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Flashcards in lecture 15: maternal recogntion of pregnancy Deck (22):
1

What is maternal recognition of pregnancy?

  • coined by RV Short in 1969 
  • balance between positive luteotrophic and negative luteolytic factors (species specific) 
  • timing and strength of signal key – early embryo loss 
  • MRP: physiological process through which the conceptus modulates maternal function to preserve pregnancy, notably prolongation of the life span of the CL and of progesterone secretion 

2

What is the zygote?

  • fertilised/activated ovum that is now diploid 

3

What is the conceptus?

  • any stage of development that represents the full product of conception, i.e. the embryo/foetus and its associated extraembryonic tissues (placenta) 

4

What is the embryo?

  • strictly, the embryo proper develops into the foetus and excludes the extraembryonic tissues. However, in common usage, embryo is often used to refer to the whole early conceptus. 

5

What is the blastocyst?

  • stage of embryonic development at which the embryo (strictly conceptus) has formed a cavity, at which in most species has differentiated into two cell lineages: ICM → embryo proper; trophoblast → contributes to placenta
  • NB: trophectoderm = the earliest tissue of the trophoblast lineage 

6

What is a foetus?

  • embryonic stage after the start of organ development 

7

What is the time (in days) after ovulation at which various developmental and maternal events occur?

invasive 

  • mouse
    • cleavage to four cells: 1.2 - 2
    • major burst of transcription: 2-cell
    • conceptus enters uterus: 3
    • formation of blastocyst: 3
    • time of attachment: 2.5
    • luteal regression time if mating infertile: 10-12
    • duration of pregnancy: 19-20
  • rat
    • cleavage to four cells: 2-3
    • ​major burst of transcription: 2-cell 
    • conceptus enters uterus: 3
    • formation of blastocyst: 2.5
    • time of attachment: 4.5 - 5.5
    • luteal regression time if mating infertile: 10-12
    • duration of pregnancy: 21-22
  • rabbit
    • cleavage to four cells: 1-1.5
    • major burst of transcription: 8-16-cell 
    • conceptus enters uterus: 3.5
    • formation of blastocyst: 3.5
    • time of attachment: 7-8
    • luteal regression time if mating infertile: 12
    • duration of pregnancy: 28-31
  • human 
    • cleavage to four cells: 2
    • major burst of transcription: 4-8-cell
    • conceptus enters uterus: 3.5
    • formation of blastocyst: 4.5
    • time of attachment: 7-9
    • luteal regression time if mating infertile: 12-14
    • duration of pregnancy: 270-290

non-invasive

  • sheep
    • cleavage to four cells: 4
    • major burst of transcription: 8-16-cell
    • conceptus enters uterus: 2-3
    • formation of blastocyst: 6-7
    • time of attachment: 15-16
    • luteal regression time if mating infertile: 16-18
    • duration of pregnancy: 144-152
  • pig
    • cleavage to four cells: 1-3
    • major burst of transcription: 4-cell 
    • conceptus enters uterus: 2
    • formation of blastocyst: 5-6
    • time of attachment: 18
    • luteal regression time if mating infertile: 16-18
    • duration of pregnancy: 
      ​112-115
  • cow
    • cleavage to four cells: 2-3
    • major burst of transcription: 8-16-cell 
    • conceptus enters uterus: 3-4
    • formation of blastocyst: 7-8
    • time of attachment: 30-45
    • luteal regression time if mating infertile: 18-20
    • duration of pregnancy: 
      ​277-290
  • horse
    • cleavage to four cells: 1.5 - 2
    • major burst of transcription: ?
    • conceptus enters uterus: 5 - 6
    • formation of blastocyst: 6
    • time of attachment: 30 - 40
    • luteal regression time if mating infertile: 20-21
    • duration of pregnancy: 
      ​330 - 345

8

What are different kinds of ovarian cycles?

  • human and other primates 
  • cows, sheep
    • waves of follicular growth during luteal phase
  • mouse, rat 
    • truncated luteal phase
    • pseudopregnancy
  • cat, rabbit
    • induced ovulation 
    • pseudopregnancy

9

What is pseudopregnancy?

  • seen in many species
  • rat and mice
    • in normal oestrous cycle is relatively short (~4 days)
    • cervical stimulation at mating causes reflex release of prolactin 
    • prolactin is luteotrophic so CL develops and secretes progesterone for 11-14 days (vs pregnancy 21-22 days)
  • cats
    • induced ovulators 
    • mating → reflex LH surge and ovulation 
    • if not pregnant, CL starts to decline after about 21 days (vs gestation 65 days) 

10

Is progesterone essential to maintain pregnancy?

  • yes
  • generally
  • not all species are the same 
  • sheep
    • hypophysectomy terminates pregnancy up until day 50 
      • waiting until after this has no effect on the pregnancy
    •  ovariectomy terminates pregnancy up until day 55
    • after this time the placenta has taken over and is capable of producing the right hormones etc to support the pregnancy independently 
    • pregnancy usually ~ 150 days
  • ​goat
    • also pregnancy ~ 150 days 
    • hypohysectomy and ovariectomy terminate pregnancy all the way up to term
    • placenta unable to take on characteristics well enough to support the pregnancy without those other organs 
  • species differ in how they may utilise maternal and/or foetal/placental progesteron production
  • LH support from pituitary 
  • supports corpa lutea and production of progesterone acting on the uterus itself 
  • after the early stages of pregnancy the placenta then takes on a role and itself is releasing gonadotrophins 
  • these are able to maintain the corpus luteum 
  • in some species we don't actually need LH from pituitary 
  • placental progesterone is also there to help in terms of the production and maintenance of the pregnancy itself, not just CL, functions both within the uterus and the ovary 

11

What is luteal rescue in primates?

  • passive luteolysis 
    • due to failure of embryonic signal 
    • endogenous factors in CL (PG and oxytocin) 
  • fertile coitus → embryo releases CG which rescues the corpus luteum → keeps producing progesterone → pregnancy maintained
  • chorionic gonadotrophin 
    • glycoprotein related to LH and FSH 
    • mostly LH like activity 
    • produced by placental tissues – syncytiotrophoblast 
    • production from about 6-7 days after fertilisation 
    • prevents CL regression 

12

What are some of the hormones in human pregnancy?

  • placental production of:
    • progesterone (absolute requirement) - CL/Placenta 
    • Oestrogens 
      • foetus, role of foetal adrenal/liver 
      • change in type of oestrogen, species 
      • oestriol >> oestrone > oestradiol (importance, in general)
      • importance for receptivity, fluid balance etc 
      • required but not absolute requirement 
      • placenta doesn't have all of the enzymes/substrates to produce all of the oestrogens 
      • produced by foetus → bound to sulphates to prevent exposure (important for male foetus)
    • hCG (urinary excretion → home pregnancy test) 
      • produced around blastocyst stage 
      • massive surge 
      • drops to just above basal
      • only required in the inital phases up to about day 100, where the placenta is able to take over
    • placental lactogen (hPL) 
      • produced around the same time as the placenta formation and slowly increases 
      • nutrient partitioning to the foetus
      • particular w/ IGFs and how they mediate that in the foetus
    • prolactin 
      • in the placenta it's all about solutes, electrolytes and water balance  
  • used as endocrine markers of foetal and placental health 

13

What is the role of CG?

  • maintains the CL 
  • injection of CG extends luteal function in non-pregnant females 
  • blocking CG action in early pregnancy prevents luteal rescue, and pregnancy fails 

14

What is MRP in other species?

  • active luteolysis 
    • action of luteolytic agent (PGF)
    • overcomes the anti-luteolytic benefits of LH 
    • most mammals – cow/sheep etc 
  • signals in other species
    • ruminants  = IFN-τ
    • pigs = oestrogen 
    • other species = ?oestrogen/PG
  • different species have evolved to use different tools 

15

What is seen in the ewe and the cow for MRP?

  • non-pregnant 
    • oestrus - LH surge 
    • prostaglandin pulsatility occurs → luteolysis → cycle occurs again
  • pregnant
    • prostaglandin F2 alpha is suppressed 

16

What is early embryo development in cows?

  • fertilisation occurs in the oviduct 
  • day 4-5 enters uterus
  • blastocyst 
  • day 9 - blastocyst gets rid of its zona pellucida 
  • the outer cells start rapidly expanding - a couple of mm a day
  • turn into what looks like a very large tape worm 
  • embryo proper/ICM does not grow at this point 

17

What is luteolysis in the cow?

  • ovarian artery coils around uterine veins 
  • around day 11-16 PGF2alpha synthesis in uterus transported by veins 
  • stimulated by oxytocin receptors
  • PGF in uterine drainage  
  • counter current system → transfer from vein to artery 
  • PG carried to ovary 
  • allows it to have direct action on the ovary instead of being circulated around the body 
  • PGF induces OT release from large luteal cells and luteolysis 
  • OT from CL stimulates PGF 2a synthesis in uterus  
  • positive reinforcement 

18

How is luteolysis blocked in the cow?

  • interferon-tau from the blastocyst suppresses OTR increase and thus PG synthesis 
  • stops PGF synthesis and release → skews production towards PGE which is beneficial in maintaining the CL 

19

What is MRP in ruminants?

  • luteolysis in cyclic cows/sheep via pituitary and CL oxytocin and uterine PGF2alpha 
  • production of IFN-tau from mononuclear trophoblast cells of conceptus from blastocyst stage 
  • blocks uterine oestrogen and oxytocin receptors upregulation. Promotes PGE2 production 
  • Acts via IFNAR1 and 2 via multiple secondary messenger pathways (JAK-STAT)
  • IFN-tau also stimulates endometrial gene expression to prepare for pregnancy 

20

What is MRP in pigs?

  • luteolysis in cyclic pigs via oxytocin and increased uterine PGF2alpha 
  • requires at least one embryo in each uterine horn 
  • rescue at day 11-13 coincident with blastocyst expansion 
    • not as large as in cow or sheep
  • expanding blastocyst makes oestrogens 
  • treatment of non-pregnant sows with oestrogen, either systemically or intra-uterine, at this time extends luteal function 
  • oestrogen from the conceptus has BOTH
    • anti-luteolytic actions 
      • diverts PGF2a to exocrine secretion (in lumen), aided by prolactin 
    • luteotrophic actions 
      • produces PGE2, → LHR 
  • conceptus also produces IFN-gamma and delta 
    • don't know what they do
    • not necessarily essential 
  • cyclic
    • endocrine
    • PGF2a secreted from uterus into uterine vein at day 11-16
    • PGF2a induces luteolysis 
  • pregnancy 
    • exocrine
    • PGF2a secreted from uterus into uterine lumen at day 11-16 
    • blastocyst oestrogens redirect direction of PGF2a secretion 
    • also increase PGE2 secretion (PGE2 luteotrophic)
    • blastocyst also makes a nocel interferons - angiogenic/immune effects?

21

What is MRP in horses?

  • really don't know much about horses
  • luteolysis in cyclic mares via uterine PGF2a BUT 
  • conceptus produces PGF2a, migrates 12-14 times a day along uterine horns - has to go up and down etc etc, needs to be very active, trying to stop that will induce luteolysis 
  • antiluteolytic/luteolytic signal unknown
  • expanding blastocyst makes oestrogens, principally oestrone (also horse specific equilin and equilenin). Also IFN-delta
  • PMSG/eCG made from d40 → secondary CL until d140
  • stimulates the ovary to go through folliculogenesis → ovulates 
  • progesterone is not the principle prostagen in horses 
  • now discovered that the placenta makes progesterone but it is very quickly converted by 5alpha-reductase to dihyrdoprogesterone - DHP keeps pregnancy going 
  • march this year 
  • foetal androgens (DHA sulfate) used by placenta come from foetal gonads not adrenal 

side note

  • camelids (llamas etc)
    • involves increased PGF2a but anti-luteolytic signal unknown 
    • left horn implantation 
    • oestrus 
      • female camel will just sit down 

22

summary: MRP

  • multiple physiological changes in mother due to pregnancy 
  • maintenance of progesterone secretion by CL 
  • luteotrophic support (primate - CG production)
  • anti-luteolytic effects
    • prevents PG synthesis 
    • redirect PG away from ovary 
  • multiple mechanisms may operate simultaneously 
  • initiate signal before others take over  
  • timing is everything