used before C-section
•
•
Often also involves myometrium(“metritis”) Fever, abdominal pain, uterinetenderness
•
Usually diagnosed clinically
•
•
Polymicrobial infections •
Gram positives, gram negatives, anaerobes
•
Staph, strep, E. coli, Bacteroides
•
Broad-spectrum antibiotics used
•
Classic regimen:clindamycin plus gentamycin
•
Alternative:
•
RPOC
Cure rate >90%
ampicillin-sulbactam
Chronic Endometritis
Retained Products of Conception •
Placental/fetal tissue remaining in uterus
•
Intrauterine devices (IUDs)
•
May occur after delivery or miscarriage
•
Pelvic Inflammatory Disease
•
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
•
•
•
67
•
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 •
•
•
•
Endometrial Polyps
Indication for biopsy
Biopsy hallmark: plasma cells White blood cells may be normal in endometrium
•
Hyperplastic growth of glands and stroma
•
Most (95%) benign
•
•
Plasma cell indicates chronic inflammation
•
•
•
Histology: •
Stroma
•
Glands
•
May see smooth muscle
•
Associated with unopposed estrogen
•
Common nearmenopause •
Ovarian estrogen production
•
Chronic anovulation lack of progesterone
Partial agonist to endometrium
•
Endometrial proliferation
•
•
•
•
Stop bleeding
•
Prevent infection
•
Small chance malignancy
•
Selective estrogen receptor modulator (SERM) Competitive antagonistof breast estrogen receptor
•
Estrogenagonist in other tissues (bone/uterus)
•
Tamoxifen •
May cause painless uterine bleeding Removed surgically
Tamoxifen
Endometrial Polyps •
Project from endometrium(“exophyticmass”) Often asymptomatic
Hyperplasia Polyp formation(up to 36% of women) May cause endometrial cancer
68
Used in ER positive (ER+) breast cancer
Endometriosis •
Endometrial tissueoutside uterus
•
Glands and stroma
•
•
May occur anywhere Several common locations •
Ovary/Fallopian Tubes Uterosacral ligaments
•
Rectovaginal septum
•
Pelvic peritoneum
•
Endometriosis Jason Ryan, MD, MPH
Endometriosis
Endometriosis
Pathogenesis
Symptoms
•
•
•
Exact etiology unknown, several theories Retrograde flow •
Movement of menstrual tissue through fallopian tubes
•
Travels to ovaries, peritoneum
•
Metastasis
•
Metaplasia
•
Stem cells
•
•
•
•
Ectopic endometrial tissuehormone-sensitive •
Growth from estrogen
•
Atrophy from progesterone withdrawal
Growth, bleeding, inflammation in ectopic sites
Spread through venous or lymphatic system
Endometrium from coelomic epithelium in development Progenitor cells develop into endometrial tissue
Estradiol (17β-estradiol)
Endometriosis
Endometriosis
Classic Symptoms
Other Symptoms
•
Cyclic pelvic pain
•
Dysmenorrhea, menorrhagia
•
•
Growth/bleeding of ectopic tissue
•
Painful periods (dysmenorrhea)
•
Heavy bleeding (menorrhagia)
•
•
Infertility
Dyspareunia •
Painful intercourse
•
Ectopic tissue near vagina
Dyschezia •
Painful defecation
•
Ectopic tissue near rectum
Dysuria
•
Many women unaware of disorder
•
Ovarian/fallopian lesions infertility
•
Painful urination
•
~40% infertile woman have endometriosis
•
Ectopic tissue near bladder
•
69
Progesterone
Endometriosis
Endometriosis
Diagnosis
Diagnosis
•
Physical exam may be normal
•
Vaginal tenderness
•
Nodules in posterior fornix
•
Ovarian mass
•
•
Normal uterus size
•
Retroverted uterus
•
•
Upper vagina behind cervix
•
Enlarged uterus: adenomyosis
Uterus tipped backwards
•
Detected on physical exam May be seen in normal women
•
More common in women with endometriosis
Endometriosis
Endometriosis
Diagnosis
Other Features
•
•
•
•
Definitive diagnosis:biopsy of lesion Often requires surgical exploration
•
Classic ovarian finding:chocolate cyst
•
Classically occurs in women of reproductive age Improves at menopause and in pregnancy Increased risk ofovarian epithelial cancer
Endometriosis
Endometriosis
Treatment
Treatment
•
Definitive treatment: surgical removal
•
Nonsteroidal anti-inflammatorydrugs (NSAIDs) •
•
Reduce inflammation
70
Oral contraceptivepills(OCPs) •
First line therapy
•
Suppress ovarian function
•
Key component: progestins
•
Suppress ovaries cause anovulation
•
Anti-estrogen
limit endometrial growth
Leuprolide
Danazol
•
GnRH agonist
•
Steroid
•
Binds to receptors inpituitary
•
Weak androgen and progesterone activity
•
•
•
Down-regulation of GnRH receptor Pituitary desensitization ↓ LH/FSH
•
•
↓ estrogen production from ovaries
•
Inhibits LH surge anovulation Suppresses ovarian function Rarely used due to side effects
Danazol
Danazol
Adenomyosis
Adverse Effects •
•
Androgen effects •
Weight gain
•
Edema
•
Decreased breast size
•
Acne and oily skin
•
Increased hair growth
•
Deepening of the voice
Danazol
•
Low estrogen effects: hot flashes
•
Intracranial hypertension (pseudotumor cerebri) •
Adenomyosis Less responsive to medical therapy
•
Definitive treatment: hysterectomy
•
Two major symptoms:
•
Headache, papilledema
•
•
Endometrial glands/stroma in myometrium Hyperplasia of basal endometrium into myometrium Diffusely enlarged uterus(“globular”)
•
71
•
Heavy menstrual bleeding
•
Painful menstruation
Often co-exists with endometriosis
Leiomyoma Fibroid •
Benign tumor ofmyometrium(smooth muscle)
•
Usually multiple tumors
•
Endometrial Cancer
•
•
Occur in pre-menopausal women Growth stimulated by estrogen Usually resolve at menopause(↓ estrogen)
Jason Ryan, MD, MPH
Leiomyoma
Leiomyoma
Fibroid
Fibroid
•
•
Histology: Smooth muscle cell proliferation
•
Usually asymptomatic Often detected as pelvic mass on exam Can be visualized with ultrasound
•
May cause:
•
Leiomyosarcoma
•
Irregular bleeding (often heavier, longer menstrual flow)
•
Infertility
•
Pelvic pain
Endometrial Hyperplasia
•
Malignant smooth muscle tumor of uterus
•
Stimulation of endometrium byunopposed estrogen
•
Arise de novo (not from fibroids)
•
Absence of progesterone stimulation/withdrawal
•
Usually occurs in peri/postmenopausal women
•
•
Occur inpost-menopausal women Usually a single large mass
72
•
Menstruation has slowed or stopped
•
Anovulation no progesterone from ovary
•
Any estrogen source hyperplasia
Endometrial Hyperplasia
Endometrial Hyperplasia
Sources of Estrogen
Clinical Features
•
Obesity •
•
Polycystic ovarian syndrome (PCOS) •
•
•
•
•
Presents as abnormal uterine bleeding
•
Same presentation as endometrial carcinoma
•
Obesity/anovulation
•
Same risk factors as endometrial carcinoma Diagnosis: endometrial biopsy •
Estrogen agonist
Abundant, crowded glands
Hormone replacement therapy (estrogen only) Ovarian granulosa cell tumor •
Secrete estrogen
•
May present with uterine bleeding and adnexal mass
Endometrial Hyperplasia
Endometrial Hyperplasia •
•
Tamoxifen •
•
Increased conversion androgens estrogens (estrone)
Treatment •
Risk forendometrial carcinoma Graded based on histology
Low risk forms:Progestins •
Oppose estrogen effects
•
Simple, complex
•
Reverse hyperplasia
•
Presence of atypical cells
•
Improve bleeding
•
Complex, atypical: high risk of cancer
Endometrial Carcinoma
High risk forms: Hysterectomy
Endometrial Carcinoma
•
Most common gynecologic cancer
•
Diagnosis: endometrial biopsy
•
Most common inpost menopausal women
•
Often preceded by endometrial hyperplasia
•
•
Average age of diagnosis ~60 years old
•
Menopause: anovulation more estrogen exposure
•
•
Classic presentation:abnormal uterine bleeding
•
73
Often driven byunopposed estrogen Usually detected early Often treated withtotal abdominal hysterectomy
Endometrial Carcinoma
Endometrial Carcinoma
Pathophysiology
Endometriod Subtype
•
Classifiedhistologically
•
•
Major types: Endometriod and serous
•
•
Endometriod subtype (Type I)
•
•
Serous subtype (Type II)
•
•
Due toestrogen-dependent hyperplasia Risk factors: more estrogen = more risk Resembles endometrium(“endometriod”)
Estrogen-dependent hyperplasia Estrogen independent
Endometrial Carcinoma
HNPCC
Serous Subtype
Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome
•
•
Estrogen-independent tumors Pink, serous material on biopsy Arise fromatrophic endometriumpost-menopause
•
Most frequently altered gene:p53 tumor suppressor
•
•
•
•
•
•
Present in 90% tumors
Poor prognosis (more aggressive type)
74
Germline mutation in DNA mismatch repair genes Leads to coloncancer Also increased risk of endometrial cancer •
Most common non-colon malignancy
•
Lifetime risk up to 70% (3% in general population)
Ovarian Cysts •
Often detected by ultrasound
•
Often “functional” •
From normal ovarian structure
•
Follicle
•
Ovarian Cysts
Corpus luteum
Jason Ryan, MD, MPH
Hormone Synthesis
Ovarian Follicle •
•
Estrogens •
Egg surrounded by cells Two key cell types:theca and granulosacells
•
Follicular Cysts
Theca cells •
Convert cholesterol into androstenedione (androgen)
•
Stimulated by LH
Granulosacells •
Convert androstenedione into estradiol (estrogen)
•
Stimulated by FSH
Follicular Cysts
•
Common cause of ovarian mass in young women
•
Lined by granulosa cells
•
st half cycle) Derive from an ovarian follicle (1
•
Filled with estrogen
•
•
Failure of ovarian follicle to rupture Or when follicle ruptures and reseals
•
•
•
75
May continue to release estrogen May stimulate endometrial growth Classic symptoms: pain plus irregular bleeding
PCOS
Corpus Luteal Cyst
Polycystic Ovarian Syndrome •
Multiplefollicular cysts
•
Corpus luteum: large structure
•
Amenorrhea
•
Forms 2nd half of menstrual cycle
•
Failure to involute cyst
•
•
Excess androgens Insulin resistance/diabetes
Corpus Luteal Cyst •
•
•
Theca-lutein Cysts •
May continue producing progesterone May delay menstruation Classic presentation •
Pain
•
Missed period
•
Adnexal mass
•
Usuallybilateral, multiple cysts Luteinized theca cells with edema •
•
•
•
76
Hyperplasia of theca cells
Benign Associated with high β-hCG levels •
Twins
•
Molar pregnancy
Usuallyregress
Ovary Structures •
Oocytes (eggs)
•
Supportingcells
•
Ovarian Epithelial Tumors
•
•
•
•
•
•
Fibroblasts Sex cord stromal tumors
Adenomas/Carcinomas
Epithelial Cell Tumors
Ovarian Surface Epithelium •
Theca/granulosa
Surface epithelium •
Jason Ryan, MD, MPH
Germ cell tumors
Clinical Features •
Simple cuboidal epithelium Single layer of cells Derived fromcoelomic epithelium
•
Often a “silent” disease Classic presentation:adnexal mass
•
Vague abdominal symptoms
•
Identified on pelvic exam or imaging
•
Epithelial lining of intraembryonic celom
•
Space that gives rise to thoracic and abdominal cavities
•
Bloating
•
Forms outer layer of male/female gonads
•
Early satiety
•
Also forms lining of body wall, liver, lungs, GI tract
•
Pelvic/abdominal pain
•
Epithelial Cell Tumors
Average age: 63 years old
Epithelial Cell Tumors
Clinical Features •
Rarely can present with acute symptoms
•
Most common type of ovarian tumors
•
Often in advanced disease
•
Serous (40%)
•
Bowel obstruction •
Mucinous (25%)
•
Endometrioid (10%)
•
Benign, malignant, or borderline
•
•
•
•
•
Local spread through peritoneum
Ascites Pleural effusion •
Malignant pleural effusion (pleural metastasis)
•
Cancer cells in pleural fluid
•
•
Venous thromboembolism
77
Secrete serum (water)
Secrete mucous
Similar to endometrium
•
Benign: adenoma
•
Malignant: adenocarcinoma
Serous Cystadenoma
Serous Cystadenocarcinoma
•
Oftenbilateral
•
Most common malignant ovarian tumor
•
Cyst filled with watery fluid
•
Complex cysts with watery fluid
•
Thin wall of single cells lining cyst
•
•
Mucinous Tumors •
•
Pseudomyxoma Peritonei •
Mucinouscystadenoma •
Thin walled cyst filled with mucous
•
Often larger than serous tumors
•
Often “multiloculated”: many small cavities, recesses
Mucinous cystadenocarcinoma •
Growth of epithelial layer Cells similar to fallopian tube cells
Malignant variant of cystadenoma
Endometrioid Tumors
•
Mucinous spread to abdomen “Mucinous ascites”
•
Diffuse gelatinous material in abdomen/pelvis
•
Bowelobstruction may occur
•
Seen in appendix cancer
Brenner Tumor
•
Contain tubular glandssimilar to endometrium
•
Rare subtype of epithelial ovarian tumor
•
Often occur in patients withendometriosis
•
Containsbladderepithelial (transitional) cells
•
Good prognosis
•
•
Often identified at early stage
•
Sensitive to chemotherapy
•
•
78
Usually benign Often found incidentally “Coffeebean”nuclei seen on biopsy
Epithelial Cell Tumors
Epithelial Cell Tumors
Risk Factors
Risk Factors
•
More ovulation associated with more risk
•
Family history of ovarian cancer
•
Infertility (any cause)
•
•
•
Polycystic Ovarian Syndrome (PCOS) Endometriosis Tubal ligation: Protective(↓ risk) •
HNPCC
BRCA1 and BRCA2 •
•
•
Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome •
BRCA1/BRCA2 genes DNA repair proteins Gene mutation associated with breast/ovarian cancer Common amongAshkenaziJews
•
•
Non-Jewish population in US: 1 in 400
•
Endometrial cancer (most common non-colon malignancy)
•
Ashkenazi Jewish population in US: 1 in 40
•
Ovarian cancer (epithelial serous)
Cancer Antigen 125 •
Biomarker for epithelial ovarian cancer
•
Poor performance for screening
•
Germline mutation in DNA mismatch repair genes Leads to coloncancer Also increased risk of:
•
CA-125
•
Possibly related to fallopian tube factors cancer
Useful in evaluatingadnexal mass Useful in monitoring response to treatment •
Serial measurement for follow-up
79
Ovary Structures •
Oocytes (eggs)
•
Supportingcells
•
Ovarian Stromal Tumors
•
•
•
•
Stromal Cell Tumors •
•
•
Theca/granulosa Fibroblasts Sex cord stromal tumors
Surface epithelium •
Jason Ryan, MD, MPH
Germ cell tumors
Adenomas/Carcinomas
Granulosa Cell Tumors •
“Sex cord stromaltumors” Fibroblasts, theca cells, granulosa cells Often producehormones
•
Most common ovarian stromal tumor Tumors derived of granulosa-type cells May contain theca cells(“granulosa-theca celltumor”)
•
Secreteestrogens
•
Usually unilateral
•
May become malignant(“malignantpotential”)
•
Estradiol (17β-estradiol)
Granulosa Cell Tumors
Granulosa Cell Tumors •
•
Clinical Features
Adult subtype (95% cases) •
Median age 50 to 54 years
•
Symptoms from excess estrogen production
•
Often present as largeadnexal mass
•
Estrogen symptoms
Juvenile subtype •
Develop before puberty
•
“Sexual precocity” from excess estrogen production
•
Puberty at very early age (usually < 8 years old)
•
Endometrial hyperplasia
•
Often bleeding in postmenopausal woman
uterine bleeding
•
Breast tenderness
Associatedwithendometrial carcinoma •
80
•
Endometrial bi opsy often performed
Granulosa Cell Tumors
Fibroma
Histology •
Pathognomonic finding:Call-Exnerbodies
•
Benign tumors of fibroblasts
•
Cells surrounding space filled with pink material
•
Solid, white tumor
•
•
•
Occur in postmenopausal women Usually present as a pelvic/adnexal mass
•
Two classic clinical associations
•
Ascites and Meigs Syndrome •
•
•
•
•
Ovarian fibroma
•
Ascites
•
Pleural effusion
•
Etiology unclear Probably related tocapillary leakfrom tumor factors Removal of tumor resolves ascites and effusion
•
Tumor of Sertoli and Leydig cells •
Often occur in males as testicular tumors
•
May occur in the ovary
Tumor producesandrogens •
Breast atrophy
•
Amenorrhea
•
Sterility (anovulation)
•
Hirsutism
Ascites
•
Meigs syndrome
•
Usually co-exist with fibromas(“fibrothecoma”) Pure thecoma: rare May produceestrogens
•
May lead to endometrial hyperplasia/bleeding
•
Sertoli-Leydig Cell Tumor •
•
Thecoma
Ascites occurs in 40% cases of ovarian fibroma Meigs syndrome •
Usually unilateral No hormone activity
81
Ovary Structures •
Oocytes (eggs)
•
Supportingcells
•
Ovarian Germ Cell Tumors
•
•
•
•
Ovarian Germ Cell Tumors •
•
Occur inyoung women Usually 10 to 30 years old Many secrete AFP orβ-hCG
•
Tumors ofgerm cell derivatives
•
•
Germ layers (Teratoma)
•
Germ cells (Dysgerminoma)
•
Yolk sack (Yolk sac tumors)
•
Placental tissue (Choriocarcinoma)
Theca/granulosa Fibroblasts Sex cord stromal tumors
Surface epithelium •
Jason Ryan, MD, MPH
Germ cell tumors
Adenomas/Carcinomas
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
Dermoid Cyst
Mature Cystic Teratoma
Mature Cystic Teratoma
•
•
•
“Dermoid” = skin like Contain hair, squamous cells, sebaceous (oily) material Walls may contain calcification,tooth-like material
•
Usually asymptomatic, unilateral
•
Characteristic features onultrasound
•
82
10-20% bilateral
Dermoid Cyst
Struma Ovarii
Mature Cystic Teratoma •
Usuallyremoved surgicallyto avoid complications: •
Torsion
•
Rupture tumor material in abdominal cavity peritonitis
•
Small risk (<1%) of malignant transformation
•
Elements may become malignant
•
Skin malignancies common
•
Squamous cell carcinoma most common
Specialized subtype of teratoma
•
Mostly thyroid tissue (“monodermal”)
•
•
•
Hyperthyroid symptoms Ovarian mass
Dysgerminoma •
•
Malignant teratoma Solid mass Containimmature fetal tissue
•
Most commonly containneural tissue
•
•
Elements of all three germ layers
•
•
Rarely (<10% cases) may causehyperthyroidism Classic board case: •
Immature Teratoma •
•
•
Most common malignantgerm cell tumor Same characteristics asseminoma in males •
•
Seminoma much more common
Unilateral in 90% of cases May produce enzymes/hormones (tumor markers) •
Lactate dehydrogenase (LDH)
•
Placental alkaline phosphatase
•
Β-hCG
Highly responsive to treatment
Yolk Sac Tumor
Dysgerminoma
Endodermal Sinus Tumor
•
Histology: undifferentiated germ cells
•
Rare malignant germ cell tumor
•
Nests of large cells with clear cytoplasm
•
Derives from extraembryonic yolk sac cells
•
•
Central nuclei “Fried egg” appearance
•
•
Similar to endodermal sinuses of yolk sac in rats Secretealpha fetoprotein (AFP) •
83
AFP normally derives from yolk sac
Yolk Sac Tumor
Yolk Sac Tumor
Endodermal Sinus Tumor
Endodermal Sinus Tumor
•
Large, solid mass
•
Hallmark:Schiller-Duval bodies
•
Necrosis and hemorrhage
•
Glomerular-like structures(“glomeruloid”)
•
•
Commonly presents with abdominal pain Also occurs in males in testes
Choriocarcinoma •
Choriocarcinoma •
•
Rare malignant gestational neoplasm Often follows normal or molar pregnancy Rarely may occur in ovary as germ cell tumor
•
Syncytiotrophoblast and cytotrophoblast cells
•
No formation of villi
•
Pituitary Hormones
Secretehuman chorionic gonadotropin (hCG) •
Useful for diagnosis
•
Mimics LH
•
May cause precocious puberty in girls
•
May cause irregular vaginal bleeding
•
Mimics TSH may lead to hyperthyroidism
Choriocarcinoma
α-subunit
α-subunit
α-subunit
α-subunit
α-subunit
FSH β
LH β
TSH β
HCG β
84
•
Aggressive hematogenous spread
•
Often in lungs, liver, bone at diagnosis
•
More difficult to treat/cure than placental tumors
Breast •
Produces milk for baby
•
Made up of ~15 to 20 lobes
•
•
•
Breast Tissue
•
Each lobe: multiple lobules Each lobe attached to duct Each duct drains to the nipple Lobes surrounded by stroma/fat
Jason Ryan, MD, MPH
Terminal Duct Lobular Unit •
•
Functional unit of breast Extralobular terminal duct: attaches to lobule Intralobular terminal duct: duct system into lobule
•
Clusters of acini (sacs) within lobule that secrete milk
•
Terminal Duct
Breast Epithelium •
•
Lines surface of ducts and lobules Containstwo layers over basement membrane Luminal epithelial cells
•
Myoepithelial cells
•
•
Secrete milk
•
Contractile
•
Respond to oxytocin
Lobule
Terminal Duct Lobular Unit
Milk Lines
Hormones
•
Two thickenings ofectoderm
•
Breast tissue: hormone sensitive
•
Form breasts/nipples
•
Estrogens
•
Axilla to groin Form mammary ridges Disappear later except for breast
•
Extra nipples may form
•
•
•
•
•
Major effect on ducts
•
Puberty: estrogen increases breast size in females
•
Menstrual cycle: cyclic increase in breast size (tenderness)
•
Pregnancy: increase in breast size
Progesterone •
Mostly acts on lobules
•
Growth in lobules (preparation for pregnancy/delivery)
Prolactin •
85
Increased levels in pregnancy
increases breast size
Pregnancy
Maintenance of Lactation
•
Growth of breast tissue
•
Requires removal of milk andnipple stimulation
•
Driven byhormones
•
Triggersprolactinrelease from anterior pituitary
•
•
Estrogens, progesterone, and prolactin
•
Possibly some effect of hCG
•
•
In pregnancyno significant milk formation •
•
•
•
Inhibited by progesterone and estrogens
•
Breast Feeding Benefits •
Lactose Antimicrobial components
Benefits to child •
Lowers risk of infant infections (GI, pulmonary)
•
Antibodies (mostly IgA – passive immunization)
•
Possible long-term benefits
•
Macrophages
•
Some studies show reduced allergies, diabetes, obesity
•
Lymphocytes
•
Lactoferrin (anti-microbial)
•
Lysozymes (breaks down bacterial cell walls)
Breast Feeding Benefits •
Prolactin inhibits ovulation during lactation
Delivery: fall in hormones Milk production occurs
Breast Milk Contents •
Also oxytocin from posterior pituitary Absence of milk removal: involution
Galactorrhea
Benefits to mother •
Decreased risk of breast and ovarian cancer
•
Possible decreased risk of cardiovascular disease
•
Faster childbirth recovery
•
Reduced stress
•
Maternal-infant bonding
•
Enhanced weight loss
•
Longer postpartum anovulation
86
•
Production of milk outside lactation
•
Common complaint:“Nipple discharge”
•
Most causes related toprolactin •
Prolactin milk production
•
Prolactin release inhibited by dopamine (hypothalamus)
•
Dopamine antagonists ↑ prolactin milk production
Galactorrhea •
•
Chronic nipple (neurogenic) stimulation •
Chronic stimulation ↑ prolactin
•
Example: poorly fitting bra
Prolactinoma •
•
•
Gynecomastia •
Breast development in males
•
May be physiologic
•
May occur in association with galactorrhea
Pituitary tumor Galactorrhea: classic sign
Drugs •
Typical antipsychotics (Haldol)
Gynecomastia
Gynecomastia
Physiologic Causes
Other Causes
•
•
•
•
Common innewborn male babies •
Placental transfer of maternal estrogens
•
Resolves with time
•
Some androgen to estrogen conversion
•
Transient
Klinefelter syndrome (male 47,XXY)
•
Several classic drugs
•
Common inolder men (>50) •
Less testosterone, more fatty tissue
87
Decreased liver metabolism of estrogens
•
Common atpuberty in males •
Cirrhosis
Male hypogonadism (↓ testosterone)
•
All have anti-androgen effects
•
Spironolactone (diuretic)
•
Cimetidine (H2 blocker)
•
Ketoconazole (anti-fungal)
Breast Mass Evaluation •
•
•
Breast Disorders
•
Clinical features •
Change with menstrual cycle
•
Discharge
Mammography
(microcalcifications)
Ultrasound (fluid filled cysts) Biopsy
Jason Ryan, MD, MPH
Fibrocystic Changes
Fibrocystic Changes
All •
•
•
Occur in terminal duct lobular unit
“Non-proliferative”
•
Fluid-filled, round cysts
•
Not associated with risk of cancer
•
Filled with dark fluid
•
“Blue domed” cyst on gross specimens
•
•
Must be distinguished from breast cancer
•
Proliferation of epithelial cells
•
No atypia (normal cells)
•
Epithelial hyperplasia
•
Sclerosing adenosis
•
Intraductal papilloma
Fibrosis
•
Apocrinemetaplasia
are BENIGN
Cyst rupture inflammation fibrosis
•
Also called “benign epithelial alteration”
•
Alterations to lobular epithelial cells
•
Take on appearance of apocrine (gland) cells
Epithelial Hyperplasia •
Normalducts/lobules: double-layer epithelium
•
Hyperplasia:↑ luminal/myoepithelial cells
•
Small increase in risk of breast cancer Key types •
•
•
Proliferative Breast Disorders
•
Simple cysts
•
Occur in premenopausal women Present as “lumpy, bumpy”breasts
•
•
Group of breast changes/lesions All arebenign
88
Luminal cells and myoepithelial cells
•
Distended ducts or lobules
•
Lumen filled with cluster of cells
Sclerosing Adenosis •
Increased number of compressedacini
•
Dense stroma
•
May result in calcifications
Intraductal Papilloma •
•
Growth of ductal epithelial cells •
“Intraductal”
•
Proliferation of normal epithelial cells
•
Develop in ducts or lactiferous sinuses
Cells grown in“finger-like” projections “Papilla” •
Intraductal Papilloma •
•
Stromal Tumors •
Present withbloody/serous discharge May also have a small mass near the nipple
Most breast cancers: carcinomas •
•
•
•
Fibroadenoma
Arise from epithelial cells
Stromal tumors •
Fibroadenoma
•
Phyllodes Tumor
Both arise from intralobular stroma Stromal growth may trigger epithelial proliferation
Fibroadenoma
•
Most commonbenign breast tumor
•
Occurs ages15 to 35 years(premenopausal)
•
Masses offibrous and glandular tissue
•
Hormone sensitive
•
•
Compressed epithelial lined spaces Hypoechoic on ultrasound
•
Increase in size during menstrual cycle/pregnancy Decrease in size after menopause Well-defined, solid, mobilemass
•
Develop in lobules
•
•
89
Phyllodes Tumor •
Mammary Duct Ectasia
Also astromalfibroepithelial tumor •
Usually benign
•
Low grade forms similar to fibroadenomas
•
High grade variants can metastasize
•
Benign inflammatory condition
•
Affects older women (~50 years old)
•
• •
•
•
Usually present in older women (>60 years) Phyllodes = Greek word“leaf like” Leaf-like growths of stroma covered by epithelial cells
•
•
•
•
Often biopsy, surgery
•
Sports injury, seatbelt injury
•
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
Usually no pain, erythema Must be differentiated from breast cancer
Acute Mastitis •
Results fromtrauma •
Due tochronic inflammation and fibrosis Presents as breast mass withthick, white discharge
Lactational Mastitis
Fat Necrosis •
Classically in multiparous women Distension (ectasia) of subareolar ducts (nipple)
•
Occurs in women duringbreast feeding Trauma to skin around nipple Breast erythema, tenderness
•
Often fever,malaise
•
Most commonly infection withS. Aureus
•
Usual treatment:d icloxacillinor cephalexin
•
•
•
Mother should continue nursing Can progress to abscess requiring drainage
Biopsy shows fat necrosis with inflammatory cells
Periductal Mastitis
Periductal Mastitis
Squamous Metaplasia of Lactiferous Ducts
Squamous Metaplasia of Lactiferous Ducts
•
Inflammation of subareolar ducts
•
Inflammation squamous metaplasia
•
More than 90% cases occur infemale smokers
•
Duct epithelium cuboidal squamous
•
Smoking toxic to subareolar ducts
•
Smoking may cause relative vitamin A deficiency in ducts
•
•
•
90
Periareolar mass withredness, tenderness, warmth Often 2° infection requiring antibiotics Often requires incision/drainage
Breast Disorders
Breast Disorders
Summary
Summary
•
•
Fibrocystic changes •
Cysts, fibrosis, apocrine metaplasia
•
Benign
Proliferative breastdisorders •
•
•
Epithelial hyperplasia, sclerosis adenosis, papilloma Associated with increased risk
•
Not usually precursors of cancer
Stromal tumors •
Fibroadenoma
•
Phyllodes tumor
91
•
Mammary duct ectasia (white discharge)
•
Fat necrosis (trauma)
•
Mastitis (erythema, tenderness)
Breast Carcinoma
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)
Jason Ryan, MD, MPH
Breast Carcinoma
Breast Carcinoma
Risk Factors
Risk Factors
•
•
•
•
•
•
Female gender (99% of cases) Age (peak incidence 70-80 years) Race Non-Hispanic white women: greatest risk
•
1st degreerelative with breast cancer •
Mother, sister, daughter
Increasedestrogen exposure •
Earle menarche/late menopause
•
Obesity
•
Breast feeding = protective
Age atfirst livebirth •
Young (<20) = protective
•
Older (>35) = higher risk
Breast Carcinoma
Breast Carcinoma
Detection
Major Types
•
Palpable breast mass
•
Mammography
•
Ductal v ersus lobular •
Ductal = resemble duct cells
•
Detects micro-calcifications
•
Lobular = resemble lobules
•
Occur in malignant lesions
•
Both types from TDLU
•
Also seen in fat necrosis and sclerosing adenosis
•
In situ versus invasive •
In situ = limited by basement membrane
Terminal Duct
Terminal Duct Lobular Unit
92
Lobule
Breast Carcinoma
DCIS
Major Types
Ductal Carcinoma In Situ
•
Almost all (95%) are adenocarcinomas
•
Malignant growth of epithelial cells of TDLU
•
Arise from epithelial cells of ducts/lobules
•
Fills ductal lumen
•
At diagnosis >70% have invaded basement membrane
•
Limited by intact basement membrane
Terminal Duct
Lobule
Terminal Duct Lobular Unit
DCIS
Paget Disease
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
•
•
Erythema at nipple due to underlying malignancy Occurs when DCIS extends to nipple May cause bloody nipple discharge
•
Paget cells seen on biopsy
•
LCIS
Paget Disease
Lobular Carcinoma In Situ
•
Palpable mass in >50% cases
•
•
~50% have mass on mammogram
•
Proliferation of cells in ducts/lobules
•
Usually invasive carcinoma found
•
Limited by intact basement membrane “Discohesive growth:” loose intercellular connections
•
Round cells clumped together
•
93
Loss of adhesion protein E-cadherin
LCIS
LCIS
Lobular Carcinoma In Situ
Lobular Carcinoma In Situ
•
Does not lead to micro-calcifications
•
Usually an incidental findingon biopsy
•
•
•
Often bilateral May be multi-focal
•
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 •
•
Invasive Ductal Carcinoma •
Most common type (~80%) invasive carcinoma Biopsy: duct cells with stroma
Most commonly in outer quadrant of breast •
More breast tissue
Lateral
Midline ~50% cases
Invasive Ductal Carcinoma
Inflammatory Carcinoma
Histologic Subtypes •
Lobular carcinoma
•
Mucinous carcinoma
•
•
•
Tubular carcinoma Papillary carcinoma Medullary carcinoma •
•
•
•
•
•
Common among BRCA1 gene carriers
•
Inflammatory carcinoma
94
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
Breast Carcinoma
Invasive Lobular Carcinoma •
Cells grow in“single file”
•
Lack of E-cadherin adhesion protein expression •
•
Prognosis •
Can’t stick together in clumps
Often bilateral with multiple lesions
•
•
•
•
Important for prognosis and therapy Estrogen receptor positivity (ER+)
Detected by biopsy
•
Sentinel node biopsy often performed
ER+ and PR+ tumors
May respond to Tamoxifen (SERM)
•
HER2+ tumors
•
“Triplenegative”tumors
•
Cell surface tyrosine kinase receptor
Estradiol (17β-estradiol)
Most important prognostic factor for invasive cancer
•
•
Progesteronereceptor positivity(PR+) Human epidermal growth factor receptor-2 (HER2) •
•
Predictive Markers
Predictive Markers •
Axillary lymph node metastases
May respond to Trastuzumab
•
Highly aggressive
•
More common in women under 40
•
African-American women: highest risk
Progesterone
Familial Breast Cancer
BRCA1 and BRCA2
•
Cause about 10% of breast cancers
•
More common amongAshkenaziJews
•
BRCA1 and BRCA2 gene mutation:
•
Germline gene mutation
•
•
•
Both gene mutations associated with breast cancer
•
Cause of ~85% of single gene familial cases
•
•
Genes code forDNA repair proteins Also associated with other malignancies •
BRCA1: Ovarian cancer
•
BRCA2: Male breast cancer and pancreatic cancer
Autosomal dominant Incomplete penetrance •
95
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
•
Key associations:
•
Most breast tissue in males near nipple
•
Klinefelter syndrome (3 to 8% cases)
•
BRCA2 gene mutations (4 to 14% cases)
96
Penis Anatomy •
Three cavernous bodies(“the corpora”)
•
Corpus cavernosa: Two large spongy tissue beds
•
Corpus spongiosusm: Smaller spongy tissue bed •
Surrounds urethra
Penile Disorders Jason Ryan, MD, MPH
Penis Anatomy •
•
Penis Physiology •
Tunica albuginea •
Latin: “tunica” = covering, “albuginea” = white
•
White connective tissue surrounding corpus cavernosa
•
Buck’s fascia •
Covers all three erectile structures
•
•
Penis Physiology •
Smooth muscle contraction
•
Corpora shrink
•
Venous outflow
•
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
Peyronie Disease
Detumescence •
Key structures: arterioles and corpora Flaccid penis:
•
Abnormal tunica albuginea
•
Acquireddisorder •
97
Likely related to trauma in a susceptible individual
•
Localized fibrosis of tunica albuginea Pain
•
Nodule
•
Abnormal curvature when erect
•
Erectile dysfunction
•
Peyronie Disease •
•
Penile Fracture
Treatment: Pentoxifylline •
Phosphodiesterase inhibitor
•
Reduces inflammation
•
Prevents collagen deposition
Ruptureof tunica albuginea
•
Often associated with urethral damage
•
•
Caused by blunt trauma Audible snap pain, swelling, ecchymosis
Injection or oral administration
Priapism
Priapism •
•
•
Persistent erection Lasting more than 2-4 hours
•
Not due to sexual activity
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
Ischemic Priapism
Etiology
Treatment
•
Failure of cavernosal outflow
•
Urologic emergency
•
Two classic causes: Sickle cell and drugs
•
Hypoxia, acidosis of penile blood occurs
•
Sickle cell anemia
•
•
•
Veno-occlusion
•
Drugs •
Block smooth muscle contraction
•
Antipsychotics/antidepressants (trazadone, SSRIs)
•
Alpha blockers (doxazosin, tamsulosin, terazosin, prazosin)
•
Erectile dysfunction drugs
•
98
May cause permanent erectile dysfunction May leads to penile necrosis Treatments: •
Corporal aspiration
•
Intracavernosal phenylephrine
•
Surgery
Condylomata Acuminata
Condylomata Acuminata
Anogenital Warts
Histology
•
•
•
•
•
•
STD caused by papillomavirus (6, 11)
•
Treatment: •
Chemical agents
•
Surgical therapy
Does not lead to cancer
Squamous Cell Carcinoma
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
•
•
Peri-nuclear clear vacuolization (koilocytosis)
Soft, tan, cauliflower-like lesions “Verrucous” = warts Also seen vulva, perianal area (rectal bleeding)
Risk Factors •
Uncircumcised penis •
•
•
Common in Africa, Asia, South America
Squamous Cell Carcinoma
Circumcision: reduced exposure to carcinogens
HPV Infection •
HPV DNA in 30-50% of cases
•
Types 16 and 18
Smoking
Erectile Dysfunction
Pre-malignant (in situ) lesions •
In situ carcinoma (no basement membrane invasion)
•
Inability to achieve/maintain an erection
•
Bowen disease
•
Associated with many conditions
•
•
•
Gray-white plaque (leukoplakia) on shaft of penis
Erythroplasia of Queyrat
•
Heart disease
•
HTN
•
Dark red lesion on glans of penis
•
Diabetes
•
Bowen disease of the glans
•
Obesity
•
Certain medications
•
Smoking
•
Alcoholism and other forms of substance abuse
•
Sleep apnea
Bowenoid papulosis •
Multiple, red-brown papules
99
Phosphodiesterase 5 inhibitors
Phosphodiesterase 5 inhibitors
Sildenafil, Vardenafil, Tadalafil
Uses
•
PDE5 breaks down cGMP in smooth muscle cells
•
Erectile dysfunction (improved blood flow)
•
Inhibition more cGMP relaxation
•
Pulmonary hypertension (↓PVR)
•
Improved response to NO
•
Benign prostatic hyperplasia (BPH) •
Only tadalafil has FDA approval
NO GMP
cGMP
GTP
PDE5 RELAXATION
Smooth Muscle Cell
Phosphodiesterase 5 inhibitors
Phosphodiesterase 5 inhibitors
Side Effects
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
100
Vision problems •
Temporary blue vision (cyanopia)
•
Only reported with sildenafil
•
Drug cross-reacts with PDE-6 in retina
•
Resolves in hours
Testicular torsion •
Testicle rotates in scrotum
•
Twists spermatic cord •
Forms at deep inguinal ring
•
Travels through inguinal canal
•
Scrotal Disorders
•
Enters scrotum through superficial inguinal ring Ends at testes
•
Carries arteries, veins, ductus deferens
Jason Ryan, MD, MPH
Testicular torsion •
Testicular torsion •
Scrotalligament •
Secures testis to scrotum
•
Limits movement i n scrotum
•
Abnormal function may lead to torsion
•
Allows testes to twist
•
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
Hemorrhagic infarction
Clinical Features
Neonatal form (rare) •
•
Testicular torsion
Testicular torsion •
•
Compression of thin-walled venous outflow Continued inflow through arteries (thick walled) Engorgement of testicle
•
101
•
Painful, swollen testicle
•
Absent cremasterreflex •
Stroking inner thigh
•
Normal response: contraction of cremaster muscle
•
Pulls ipsilateral scrotum/testis up
Testicular torsion •
May lead to infertility
•
Treatment: urgent surgery •
Detorsion (manual or surgical)
•
Orchiopexy (fi xation of testicle)
•
•
Varicocele •
Testicle removal (if nonviable)
Must treat contralateral testis
Varicocele •
•
Varicocele •
Caused by obstruction to outflow of venous blood More common onleft •
•
•
•
Compressed between aorta and superior mesenteric artery
“Nutcracker effect”
•
Right vein drains directly to IVC
•
Associatedwithrenal cell carcinoma
•
Invades renal vein
Varicocele
•
Surgery (varicocelectomy) Isolate dilated/abnormal veins
•
Redirect blood flow to normal veins
Interventional radiology procedure
•
Catheter inserted into dilated/abnormal veins
•
Coil or sclerosants used to clot off veins
•
Valsalva
•
Standing
Diagnosed byultrasound Can cause infertility •
↑ temperature
•
Poor blood flow
•
Accumulation of fluid intunica vaginalis
•
Scrotal swelling
•
Transilluminates with light
•
Embolization •
Dilated veins = “Bag of worms”
More swelling with:
Hydrocele
Treatment
•
Scrotal pain and swelling •
Left spermatic vein left renal (long course)
•
•
•
Dilatation ofpampiniform plexusof spermatic veins
•
102
Small, fluid-filled sac attached to testicle
Differentiates from solid mass (i.e. tumor)
Hydrocele •
•
Spermatocele
Newborn form •
Incomplete closure of processus vaginalis
•
“Communicating hydrocele”
•
Peritoneal fluid collects in tunica vaginalis
•
Usually resolve spontaneously by 1 year of age
“Noncommunicating hydrocele”
•
Often idiopathic
•
May be 2° to infection, torsion, trauma
•
May become bloody (“hemotocele”)
•
•
Abdominal
•
Inguinal canal
Orchiopexy
•
Surgical placement of the testis in scrotum
•
Sperm counts usually become normal
Low sperm counts •
•
•
•
Usually occurs by 6 months of age
•
Can diagnosis with ultrasound
•
Treatment
•
•
Complications
Cryptorchidism Testes may descend ontheir own
Mass at top of testicle Separate from testis
Cryptorchidism
Can be unilateral/bilateral
•
Usually asymptomatic Detected on physical exam
•
•
“Hidden testes” Usually due to undescended testes •
Usually at head (top) of epididymis
•
Cryptorchidism •
Large epididymal cyst
•
•
Adult form •
•
103
↑ temperature effects on Sertoli cells
↑ risk of germ cell tumors Inguinal hernias Testicular torsion
Testicular Malignancy •
Many similarities to ovarian malignancies
•
Key difference: no common epithelial cancers
•
Two main categories: •
•
Testicular Tumors
Germ cell tumors Sex cord-stromal tumors
Jason Ryan, MD, MPH
Testicular Tumors •
•
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
•
Usually present as painless, testicular mass Do nottransilluminate Often evaluated with ultrasound
•
If cancer suspected: orchiectomy
•
Usually not biopsied
•
Germ Cell Tumors
•
Risk of tumor seeding
•
Into scrotum or spread to inguinal nodes
Germ Cell Tumors
•
Most common type (95%) of testicular malignancy
•
Always malignant (capable of metastasis)
•
Usually occur in young men 15-34 years old
•
Often a mix of subtypes
•
Key risk factors:
•
•
Cryptorchidism
•
Kleinfelter syndrome
•
104
Highlycurable 5-year survival ~95%
Seminoma
Seminoma
•
Most common germ cell tumor
•
Homogenous mass
•
Same characteristics asd ysgerminomain females
•
Grey-white appearing
•
Seminoma much more common
•
Dysgerminoma: r are ovarian cancer
•
•
No hemorrhage or necrosis May produce β-hCG •
•
•
•
Placental alkaline phosphatase •
Old marker
•
Poor sensitivity
Treatment •
•
Histology: undifferentiated germ cells Nests of large cells with clear cytoplasm Central nuclei
•
“Fried egg” appearance
•
Surgery +/- chemo/radiation
Embryonal Carcinoma
Seminoma •
Tumor marker in 15% cases Syncytiotrophoblast tissue in tumor
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
Yolk Sac Tumor
Endodermal Sinus Tumor
Endodermal Sinus Tumor
•
Most common GCT children <3 years old
•
Hallmark:Schiller-Duval bodies
•
Derives from extraembryonic yolk sac cells
•
Glomerular-like structures(“glomeruloid”)
•
•
Similar to endodermal sinuses of yolk sac in rats Secretealpha fetoprotein (AFP) •
AFP normally derives from yolk sac
105
Choriocarcinoma •
Rare malignant gestational neoplasm
•
Often follows normal or molar pregnancy
•
•
•
Choriocarcinoma •
SecretehCG
•
May causegynecomastia
•
Rarely may occur intestes/ovaryas germ cell tumor Syncytiotrophoblast and cytotrophoblast cells
•
•
No formation of villi
•
•
•
Pure choriocarcinoma: most aggressive GCT May not cause palpable testicular mass Aggressive hematogenous spread
•
Often in lungs, liver, bone at diagnosis
•
•
•
•
Clinically divided into two categories Seminomas
•
estrogens
gynecomastia
Mimics TSH
Cells from all three germ layers •
Ectoderm (skin, hair follicles)
•
Endoderm
•
Mesoderm (cartilage)
Large mass
•
Neural tissue, muscle, cartilage Often part of a mixed tumor in adults
•
Pure teratoma usually seen in young children
•
Germ Cell Tumors •
Androgen
Teratoma
More difficult to treat/cure than placental tumors
•
hCG stimulates Leydig cell aromatase activity
May causehyperthyroidism •
Choriocarcinoma
Useful for diagnosis
•
Mean age: 20 months
•
Usually before age 4
Mixed Germ Cell Tumors •
Testicular tumors often mix of subtypes •
Teratoma, embryonal carcinoma, yolk sac tumor
•
Remain localized for a long time
•
Seminoma, embryonal carcinoma
•
70% identified in stage one
•
Embryonal carcinoma, teratoma
•
Mets to lymph nodes first
•
Hematogenous spread late
•
Non-seminomas •
Early metastasis
•
Often hematogenous
106
Prognosis usually worse for mixed tumors
Leydig Cell Tumor
Sertoli Cell Tumor
Non-Germ Cell Tumor
Androblastoma
•
Produceandrogens and estrogens
•
Usually do not produce hormones
•
Gynecomastia
•
Most are benign
•
•
•
Sexual precocity (early puberty) Golden brown mass (high lipid content) Reinkecrystals in cytoplasm of tumor cells
Extragonadal GCT
Testicular Lymphoma •
•
•
•
Non-Hodgkin lymphomamay involves testes •
•
Extragonadal Germ Cell Tumors
Diffuse large B-cell lymphoma most common subtype
•
5% testicular cancers = lymphoma Most common testicular tumormen > 60 years old Testicular mass may be presenting complaint
•
•
107
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 •
Round gland a base of bladder
•
Anterior to rectum
•
Encircles urethra
•
•
Prostate
•
Palpation on digital rectal exam
Produces prostatic fluid Stimulated byandrogens
Jason Ryan, MD, MPH
Acute Prostatitis
Acute Prostatitis •
•
•
•
Symptoms •
Acute inflammation of the prostate Usuallybacterial Older man •
Similar organisms to cystitis
•
E. coli most common
•
Also proteus, pseudomonas
Sexually-active, younger men •
Neisseria gonorrhoeae
•
Chlamydia trachomatis
•
Chronic/recurrent prostatitis symptoms
•
Evidence of bacterial infection
Symptoms of prostatitis (pain, difficulty voiding)
•
May present as chronic pelvic and low back pain
•
Sometimes bl ood in semen
•
No bacteria identified
•
Etiology unclear
•
Prostate edematous/enlarged (“boggy”)
•
Exquisitely tender
Workup: Urine analysis (WBC) and culture
Benign Prostatic Hyperplasia •
Age-related condition
•
Common in men >50
•
Chronic abacterial prostatitis •
Digital rectal exam:
BPH
Chronic bacterial prostatitis •
•
•
Chronic Prostatitis •
•
Fevers, chills, malaise Dysuria, frequency Cloudy urine
•
•
•
108
Hyperplasiaof stromal and epithelial cells Results in partial or complete urinary obstruction Not a premalignant condition
BPH
BPH
Symptoms
Histology
•
Hesitancy (cannot start urine stream)
•
•
Frequency (incomplete voiding)
•
Transitional zone
•
Urethra compressed into“slit”
•
•
•
•
Dribbling Bladdermayhypertrophy
“Nodular”
Rarely may cause complete obstruction •
Bladder distention
•
Hydronephrosis
Increased risk of UTIs
BPH
BPH
Treatment
Treatment
•
•
•
hyperplasia
•
Growth driven by dihydrotestosterone (DHT) Treatment:5α-reductase inhibitors (Finasteride) Slow onset symptom relief
•
•
α1-blockers •
Smooth muscle relaxation
•
Tamsulosin: Uroselective (α1A not α1B - no hypotension)
PDE-5 inhibitors •
Also cause smooth muscle relaxation
•
Tadalafil
Surgery •
Transurethral resection of the prostate (TURP)
5-α reductase Testosterone
Dihydrotestosterone (DHT)
Prostate Adenocarcinoma
Prostate Adenocarcinoma
•
Most common form of cancer in men
•
Occur in peripheral zoneof prostate
•
2nd most deadly (lung)
•
Classically posterior lobe
•
•
Occurs in older men (>50) More common among African Americans
109
PSA
Prostate Adenocarcinoma
Prostate-specific antigen
•
Usually asymptomatic (rarely causes dysuria)
•
Androgen-regulated substance found in semen
•
Often felt asnoduleon digital rectal exam
•
Produced by normal and malignant prostate tissue
•
•
Screening with PSA Diagnosis: prostate biopsy •
•
•
•
Transrectal biopsy Often with transrectal ultrasound (TRUS) guidance
•
•
•
Antichymotrypsin
•
Macroglobulin
0-4 ng/mL: Normal 4-10 ng/mL: Elevated
•
>10 ng/mL: Highly suspicious for cancer
Prostate Cancer Grading •
Most PSA bound to protease inhibitors in blood: •
•
•
Free PSA •
Elevated inBPH and prostate cancer Can be used for screening (controversial)
•
•
Can measure % free versus bound PSA Prostate cancer produces more bound PSA ↑ total PSA with ↓ % free PSA
Prognosis based on stage and grade Stage: Extent of tumor growth/spread Grade: Gleason system •
Score done by pathologist based on biopsy findings
•
Based on well- versus poorly-differentiated cells
Prostate Cancer
Metastasis
Treatment
•
Hematogenous spread tospine
•
Surgery
•
May cause back pain and↑ alkaline phosphatase
•
Flutamide
•
Osteoblasticlesions •
Leuprolide
•
Competitive inhibitor of androgen receptors
•
Deposition of new bone
•
Contrast with osteolytic (breakdown)
•
GnRH analog
•
Prostate CA: classic osteoblastic lesion
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IM or SQ continuous (not pulsatile) therapy
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Myeloma: classic osteolytic disease
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Suppresses pituitary FSH/LH release
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Sex Chromosome Disorders •
Aneuploidy of sex chromosomes
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Turner syndrome (45 X)
•
Disorders of Sexual Development
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DSD
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Congenital discrepancy between Chromosomal sex (XX/XY)
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Gonads (testes/ovaries)
•
External genitalia
•
•
•
•
SRY TDF Testes
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Leydig cells DHT
External genitalia Penis/Scrotum Prostate
Testosterone
Sometimes severe acne
•
Learning disability, autism
Default genital development is female Male development requires special factors: •
Testosterone
•
Dihydrotestosterone
•
Mullerian inhibiting factor
Disorders of sexual development •
Presence of male factors in XX (female)
•
Absence of male factors in XY (male)
Key test : Karyotype
Clinical Presentation
Y Chromosome MIH
Sertoli cells
Tall
•
DSD
Male Development Mullerian Degeneration
Normal appearing male Normal fertility
•
Sexual Development
Disorders of Sexual Development
•
•
•
Jason Ryan, MD, MPH
•
Klinefelter syndrome (47 XXY) Double Y males (XYY)
Mesonephric Ducts
Internal Genitalia Seminal vesicles Epididymis Vas deferens
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Ambiguous genitalia •
Common presentations of D SD
•
XX female exposed to excessive androgens
•
XY male with insufficient androgens
Female external genitalia •
XY male with lack of androgen activity
•
Often discovered at puberty
Ovotesticular DSD •
•
•
Ovotesticular DSD
Ovaries and testes in same individual
•
Separate ovaries and testes
•
Abnormal vagina
•
Ovotestes (both tissue types in one struture)
•
Hypoplastic uterus
•
Undescended testes (cryptorchidism)
•
Abnormal penis
80% cases in XX individual Diagnosis by gonadal biopsy
•
•
DSD
•
Puberty: breast development, menstruation may occur Most individualsinfertile
XX DSD
Types •
Range of male/female genital development
•
•
XX DSD •
Genetic female with abnormal sexual development
•
Presence of male factors in XX (female)
•
•
XY DSD •
Genetic male with abnormal sexual development
•
Absence of male factors in XY (male)
•
↑ ACTH Cholesterol
Congenital adrenal hyperplasia
•
Gestational hyperandrogenism
Fetus vulnerable 7-12 weeks gestation
•
Classic cause of CAH (90% of CAH)
•
Low cortisol symptoms (hypoglycemia)
•
Low mineralocorticoid symptoms
•
Cortisol
•
21-α Hydroxylase Deficiency
21-α Hydroxylase Deficiency
Aldosterone
Ovaries usually present External genitalia ambiguous Female baby exposed to androgens
Androgens
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•
Salt loss (volume depletion)
•
Hyperkalemia
Androgen symptoms •
Girls (XX): ambiguous genitalia
•
Boys (XY): precocious puberty (early onset)
Placental Aromatase Deficiency
Gestational Hyperandrogenism •
Maternal source of androgens in pregnancy
•
•
Mother developshirsutism and virilization
•
•
•
Leads to virilization of female fetuses Rare gestational masses •
•
•
•
•
Placenta synthesizes estradiol from testosterone Aromatase deficiency androgen excess Increased androstenedione and testosterone Maternal/fetal virilization
Luteomas m ost common Secrete testosterone and dihydrotestosterone
Maternal administration progestins or androgens •
Some progestins have androgen activity
•
Given for threatened abortion Aromatase Androstenedione
XY DSD •
•
Testes present External genitalia ambiguous or female Male baby under-exposed to androgens
•
Many potential causes
•
•
Gonadal dysgenesis
•
5-α reductase deficiency
•
Androgen insensitivity
•
Rare forms of CAH (↓ androgens)
•
Testosterone synthesis defects
Swyer Syndrome •
•
•
•
Female external genitalia
•
•
Müllerian ducts (no Sertoli cells no MIH)
•
•
No puberty/menstruation No functioning ovaries to produce ↑ estrogen
•
Usually given estrogen supplementation
XY gonadal dysgenesis Female with XY chromosomes and no ovaries Streak gonads •
Mainly fibrous tissue
•
Risk of malignancy (often removed surgically)
5-α Reductase Deficiency
Swyer Syndrome
•
Estradiol (17β-estradiol)
Testosterone
Autosomalrecessivedisorder 46,XY male able to make testosterone, not DHT
Testosterone
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5-α reductase
Dihydrotestosterone (DHT)
5-α Reductase Deficiency •
•
Normal internal genitalia
•
Typical case
•
Normal epididymis, vas deferens, seminal vesicles
•
XY male with ambiguous genitalia
•
Empty into a blind-ending vagina
•
Female child with masculinization at puberty
•
Bilateral undescended testes
•
Normal testosterone levels
•
Vas deferens, seminal vesicles present
•
Absence of uterus
•
Blind vagina
•
Missing/abnormal male external genitalia
External genitalia predominately female •
•
5-α Reductase Deficiency
•
Absent external male genitalia Range of female genitalia seen
•
Sometimes ambiguous genitalia
Masculinization at puberty •
Increased testosterone muscle growth
•
Some DHT production
CAIS
CAIS
Complete Androgen Insensitivity Syndrome
Complete Androgen Insensitivity Syndrome
•
•
Mutation ofandrogen receptorin males (XY) Testes form in utero (SRY gene present) No ovaries
•
No internal or external male genital development
•
•
•
•
No cellular response to androgens
Sertoli cells (testes) present MIH •
Degeneration of mullerian structures
•
Absent uterus, fallopian tubes
•
XY male with female appearance Abdominal testes Amenorrhea at puberty (no uterus)
•
At puberty:
•
XY DSD
•
Breasts develop (testosterone
•
No armpit/pubic hair (depends on androgens)
estrogen)
Disorders of Sex Development
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Kallmann Syndrome •
•
•
•
•
Kallmann Syndrome
Hypogonadotropic hypogonadism plus anosmia Caused by GnRH deficiency ↓ LH/FSH KAL1 gene mutation
•
•
Primarily a disease of males (5:1 ratio)
•
Newborn females appear normal
•
Some newborn males: micropenis/cryptorchidism
Impaired migration GnRH neurons tohypothalamus
Kallmann Syndrome •
•
Diagnostic Tests •
Often discovered at puberty Females •
Little or no breast development, no axillary hair
•
1 ° amenorrhea
•
Karyotype Abdominal imaging
•
17-hydroxyprogesterone
•
Testosterone and DHT
•
Males •
No facial or body hair
•
No increase muscles mass
•
Failure of the voice to deepen
•
Luteinizing Hormone •
Secreted by pituitary
•
Negative feedback by testosterone •
Should be low when testosterone high
•
Should be high when testosterone low
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Abdominal testes, uterus
Elevated in CAH due to 21-hydroxylase deficiency
•
Both elevated in CAIS
•
↓ DHT in 5α r eductase deficiency
Hypogonadism •
Decreased activity ofgonads (ovaries/testes)
•
Primary: Disorder of gonads
•
Secondary: Hypothalamus/pituitary disease •
Loss of LH/FSH
Hypogonadism Jason Ryan, MD, MPH
Male Hypogonadism
Male Hypogonadism •
•
Clinical Features •
Primary hypogonadism •
Testosterone low
•
LH/FSH increased
•
Hypergonadotropic hypogonadism
•
Vary with on age of onset Pre-puberty
•
Adult
•
Secondary hypogonadism •
Testosterone low
•
LH/FSH low (or normal)
•
Hypogonadotropic hypogonadism
Failure to undergo puberty normally
•
Decreased energy
•
Decreased libido
•
Infertility
•
Loss of sexual hair, muscle mass, bones (untreated for years)
1° Male Hypogonadism
2° Male Hypogonadism
Select causes
Select causes
•
Klinefelter syndrome
•
Pituitary tumors
•
Myotonic dystrophy
•
Pituitary apoplexy (hemorrhage into gland)
•
Kallmann syndrome (GnRH deficiency/anosmia)
•
•
Swyer syndrome (gonadal dysgenesis) Mumps
116
Female Hypogonadism •
•
Primary hypogonadism •
Estrogen low
•
LH/FSH increased
•
•
•
Primary amenorrhea
•
Secondary amenorrhea
•
•
Failure to menstruate by age 15
Cessation of menses
Estrogen low LH/FSH low (or normal)
Presents withamenorrhea
Mullerian agenesis
Primary Amenorrhea •
•
Secondary hypogonadism •
•
Amenorrhea
Mayer-Rokitansky-Küster-Hauser Syndrome •
Pituitarydisorders •
Hypopituitarism
•
Kallmann syndrome (5:1 male ratio)
Ovarian disorders •
Turner syndrome – most common cause
•
PCOS in adolescence (androgen excess)
•
Underdevelopment of Mullerian system Congenital absence of vagina Usually no cervix or uterus
•
1° amenorrhea
•
Normal 2° sexual characteristics
•
Anatomic disorders •
Mullerian agenesis (absent vagina/uterus)
•
Breasts, pubic hair
•
Ovaries functional
•
Normal hormone levels
Secondary Amenorrhea
Secondary Amenorrhea
Selected Causes
Selected Causes
•
Pregnancy (anovulation)
•
Menopause
•
•
•
Hyperprolactinemia Thyroid disease •
Hyper and hypothyroid
•
Anovulation
•
Multiple mechanisms
•
•
117
Corticosteroids/Cushing syndrome •
Cortisol suppresses GnRH
•
Low LH/FSH
•
Low estradiol
Cirrhosis •
Disruption of hormone metabolism
•
Variable levels of testosterone, estradiol, and prolactin
Spironolactone •
Anti-androgen (disrupts estrogen/androgen balance)
•
May stimulate progesterone receptors
Primary Ovarian Insufficiency
Asherman Syndrome
Premature Ovarian Failure
•
Uterine adhesions
•
Hypergonadotropic
•
Adhesions/fibrosis of endometrium
•
Before 40 years of age
•
•
•
Infertility 2° amenorrhea
•
•
90% cases fromuterine curettage •
Dilation and curettage (“D&C”)
•
Cervix dilated, uterus scraped with a curette
•
Damage to regenerative layer (basalis)
•
•
•
•
•
Often done after pregnancy/miscarriage to remove tissue
Key Diagnostic Tests
•
hCG Prolactin TSH
•
FSH
•
•
•
Clinic features similar to menopause Hot flashes Vaginal dryness Elevated FSH Elevated LH Low estrogen
Functional Hypothalamic Amenorrhea
Secondary Amenorrhea •
hypogonadism
•
•
Common cause 2° amenorrhea Decrease GnRH secretion Low serum estradiol
•
LH/FSH low or normal
•
Risk factors
•
High FSH seen in ovarian failure
Brain MRI (exclude pituitary mass)
118
•
Eating disorders
•
Excessive exercise
•
Weight loss
•
Stress