Fertilization, Pregnancy, Embryonic Development

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Fertilization, Pregnancy, Embryonic Development
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Fertilization

• Human sperm fertilizable 48-72 h after ejac
• Isthmic preparation
• Human ova fertilizable 24-48 h after ovn
• Ampulla
• Sperm hyaluronidase penetrates corona radiata

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• Ovum ZP3
• Glycoprotein
• Recognition
• Sperm membr FA-1
• Prot receptor tyr kinase
• Actn ? autophosphn ? cell prot phosphn
• ? Actn voltage gated Ca channels ? AR
• Release, actn acrosin (trypsin-like)
• Penetration ZP

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• Sperm head fuses w/ oocyte
• 2nd Meiotic divn
• ? Mature oocyte polar body
• Mechs to prevent polyspermy
• Fusion male, female pronuclei ? diploid zygote
• Mitosis ? morula ? blastocyst
• Blastocyst ? uterus
• Implantation ? devt chorion, placenta

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Implantation, Early Embryo Development

• Implantation begins 5-6 d after fertn (d 21
  cycle)
• Completed 11 fertn d
• Coincides w/ peak prodn progesterone by CL
  (midluteal)
• Progesterone impt to preparation decidual,
  secretory endometrium
• If no fertn, CL would begin decline now

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• Inner blastocyst cell mass ? embryo proper
• Outer cells trophoblasts
• Contact, signal uterine epith
• EGF receptor on embryo nec
• Uterine cell cytokine (LIF) nec
• Two cell popns
• Syncytiotrophoblasts
• Cytotrophoblasts

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• Syncytiotrophoblast postmitotic surface layer
• From fusion of cytotrophoblast plasma membrs
• Form initial chorionic shell
• Erodes endometrial capillaries, veins
• Perfused by maternal blood
• Cytotrophoblast mitotic cells
• Inner cells Langhans or villous
• Form chorionic villi
• Peripheral cells
• Form trophoblastic shell
• Form trophoblastic cell columns

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• Syncytiotrophoblast cells secrete hCG ? maternal
  circn
• Detectable w/in 24 h beginning implantation
• Incrs w/ incrd trophoblast cell mass (peak end
  1st trimester)
• Functions
• Stims luteal function
• Induces morning sickness
• Stim area postrema of brain ? n/v
• Stims fetal androgen secrn
• Impt to masculinization of fetal genitalia

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• hCG stims luteal function
• Incrs hormone prodn at CL
• Progesterone uninterrupted
• Mandatory until parturition
• Functioning CL mandatory for maintenance first 7
  wks
• At 5 wks after fertn, placental prodn
  progesterone sufficient
• Hormones _at_ sustained CL ? strong neg feedback at
  ant pit
• Plasma FSH, LH suppressed
• Gonadotrophs unresponsive to GnRH

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• Chorionic villi dev by 2nd week after fertn
• Blood vessels here
• Spiral endometrial arteries
• Anchors to endometrium, placenta
• Development her ? umbilical cord
• Definitive placenta at 11-12 fertn wk
• Structures can withstand high maternal blood
  pressure
• Incrd placental perfusion correlates w/ peak
  plasma hCG concents

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Placenta

• Interface between maternal, fetal tissues
• Maternal decidua
• Endometrial lining
• Falls off at parturition
• Supplied by spiral arteries
• Fetal cells trophoblasts
• Exchange organ
• Barrier

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• Incomplete twin of fetus
• GI, lung, kidney
• Immunologic
• Transfer immunoglobulins (exc IgG)
• Prevent fetus rejection
• Endocrine
• Synth hormones, binding prots
• Transport hormones
• Degrade hormones

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• Placenta secretes variant of GH
• GH-V
• Replaces maternal GH _at_ 15-17 w gestation
• May promote fetal growth
• May be impt to pancreatic islet cells
• Causes rising plasma IGF-1
• Neg feedback ? suppression pit GH

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Fetoplacental Unit

• Sim to theca lutein, granulosa lutein cooperation
  in progesterone/E2 production
• 3 Main hormonal groups
• Estrogens
• Progesterone
• Corticosteroids

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• Estrogens
• From androgens by fetal adrenal cortex
• Fetus doesnt express 3bhydroxysteroid
  dehydrogenase (isomerase)
• So all pregnenolone ? dehydroepiandrosterone
  (DHEA)
• Placenta doesnt express p450C17
• Cant make 17-OH progesterone
• Cant make androstenedione
• Cant make DHEA
• Impt to protection female fetus from androgens
• Placenta makes mostly estriol
• Sensitizes uterine smooth muscle to oxytocin

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• Progesterone
• Syncytiotrophoblasts synth de novo
• From cholesterol derived from maternal plasma
• Placenta expresses much p450scc
• Tubulovesicular mitochondria
• Placenta cant synthesize cholesterol
• Pregnenolone ? progesterone
• Placenta doesnt express p450C17
• So only progesterone
• Enters both fetal, maternal circulations

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• Corticosteroids
• In fetus, progesterone is precursor to
  adrenocortical hormones
• Glucocorticoids
• Genly growth inhibitors, so minimized
• Placental enzs break down maternal glucocorts
• Uses maternal ACTH at fetal adrenal cortex
• Diff enzymes expressed _at_ diff devl stages
• 25th gestational week, rising corticosteroids
• Impt to feedback mechs
• Impt to organ maturation

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Embryonic Development/ Endocrinology

• Innate bisexual potential ? decision to male or
  female
• Sex determination
• Chromosomal (Ymale)
• Gonadal (testismale)
• Genal (external genitalia)
• Sexual/gender identity (psychosocial)
• Sexual orientation (attraction)

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Chromosomal Sex

• Established during fertn
• Fusion male/female pronuclei ? diploid
  chromosomal
• Oocyte X sex chromosome
• Sperm X or Y sex chromosome
• Female normal karyotype 46,XX
• Male normal karyotype 46,XY

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Gonadal Sex

• Established during embryonic development
• 5th week urogenital ridge devd
• Adjacent adrenal gland
• 6th week indifferent gonad from urogenital
  ridge
• Requires expression WT-1 gene ? zinc-finger
  transcription factor
• Nec for gonad, kidney expression (mice)
• Requires expression Steroidogenic Factor-1 (SF-1)

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• SF-1
• Impt to induction steroidogenic enzs (mice)
• Impt to devt adrenal glands, gonads,
  ventromedial nucleus hypothal (mice)
• Impt to devt testis from indiff gonad
• Stims testic differentiation ? Sertoli cell
  appearance
• Stims Sertoli prodn AMH AntiMullerian Hormone
  MIF
• Stims expression steroidogenic enzymes by devng
  Leydig cells

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Testis Development

• Mandatory expression Sex determining Region Y
  (SRY gene) ? SRY transcription factor ( Testis
  Determining Factor (TDF))
• Related to SOX genes that are impt to development
  cartilage, testis
• SRY transcription factor probably suppresses
  Dosage Sensitive Sex reversal (DSS) gene
• DSS suppresses SF1
• So SRY ? disinhibition SF-1

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• Now SF-1 ? testicular differentiation
• Sertoli cells
• Steroidogenic enzs in Leydig cells
• AMH
• Mullerian ducts would dev into female tract
• AMH ? inhibition devt Mullerian ducts

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Sertoli Cells in Developing Testis

• Secrs AMH
• 43-50 d embryonic life
• Paracrine
• ? Involution Mullerian duct
• Absence AMH ? Mullerian duct devt regardless of
  sex steroid env
• ? Fallopian tubes, uterus, upper vagina
• Normal condition in females

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Leydig Cells in Developing Fetus

• Secrete testosterone from embryonic d 60 (wk 8-9)
• Not yet controlled by hypothal-hypophyseal system
• hCG crucial
• Rising during 1st trimester
• Declines after wk 12
• Stims synth testosterone in developing Leydig
  cells

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• Testosterone
• Stims devt Wolffian duct structures
• Give rise to epididymis, vas deferens, seminal
  vesicles
• Must be present before embryo wk 12
• Must be converted to DHT for masculinization
  external genitalia, prostate devt

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Fetal Gonad Sex Steroid Synthesis

• 17a hydroxylase activity dominant
• Pregnenolone ? 17 a hydroxypregnenolone and 17 a
  hydroxyprogesterone
• ? androgen synth
• Testes ? testosterone
• Ovary ? androstenedione, testosterone precursors
  for estrogen
• ? Estradiol