Lecture 14 Flashcards
What effects does progesterone have in the placenta?
Suppresses myometrial contractions throughout pregnancy –> Could damage fetus and limit its space; Promotes formation of mucous plug in the cervical canal; Prepares mammary glands for lactation
What are the effects of oestrogens in pregnancy?
Proliferative effect on: Uterus (makes it as prepared as possible for implantation), Breasts (ductal structure); Preparation of uterus and cervix for labour; Induction of pro-labour genes potentially
How are sex steroid hormones (e.g progesterones/oestrogens) produced in the placenta?
Precursors and enzymes are located in different places; Need cholesterol from mother –> Needs to pass into placenta to be converted into sex hormones (oestrogen/progesterone); Some cholesterol is converted directly into progesterone and goes back into maternal circulation to have effects on cervix and breast tissue; Some cholesterol moves from placenta into foetal blood –> Transported to foetal adrenal cortex where it is converted to DHEA –> DHEA re-enters foetal blood supply and goes back to placenta where it is converted to oestrogens and oestrogens re-enter maternal blood supply
What is the biosynthetic pathway for oestrogen production in the ovaries?
Go from cholesterol to DHEA; DHEA to androstenedione; Androstenedione to either testosterone or estrone; Then go from these to oestradiol (E2) –> main oestrogen produced from ovaries
What is the biosynthetic pathway for oestrogen production in the placenta?
Go from cholesterol to DHEA; DHEA to androstenedione; Go straight from androstenedione to estrone (E3) –> no testosterone production; Slightly different form of oestrogen so binds different receptors and has different effects
What is the human progesterone paradox?
In other mammals, at the end of pregnancy, see levels of progesterone plummet –> Removes quiescent drive to the uterus and allows it to become more excitable and can contract –> Initiates labour; In humans, can still induce labour with high levels of progesterone so must be something that overrides it –> Combination of actions of oxytocin and prostaglandins override this
What makes birth different in humans?
Need certain positioning and rotations of baby during birth –> Very difficult and tricky to do –> Heads of babies are very big comparatively to the channel size; In other nearby species, don’t have this as the space through which baby has to pass is much easier and bigger; Need extra step of making tissues and ligaments as stretchy as possible to allow flex; Need to birth sooner than other mammals too –> finish pregnancy earlier than we should, e.g lots of other mammals birth babies that can walk
What evolutionary changes have occurred to our parturition genes compared to nearby mammals?
We have much higher production of oxytocin- and prostaglandin-related receptors and synthetic things –> Levels of these get much higher in the end of our pregnancy than in other species –> Shows that oxytocin and prostaglandin drive parturition sooner than it otherwise would be
What are the current hypotheses for resolving the human progesterone paradox?
There are a few aspects to overcoming the progesterone paradox –> not simply just having higher levels of oxytocin and prostaglandins; Evidence that even though progesterone levels stay high, can have more tissue-specific progesterone withdrawal –> E.g can reduce number of receptors etc so can reduce the effects of progesterone in various tissues; Evidence for increased progesterone metabolism so has more focused effect on driving mammary gland development –> But also loses some quiescent effect on uterus so increases contractility
What are the 4 phases of human parturition?
Phase 0: quiescence –> End of phase 0 = beginning of parturition; Phase 1: preparation for labour (activation) –> End of phase 1 = onset of labour; Phase 2: active labour (stimulation) –> End of phase 2 = delivery of the fetus; Phase 3: involution
What are some of the key hormones involved in phase 0 of parturition?
Progesterone; Prostacyclin
What are some of the key hormones and receptors involved in phase 1 of parturition?
Uterotrophins; Prostaglandins; Oxytocin receptor; Relaxin
What are some of the key hormones involved in phase 2 of parturition?
Uterotonins; Oxytocin; Prostaglandins
What are some of the key hormones involved in phase 3 of parturition?
Uterotonins; Oxytocin; Prostaglandins
When does parturition begin during pregnancy? What happens here?
Parturition starts at roughly week 25 which is the beginning of phase 1 –> Phase 1 is preparation for labour in last trimester –> Makes uterus much more receptive to being able to contract –> Start to produce prostaglandins, increase expression of oxytocin receptor and start producing relaxin which helps ligaments and tissues to become more stretchy –> Allows cervix to relax more and not be damaged when birthing the baby
What happens during phase 2 of parturition?
Phase 2 = active labour; Length depends on how many babies you’ve had; Really ramp up oxytocin/prostaglandin levels to drive contractions; At end of active labour, get delivery of foetus
What happens during phase 3 of labour and why?
Phase 3 = involution; Have residual levels of oxytocin/prostaglandins that drive the delivery of the placenta –> Also starts driving involution of the uterus
What happens cellularly in the uterus during parturition?
Starts at roughly week 25, start of 1st trimester; Start to get degradation of extracellular matrix around amniotic sac; As you continue to parturition, lose tissue integrity which helps with breaking waters etc to allow birth; Big changes in inflammation, expression of various ion channels to drive relaxation in cervix to allow body to pass through but also change excitability/contractability in uterus to push baby out
What sorts of mechanisms occur during the state stages of parturition? Why?
Seems like positive feedback system that drives all this –> As foetus grows, causes stretch of uterus –> Stretch stimulates increased uterine growth –> Also has increased progesterone levels from HPA which drives uterine growth and allows foetus to get bigger and positive feedback –> Reach critical point where oxytocin and prostaglandins reach really high levels to overcome high level of progesterone
Why do we use mice to study labour and the things involved in it?
Mice used as gestational period is quite short (20 days); Breed easily and have large litters; Typically make knockout versions so easy to see effects of various things on this process
How does labour occur in mice?
See in mice that there is a process of things that need to happen to drive onset of labour; See increase in production of arachidonic acid from membrane phospholipids by cPLA2; Arachidonic acid gets turned into PGF2alpha by COX-1 and PGR synthase; Causes regression of corpus luteum so lose production of progesterone; Drop in progesterone drives contractility and labour onset
What happens when the enzymes involved in the pathway for labour in mice are knocked out?
cPLA2 (-/-): No labour; COX1 (-/-): No labour; FP receptor (-/-): No labour (receives signals from PGF2α); All non-labour phenotypes rescued by surgical luteolytic (removal of the CL) or pharmacological administration of PGF2α –> Shows that increase in prostaglandins really drive drop in progesterone
How do the levels of the key enzymes involved in parturition in mice change during gestation?
Levels of COX-1, COX2 increase to drive more prostaglandins production; Have more PGF synthase so more specific production of form of prostaglandin we need; Less PGDH which breaks it down to inactive metabolites; All combine to give surge in PGF2alpha (type of prostaglandin we need) at day 15 of gestation to drive labour onset
How did studies determine the role of oxytocin in parturition in mice?
Would expect knockouts to not deliver pups properly; OT (-/-) mice can deliver pups normally without oxytocin but the pups die as mother can’t produce milk; Without oxytocin or COX, labour takes longer; Oxytocin plays important role in timing of labour and driving it to completion faster –> Really drives progress of labour –> Need prostaglandins to start things but oxytocin drives its progress; Days until labour are lengthened without oxytocin
