The female reproductive system III:
Fertilization, the placenta and mammary glands
Dr. Louis Toth – Fall [email protected]
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Fertilization requires …
…penetration of cervical mucus
…capacitation
…penetration of corona radiata (for which capacitation is necessary)
… dissolution of zona pellucida-Sperm receptor-Acrosomal reaction
… penetrating the egg’s plasma membrane- sperm-egg adhesion
Age and fertility
Infertility is a normal consequence of aging
Completion of meiosis
Sperm entry triggers completion of metaphase II
Second polar body is producedMale and female pronuclei form
Pronuclei fuse, 2n is restored
(first polar body – may or may not still be with the oocyte)
second polar body
Ovum (proper)
Zygote (proper)
Secondary oocyte
Definitions
Oogonium (“egg seed”) – precursor of the female gamete, in the fetal ovary
Oocyte (“egg cell”) – female gamete while undergoing meiosis
Ovum (“egg”) – properly, the mature, post-meiotic female gamete, but more generally the female gamete at any stage of maturation.
Zygote (“yoked”) – properly, the fertilized ovum after male and female pronuclei have fused, but more generally, the fertilized oocyte.
Morula (“mulberry”) - mass of blastomeres resulting from first few divisions of the zygote
Blastula (“little bud”) – blastomeres arranged as a hollow sphere
Fertilized ovum ( = “zygote”)
polar bodies
diploid (2n) nucleus
zona pellucida
Embryogenesis: Cleavage stages
Early cleavage: 2 cell stage
blastomeres
Day 1 PF
Total volume remains constant
Day 2 PF
Early cleavage: 4 cell stage
Day 3 PF
Early cleavage: 8 cell stage
Last stage at which the cells are totipotent: each is capable of making an entire embryo
Morula stage: 12-16 cells
Day 4 PF
At this stage, one cell can be removed for PCR and genetic testing
A way around the US government ban on stem-cell research?
Nature 442, 24 August 2006
Blastocyst stage
Day 6 PF
trophoblast
inner cell mass
Day 6 PF
Blastocyst stage
morula
ovary
blastocyst
uterus
Transport to uterus
|||||||||||||___________________________________________________________________|<--menstrual-->|<--------- proliferative ------->|<-----------|----- secretory -----|------->|1 5 15 20 25 28
|-ovul.-| |<--implantation-->|
day:
The implantation window
Day
5 P
F
Day
9 P
F
Fer
tiliz
atio
n
Implantation – day 6/7 PF
DAY 7 PF
• The part of the trophoblast which overlies the ICM contacts the endometrium
Implantation – day 8/9 PF
• the trophoblast differentiates into two layers:
• cytotrophoblast: a mitotically active cellular layer which gives rise to the…
• syncytiotrophoblast: a syncytium which grows as cells fuse into it and actively invades the endometrium
• The trophoblast rapidly begins to invade the endometriium
• By day 11 PF, the conceptus is completely embedded in the endometrium
The inner cell mass differentiates into ectoderm, mesoderm and endoderm which give rise to all tissues of the embryo
Implantation – day 10/11 PF
Ectodermepidermis, brain, nervous system
MesodermNotochordSomites
muscle, serosa, excretory system, gonadsMesenchyme
dermis, bones, cartilage, circulatory system
Endodermgut, digestive tract, respiratory tractliver, pancreas, glands
Yolkgerm cells
Embryonic origin of tissues
• Blood from the spiral arteries empties into lacunae in the syncytiotrophoblast
• The syncytiotrophoblast secretes:• human chorionic gonadotrophin (hCG)• hum. chor. somatomammotropin (hCS)• estrogens• progesterone• enzymes• prostaglandins• growth factors
Spiral arteries
Uterine glands
Implantation – day 14 PF
• The chorion, an extra-embryonic membrane surrounding the embryo, begins to send out villi into the lacunae
hCG in placenta
www-medlib.med.utah.edu
Relation of placenta
and embryo
www-medlib.med.utah.edu
Rat embryo: Comparative Placentation, K. Benirschke, UCSD
PlacentaAmnionic side
decidual platecotyledonsanchoring villi
umbilical cordamnionic sacchorionic plate
Chorionic side
20 weekembryo
Cotyledonsvisualized byinjection casting
• EMBRYONIC TISSUE IS DERIVED FROM THE TROPHOBLAST
AMNION AND CHORIONVILLIDECIDUAL PLATEEXTRACHORIONIC
TROPHOBLAST
• MATERNAL TISSUE IS DERIVED FROM THE ENDOMETRIUM
decidual cellsspiral arteries
Placenta and decidua deciduabasalis
deciduaparietalis
deciduacapsularis
Terms:gravid = pregnantdecidua = gravid endometrium
Functions of the placenta:• Exchange oxygen from the mother for carbon dioxide from the fetus
• Exchange nutrients from the mother for wastes from the fetus
• Exchange hormones between the fetus and the mother
• Carry antibodies from the mother to the fetus
• Promote the maternal blood supply by enlarging the diameter of the spiral arteries
Twins and twin placentas(IDENTICAL) (FRATERNAL)
Changes in the decidua
Two types of cells target spiral arteries
Decidual cells……derive from mother…respond to progesterone…have myofibroblast properties…prevent trophoblastic invasion
-Extrachorionic trophoblast cells……derive from placenta…fuse with spiral arteries…expand the blood supply
Placental growth
basal plate
chorionic plate22 days
31 days
60 days
Bloom & Fawcett 1986
• stem villus - grows directly from the chorionic plate
• branch villus – grows as an offshoot of a stem villus
• anchoring villus - grows across the lacuna and contact the decidua basalis
• free villus - ends in the lacunae
Describing villi
basal plate
chorionic plate
Pre-eclampsia…… is diagnosed by maternal high
blood pressure and proteinuria.
… correlates with the failure of spiral arteries to enlarge upon contact with placenta.
… might have an immunological component (fetal material in the maternal circulation?).
… has lack of free placental villi as a postpartum finding.
… Can only be treated by delivery of the fetus, but Viagra is in Phase II trials.
Normal 40wk placental villi
Pre-eclampsia 37wk placental villi
Picture credits: Benirshke, Kaufman Pathology of the Human Placenta 2nd ed.
Primary villus: core of cytotrophoblast cells surrounded by a syncytiotrophoblast shell
Secondary villus: core of mesenchyme grows into the center
Tertiary villus: capillaries grow into the mesenchyme
Chorionic plate
Decidual plate
Gray’s Anat. (Fetus)
(Mom)
Temporal development of villi
Chorionic villi in an early placenta
Secondary villi
Mature (tertiary) Chorionic villi• prevents direct contact between maternal and fetal blood
•CO2, O2, fatty acids, electrolytes, etc. cross by diffusion
• amino acids, antibodies, etc. are actively transported
Syncitial knots
Cells:Syncitiotrophoblast layerCytotrophoblast cellsHofbauer cells (macrophages)Endothelial cells
The blood-placental barrier
• prevents direct contact between maternal and fetal blood
•CO2, O2, fatty acids, electrolytes, etc. cross by diffusion
• amino acids, antibodies, etc. are actively transported
• Rh factor incompatibility
+ = , ,Ab Ab
Rh- mom Rh+ dad
AbAb
Blood doesn’t cross placenta Ab crosses placenta
1st child 2nd child
Fetal Alcohol Syndrome
www.fetalalcohol.com
Diagnosis is based on:Characteristic featuresGrowth retardationCNS abnormalities
Timing of maternal alcohol consumption plays a role.
Alcohol stays longer and achieves higher concentration in fetal circulation, compared to mother.
Mammary glands
Modified sweat glandsProduce milk after
childbirth
Adipose tissueSecretory acini
lobes & lobulesLactiferous ducts
lactiferous sinus intralobular duct interlobular duct
Alveoli
Intra-lobula
r duct
Production of Milk
prolactin
oxytocin
Suckling reflexnipple → hypothalamuscan be conditioned (e.g. to crying)+prolactin: causes production of milk+oxytocin: causes ejection of milk, ‘letdown’inhibition of GnRH inhibits ovulation
Ambrogio Lorenzetti, Siena
Mammary Gland
Inactive Pregnant Lactating
Colostrum
• produced during pregnancy and immediately after birth
• high in protein; lower in lipid than milk
• contains antibodies for passive protection of the newborn
• contains growth factors (PDGF, EGF, IGF-1)
• continuously changes in composition
•changes to milk within a few days of initiation breastfeeding
www.westerndairyscience.com
Colostrum
Lipids Proteins Carbohydrates Antibodies
Milk
• produced during pregnancy and immediately after birth
• high in protein; lower in lipid than milk
• contains antibodies for passive protection of the newborn
• contains growth factors (PDGF, EGF, IGF-1)
• continuously changes in composition
•changes to milk within a few days of initiation breastfeeding
• Vitamins• Hormones• Salts
proteinscarbs
lipids
Secreted Components of Milk
• Proteins and carbohydrates are synthesized by alveolar cells and secreted by merocrine secretion into the lumen
• Lipids are synthesized by the alveolar cells and secreted by apocrine secretion into the lumen
• vitamins, salts and hormones migrate from interstitial blood vessels through alveolar cells into the lumen
Transported Components of Milk
IgA
Transcytosed Components of Milk
IgA
IgA
IgA
IgA
• Antibodies (IgA) are synthesized by plasma cells in the interstitium and transcytosed across the alveolar cells into the lumen
Breast Cancers
Second most frequent cause of cancer deaths in US
Affects 1:8 women Ductal (80%) Lobular (10%) Infiltrating carcinoma breaches
basement membrane, metastasizes to lymphatic nodes
Tamoxifen (anti-estrogen) is drug of choice
BRCA1 & BRCA2 tumor suppressor genes are involved in familial breast and ovarian cancers
25 30 50 80
1:20000 1:2500 1:50 1:10
age
incidence
Mammography
McGill Univ. Molson Medical Informatics ProjectInteractive Mammograpgy Analysis Web TutorialJames Nguyen ’02 , David Fleiszer, MDhttp://sprojects.mmi.mcgill.ca/dir/mammography.html
http://medstat.med.utah.edu/WebPath/
fin.
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