Implantation Flashcards
prior to placental formation, what is early embryo supported by
- secretions of the uterine glands (“uterine milk” or “histotroph”)
- amino acids, proteins, glucose, ions, growth factors, hormones
- also directs trophoblast growth and differentiation
importance of histotroph in different species
- superficial placental attachment (pigs, horses, ruminants): important source of nutrition throughout gestation
- invasive placenta (primates): important for first 1/3 of pregnancy
what is histotroph production under control of
- maternal progesterone and prolactin
- conceptus trophoblast-derived interferons
what does implantation refer to
formation of the placenta that will support the embryo and fetus throughout pregnancy
stages of implantation
- apposition
- adhesion
- attachment
- invasion (some species)
is uterine epithelium (endometrium) constantly receptive to implanting embryo
no –> there is an “implantation window” where uterus is receptive (“attachment window” in farm species)
what is pre-receptive stage of implantation
- time when embryos of domestic animals grow and become spaced throughout the uterus (cannot adhere)
- epithelium covered with mucin, MUC-1 (increased by progesterone)
- these glycoproteins form adhesion barrier
what is the first thing to happen in domestic animal embryo implantation
down-regulation or removal of these glycoprotein adhesion barrier molecules to allow apposition of the trophoblast and uterine cells
signals causing down-regulation of glycoprotein adhesion barrier molecules in rodents, farm species
- rodents: increased estrogen
- farm species: maintained elevated levels of progesterone (down-regulates expression of own receptor, which down-regulates MUC-1 expression)
what happens at the same time as down-regulation of MUC-1
- loss of microvilli
- further exposure of cell-surface adhesion molecules -production of both uterine epithelial cells and embryonic trophoblast of bridging ligands
- uterus is now receptive!
other things driving changes to make uterus receptive
- down-regulation of protegesterone receptors
- trophoblast interferons (ruminants - IFN-tau)
what do weak interactions between modified uterine epithelial cells and embryo trigger
adhesion cascade, initially using weak interactions between surface carbohydrate molecules (selectins)
what does adhesion cascade do
activates or exposes stronger adhesion molecules on the apical surface of the uterine epithelial cells (integrins –> also present on trophoblast cells of embryo)
what do adhesion molecules on trophoblast and epithelial cells do
- each bind to bridging ligands such as fibronectin, vitronectin, osteopontin
- integrons of embryo attached to these ligands, integrins of uterine epithelium bound to other end –> epithelial structures are bound –> adhesion is stable, embryo attached to uterus
trophoblast in farm species
- does not do much in the way of invasion in to the deeper layers of the uterus
- pig/horse: no invasiveness –> stays bound to surface of uterine epithelium
what happens if you put pig/horse embryos outside uterus
- aggressively invasive by producing proteolytic enzymes
- uterus secretes protease inhibitors that limit this invasiveness
uterine epithelium of ruminants
- discrete areas (oval) that are devoid of uterine glands –> caruncles
- between caruncles, epithelium is richly glandular
- embryonic trophoblast cells overlying carncular epithelium become binucleate, fuse with epithelial cells to form multinucleated syncitial plaques over cauncles
- embryonic side = cotyledon
- caruncle + cotyledon = placentome
attachment of embryo, formation of placenta in carnivores, rodents, primates
- blastocyst does gradually invade the uterine stroma
- once embryo is attached, underlying uterine luminal epithelial cells undergo apoptosis
- uterine epithelial cells phagocytosed –> endotheliochorial placenta
what does penetration of luminal epithelium by invading trophoblast cells trigger
- responses in the underlying uterine stromal cells termed “decidualization”
- stromal cells hypertrophy and divide, transforming from small spindle shaped cells to large polygonal cells with extensive contacts between them –> secrete prolactin, IGF binding proteins (control trophoblast invasion)
what is control of cell fusion/invasiveness due to
expression of endogenous retroviral sequences present in mammalian genome –> accumulation of these may have had a role in evolution of placenta
what functions does placenta carry out
- functions of lungs, GI tract, kidneys, liver, some endocrine glands
- steals from mother’s circulation then returns waste products to her for disposal
maternal barriers for exchange
- endothelium lining the capillary
- connective tissue (stroma)
- uterine epithelium (endometrium)
- not all layers may be present
fetal barriers for exchange
- chorionic epithelium (outermost layer of fetal tissue)
- connective tissue
- endothelium lining the capillary
- all fetal layers present in all cases
how are placentas classified
- basis of the maternal-fetal barrier
- outermost maternal later is written first followed by outermost fetal layer (always chorion)
what is time of birth (day of gestation) determined by
either fetus, the mother, or both (species-dependent)
what determines day of birth in sheep
- fetus determines time of birth (maturation of hypothalamo-pituitary-adrenal axis)
- absence of fetal pituitary gives prolonged gestation
what determines day of birth in rabbits, rodents, marsupials
- maternal control
- fetal decapitation has little or no effect on time of birth
what determines day of birth in primates
both fetal and maternal factors
progesterone effects on uterine contractility
- important in maintaining the absence of uterine contractions (uterine quiescence)
- prevents formation of estrogen receptors, prevents gap junction formation between myometrial cells, reduces uterine innervation so b-adrenergic influences (relaxant) predominate, prevents oxytocin/prostaglandin receptor formation, prevents action of relaxin to soften cervix
estrogen effects on uterine contractility
- promotes uterine contractility
- induces receptors for uterotonic agents (oxytocin, a-adrenergics, prostaglandins), induces receptors for uterine relaxants (b-adrenergics), induces gap junctions between myometrial cells (promotes coordination/propagation of contractions), promotes synthesis of prostaglandins in animals with previous progesterone exposure
prostaglandin effects in late pregnancy/parturition
- luteolysis and synergize with oxytocin in promoting uterine contraction
- stimulation of uterine contraction, remodeling cervix prior to birth
- formation stimulated by oxytocin
relaxin effects in late pregnancy
- rat/pig/human: primary source is CL (released in association with luteal regression)
- cat/dog/horse/rabbit: primary source is placenta (release can be at any time)
- receptors in cervix, uterus, mammary gland, etc
- acts on CT in cervix, pelvic ligaments to cause softening and relaxation
3 ways oxytocin acts in late pregnancy
- causes myometrial contractions
- causes release of PGF2a from uterine endometrium
- causes release of PGE2 from mucosa of cervix
oxytocin increases in late pregnancy
- increase in receptor number occurs near term to increase tissue responsiveness
- increased expression of receptors due to increase in estradiol/progesterone (E/P) ratio
- rabbits/rodents/carnivores: due to decline in progesterone level, increase in estrogen
- other species: progesterone levels remain high - increase in estrogen alone changes E/P ratio
oxytocin and CNS in late pregnancy
- synthesis increases, nesting behavior is exhibited
- approaching term, circadian rhythm in uterine contractions is established - increases in nocturnal activity
- contractions are in response to oxytocin release
sheep and progesterone
production from ~day 60 is placental - CL no longer required
what causes birth in sheep
- maturation of the fetal hypothalamo-pituitary-adrenal axis
- hypophysectomy (removes ACTC) or disconnect of the hypothalamus and pituitary gland prevents partutition
- same in fetuses that are anencephalic
sheep placenta and hormones
- secretes progesterone
- for most of pregnancy cannot make estrogens because it backs sufficient activity of 17a-hydroxylase enzyme (can’t convert progestagens into androgens)
sheep fetal adrenals
- mature in last week of pregnancy
- respond to ACTH from fetal pituitary by producing cortisol
- increase in pituitary ACTH secretion and increase in sensitivity of the adrenals to this stimulus
“new story” (extra step) in sheep parturition
-increased cortisol increases prostaglandin synthase II (cox-2) in placental trophoblast (fetal), which increases PGE2 production
initial actions of PGE2 in sheep partutition (2)
- placental PGE2 acts in autocrine/paracrine manner to increased P450c17 enzyme (17a-hydrozylase), which allows conversion of pregnenolone to androgens –> estrogen (surge in placental estrogen)
- placental PGE2 has positive feedback on fetal hypothalmo-pituitary-adrenal axis to sustain the increase in fetal cortisol output
functions of increases in estrogen/progesterone ratio in sheep (4) and ultimate purpose
- increases oxytocin pulses from posterior pituitary
- increases oxytocin receptors on the endometrium, myometrium, other tissues
- increases formation of gap junctions in the myometrium (smooth muscles more coordinated)
- increases PGF2a formation in maternal endometrial tissue
- purpose: increase uterine contractions
what does increased PGF2a secretion do around parturition (2)
- causes luteolysis (of remaining CL functionality)
- causes release of relaxin from CL that aids PGE2 in softening of the cervix and pelvic ligaments
what happens to oxytocin during partutition
- ferguson’s reflex induces surge of oxytocin that causes powerful uterine contractions
- these and muscle contractions of abdominal wall deliver the fetus
- prostaglandin synergizes with oxytocin to increase force of myometrial contractions
hypoglycemia and maturation of fetal hypothalamo-pituitary-adrenal axis
- fetus is normally hypoglycemic in relation to the mother to allow glucose transfer down concentration gradient
- fetal pituitary responds to hypoglycemia by increasing ACTH secretion –> becomes more sensitive to hypoglycemia
- may activate HPA axis and cause large cortisol increases that induce parturition
leptin and maturation of fetal hypothalamo-pituitary-adrenal axis
energy stress in late pregnancy leads to fetal fat catabolism –> decreased adipose stores –> decreased leptin –> increased neuropeptie Y –> activation of HPA axis –> increased CRH and AVP –> birth cascade
cows/goats and initiation of birth cascade
- progesterone maintaining pregnancy is from CL (20% from placenta)
- maturation of fetal adrenal axis and secretion of cortisol induces enzymes that convert this placental progesterone into estrogen
- causes production of endometrial PGF2a and birth cascade
dogs/cats and initiation of birth cascade
- progesterone is from multiple CLs throughout pregnancy in bitch, some from placenta in queen
- trigger for parturition unknown
- some fetal involvement?
primates and progesterone near the end of pregnancy
- no reduction in progesterone prior to labor
- effective estrogen/progesterone ratio still needs to be altered in favor of estrogen if uterine contractile mechanisms are to work
how is estrogen/progesterone ratio altered in primates (3)
- placenta lacks 17a-hydroxylase –> cannot form androgens to produce estrogen - however, enzyme is not inducible by cortisol - fetal adrenal has “fetal zone” that synthesizes androgens in response to ACTH –> move to placenta, converted to estrogens
- “functional progesterone withdrawal”
- cortisol antagonizes many progesterone actions - high levels of cortisol in placenta mean that progesterone functions are reduced within the uterus –> shift in local E:P ratio
what do changes in E:P ratio do in primates
- increase oxytocin receptors, myometrial gap junctions, and prostaglandin synehtsis
- have oxytocin production locally within the uterus too
circadian timing of parturition
- many species give birth at set time of day
- function of circadian clock
- action of maternal clock sets fetal clock
