all Flashcards
what does a steroid recpetor complex bind to on DNA?
SRE
or promoter
what cell synth steroid in the testis?
leydig
What is the process of T synth in the testis
LH bind LHR on leydig
stimulates the production of T from cholesterol
T diffuse into blood
Sertolic cells have FSHR
FSH bind FSHR stimulate the conversion of T into DNT by 5a reductase
what is the phenotype of an ARKO mouse
testis size 20% of normal
spermatigoenesis arrests at spermatocyte stage
female appearance
how is estradiol made by testis?
androstendione into esterone by aromatase
esterone into 17b estradiol (reversible
androstendione also into T then aromatise
is oestogen imp in testis?
yes ko mice spermatogenesis starts but fails
what occurs in the epididymis?
sperm maturation
what occurs in the seminiferous tubules?
sperm production
what is the purpose of the menstrual cycle?
release of gamete
prepare endometrium for implantation
what are the four phases of menstrual sycle in the uterus
menstrual = failure of imp in last cycle (d1-5) proliferative = repair lining (d5-14) ovulation = release of oocyte (d14) secretory = endo secrete to support implant (d14-28)
What are the two phases of the menstrual cycle in the ovary?
follicular = follicle dev/ovul occurs at end (d1-14 luteal = corpus luteum releases prog (d14-28)
what is an oestrus cycle?
behaviour strategy to ensure mate at ovulation
inc atractiness/recpetiveness/proceptivity
do humans have an oestrus cycle?
attractivness = male prefeer female smell at ovul
receptivity - no ev
proceptivity = dance changes/female tolerate male sweat more near ovul/women isntigate sex more second half of cycle
describe the hormone/brain synthesis
kisspeptin stimulates hypothalmus to produce GnRH
GnrH stimulates the anterior pituitary to relase GN (lh and FSH
these diffuse in blood to gonads
at the ovaries Gn involved in oocyte release and sex steroid synthesis
sex steroid feedback to brain (neg and pos) and also accesory reproductive organs
what is puberty?
individual acquires the beahvioural and physiological attributes to reproduce
what factors infleunce timing of puberty?
genetics is largest factor
stressful events
intra family relationships
endocrine disruption
what evidence is there nutrition afffects initiation of puberty?
japan 1940-70 14-12.5 spanish civil war menarche incr cameroon rural 14.3, urban 13.2 malnutrition/athletes pot critical weigh needed
what evidence is there leptin is important?
increases at start of puberty
KO mice = underdev gonads/ low Gn
treatment reverse abnormalities
what evidence that leptin not the sole signal?
no Leptin receptor on GnRH neurones
what evidence is there Kisspeptin important in puberty?
disrupt the kiss1 gene = infertile
treat rats with Kp = advance time of puberty
is produced in the ARc and AVPV in hypo
its recpetor increases in AVPV at puberty
recpetor expr in GnRH neurone = act GnRH
how does the GPR54 neurone influence transcription
confirmational change reveals a domain Gaq activates Phospholipase C Gas activates adenylate cyclase PLC pathway activates diaglycerol Protein kinase c cascade that activates GnRH transcription plc pathway also release Ca plc also act MAPK mut in rec = delay
what is the link of Kisspeptin and leptin
leptin R on kiss1 neurone
what is the strucute of fsh/lh?
dimeric pr
ab units
b units specific
what are the two isoforms of lh/fsh and why do they form
acidic and basic
post transciriptional mod due to conditions
what is the properties of basic and acidic Gn
acididc =decrease rec bind/bioactivity and incr half life
basic = incr rec bind/bioactivity and decr half life
when are the differnent isoforms if the Gn imp?
basic FSH = select follicle
acidic FSH= follicle dev
basic LHM = young women
acidic LH= menopausal
what are the differences between LH and FSH release
FSH consitiutive pathway = little storage
LH packaged in electron dense granules in association with the storage pr secretogranin II at the mbm
what is the recpetor chnages thta cause LH and FSH secretion?
in a pit GnRH bind
conf change
Gaq reveal
a disassocaites activates PLC activates PKC and Ca
PKC act MAPK
MAPK in the nucleus effect the transcription of the subunits of gn
what are the regulatory drivers of folliculare dev
lh
fsh
follicle (oocyte and somatice cells)
why are the somatic cells of the follicle important
as the oocyte has no FSH and LH receptors
desccribe the development of teh primordial follicle
migrate germ cell to feltal ovary mitosis and incomplete cytokinesis (=germ cell nests) some meiosis but arrest P1 break down cellular bridges and flat layer of granulosa cells
What regulates the devlopment of the primordial follicle
theoocyte
what evidence is there that primordial germ cells in adult life in humans
oogonal stem cells in mice
inddx4 only exrp in germ cells detect with antibody then isol
put into mic with GFP
found GFP + cells throughout the tissue
= mitotically active germ cells that can be programmed in vivo
describe a primary follicle
oocyte still in p1
cuboidal granulosa cells
zona pellucia formed
describe a secondary follicle
oocyte still in p1 multiple layer g.cells zona pellucida theca cells interna (nect to g cell imp in sex steroid synth/externa (structural support) bigger strucuture
what are the singal involved in the change primary to secondary follicle and when does this chnage occur
GN independent
regulated by factors folicles release
OSF = TGFb (GDP and BMP15/ activins and inhibins promote fol dev) ko =infert
activins increase g.cell and stop thecal cell androgen synth
g.cell release anti mullerin hormone and kit ligand
kit ligand ko = no further dev (balance act vs inh factors )
occurs all the time/ takes 2-3 months
describe a tertiary foolicle
oocyte sona pellucida theca (e/i) g .cells = mural (wall of cavity) and cumulus(by oocyte antral cavity (fluid from g.cell sex steroid synth
singal involved chnage seconddary to tertiary follicle and when does it occur
FSH
every month one foolicle sel for further dev
hormone / steroid changes in early folliclular phase
no sex steroid prod = low oest = FSH rel inc
this promotes 2-3 foll change
3 foll rel sex steroids
what cell of 3 follicle involved in sex steroid synthesis
g.cell and thecal
lh bind thecal = produce androgen
androgen diffuse into g.cell
aromatase in g.cells = oest
hormonal changes in mid follicular phas
increase oest = neg feedback
decrease in FSH
sel of follicle = sensitive to FSH
what cell of the follicle have receptors for GN and how do these regulate steroid ynthesis
g.cell and theca
GPCR
Gas activate adenylate cyclase = CAMP = PKA act +phosphy pr imp for enz in steroidgenesis
what are the three main roles of follilce in regualting its own dev
OSF = influence cumulus cells (bind ser/thr kinase - act Smad mol - translocate nuc and act as TF) = regulate g.cell prolif/diff/ estrdiol prod and metabolism nutrients = g.cell prid chol (oocyte can't meotic arrest (cGMP hgih - high CAMP = act Wee1, WEe1 inh MPF
how do oocyte and somatic cell communicate>
via gap junctions
connexin 43
whatare the layers in the endometrium and cells
functional zone (lumenal and glandular epithelium) basal zone
what underlies endometrium
myometrium
what layer of endometrium is shed at menses
functional zone
what change to endometrium occur during the proliferative phase of the uterus>
F.zone luminal and glandular epithelium proliferation stromal cell proliferation endothelial proliferation (incr b suply) glands enlarge in f zone(imp for impl) incr cervical mucus incr Prec expr
what are the changes in endometrium occur during the proliferative phase of the uterus dependent on?
oestrogen from developing foollicle in ovary
what inh classical ER rec
prog
where are classical ER rec expressed
epithelial and stromal cells
not static follows oest levels
what form of ER imp in proliferative phase
alpha
are both stromal and epithelial ER classical recptors important in proliferative phase
only stromal
(Balb/c mice wiht no ERa on epithelial cells and ERKO, mix so WT and KO of ERs and ERe cells)
no rec in ep sim to wt no rec in s no prolif
how do ERa stromal and epithelial cells communicate>
paracrien signals IGF-1 made in s cell and rec in ep invitro stim prolif incr at prolif phase oest stim IGF and IGFr act PKB pathway KO = epitheial cell of endo no resp to oest ko rec = inh oest stim proli of epithelial cells
are mbn bound er imp in the prolifertive phase?
moer mice (only mbn bound)
cant get preg/ no ovul/oestrus
comaprable to ERa KO
not sufficient
are GPCR ER imp in proliferative phase >
Ko still fertlie with norm repr histology but expr follows oest dependent manner
what is the role of ERa epithelial cells
protect against apoptosis
ko assoc with incr apoptosis
also needed with ERa stromal for secretory pr production
also imp in prevention of phospy of stromal era
= regulatory control?
how do OSF influence the selcetion of the dominatnt follicle
regulate prolif of granulos proliferation
matrix proliferation = imp for movement of follicle ot ovul
influence pest prod = incr chance of sel
incr osf in culture shown to incr quality
what factors infleunce the sensitivity of the oocyte to FSH levels?
activin / inhibin
estradiol
igfs
what are activin and inhibin
TGFb fmaily pr
dimeric
produced by granulosa
the role of activin
in arly follicle
enh granlosa prolif = incr ize inc oest =autocrine
stim FSh prod
incr FSH sens (incr rec on granulosa)
the role of inhibin
later stage of maturing ollicle
inh fsh prod
sensitise follicle to fsh (incr rec on g cells)
promote LH stim androgen prod ( in thecal cells method to inc oest feedback to decr fsh
how does estradiol infuelnce senstiivity of ooctye to FSH
enh armonatase = incr oest
stimulat g.cells LH rec
suppres FSH in apit = v lov levels
how do insulin like growth factors infleunce the sensitivity of oocyte to FSH?
stimulate g.cell prolif = more oest 7augment stim effect on gn on steroidengenesis to incr oest
(incr oest in folllicular fluid of dom follicle )
how is igf activated
norm bound bp
these inh ingf activity and in mares follicular dev
fsh stimulates prod of igfbpproteases
supr of igfbp
what characteritics of dominatn follicle
high inhibin:activin
sens to low FSH
high igf;igfbp
expr LH rec
describe the hormonal events at lh surge
lot of oest
oest threshold changes to positive feedback to hypo
ERa on kiss1 neurone in avpv essential for this
fast pulse GnRH = LH
what occurs in the ovary at the LH surge?
Resumpition of meiosis
progesterone secretion
plasminogen and prostglandins activated
corpus luteum left behind in folllicle = rel prog
how does meiosis resume at ovulation
Lh surge induce PKA and PKC pathways to produce EGF-like factors
act MAPK
this interupts cell comm by phisphy connexins43
gap junction closure
dec cAMP in oocyte
no act Wee1 = no inh of MPF - resume then arrests M2
describe meiosis of the released folllicle
asym
m1 = polarise secondary oocyte and small polar body (0.5chr no cplasm)
m2 = 2nd polar body
What controls the asym division of the ovulated folicle
position of the spindle/cortical graules/microvill reorg /myosins GTPases
important for maintenance of cplasmic stores for oocyte and sperm bind (microvilli all around oocyte - factor in ageing)
What changes are occuring at the early secretory phase in the uterus?
oest higher than start of cycle - lh still but falling
(osetrogen has primed endo with Prec)
prog produced act by Prec - inh ep prolif (stormal PR only)
stimulates decidulisation of endo
mucus thickening
what is decidulisation?
gland devleopment and secretion
stromal oedema
maturation of spiral artieries
in preperation for preg
what hormonal chnages occur at the late luteal phase?
decrease in prog as corpus luteum degen
decr oest feedback to a pit decr lh
what hormonalc hanges initiates menstruation?
withdrawl of prog from endo
what physiological chnage sin menstruation?
shedding of fucntional layer is progressive process
some areas unshed/partial/completly to decrease risk of haemorrage and infection
pre men = extensive b,vessels/tall columnar ep cells/tooth glands
early zonal shedding= linear cracks/detached ep/glands stumps and surface ep
later zonal shedding = multiple tubes and remenants of glands an d b vessels
healing = fibrin matrix and new ep cells/ new and unrepaired epithelium/ small and cuboidal ep cells
what vascular chnages ccur in menstruation?
spiral artires constrict
and vaso dilation
pot mediated nitric oxide prostoglandins?
what causes matrix degradation during menstruation?
stroma expresses MMP1/2/3
epithelium expresses MMP7
regulated by progesterone
what hormone rescues the corpus luteum at preganancy?
human chorionic gonadotrpohin out of the ST from the embryo
signals via LH rec
what is the corpus luteum?
after ovulation what is left behind of the follicle
thecal cells beocme small lutein cell that prod prog
granulosa cells (mural) form large lutein cells that prof prog and oestrogen
LH req for maintenace
what is ovulation?
release of the secondary oocyte from follicle
what cells stay asssociated with the oocyte after ovulation
cumulus cells
what is the epididymis
sperm collection and maturation (here 14 days)
beocme motile
what is the vas deferens
transport tube in testis = sperm forced here by contraction in sexual arousal
what are the accessory glands
ampulla and seminal vesicle (reservoir end of vas def)
ejaculatory duct
prostate gland (prostate fluid imp in semen)
bulbourethal gland adds fluid at ejac
where does sperm production occur?
seminiferous tubules
what are the two main cell pops of the seminiferous tubules
sells of spermatogenic lineage
sertoli cells
where do you find spermatoagonia
near the basal comparment of sertoli cells near myoid cells and capillaries
where does spermatogenesis occur
sertoli cells
start at basal lamin
move towards adluminal compartment more developed sperm
1 germ cell undergoes how many round of mitosis to become spermatagonia
4
produes 16 cells
all 2n
what occurs to make spermatagonia a primary spermatocyte?
growth
what occurs to go from primary to secondary spermatocyte
one round meiosis
secondary spermatocyte to early spermatid
another round meiosis
late spermatids different from early spermatids
have flagella but cytoplam still joined
how many rounds meiosis and mitosis in spermatogeneis
4 mit
2 meiosis
how many sperm cells produced from one germ cell
64
what is the final stage of spermatogensis
spermiogensis
maturation early spermatid to spermatazoa
cytpolasmic remodelling to get classic sperm shape
the process of spermatid remodelling in spermiogensis
distal centriole = flaellum dev from MT of centriole
proximal imp for dev of sperm head
loss of resiudal body4
mitochondria
Acrosome formation - a golgi body derived vesicle whcih forms a cap
what enzyme in the acrosome cap?
hyalouronidase = released when sperm reach oocyte
digets the cumulus cells and zp
3 main parts of sperm strucutre
head
mid piece
prinicipla piece
what features in the sperm head?
DNA heterochromatin
perinuclear space
cell mbn
acrosome soread over the nuclear apex, DRY192 gene encodes a pr that anchors nuc mbn to acrosome cap
neck contains mito sheah around mt network
what features in the sperm mid piece
mito sheath
with helicoidally arranged mito
dynein needs ATP
sep from prinicipla piece by jensens ring - dense material
what features of the principal piece?
fibrous sheath
9x2 mt
no mito
where do sperm become motile?
in epididymis aar of DHT
what is spermiation?
the release of spermatids from sertoli cells prior to passage in epididymis
occurs over days
more streamlined sperm produced
how many sperm start developing each day and how many complete?
3x10*6
half die
but waries lot person to persom
even between people = one study 3 years 20-170mil/ml
how many sperm per ejaculate
39x10*6 less that 40% motile less than 4% norm morphology
what is the current trend for sperm count and why
decrease
age/smoking/oxidative stress
decr 59.3%
below 20 mil /ml big effect of fert suc above no big diff
how many sperm in the female tract
vag 107
uterus 105
10*2 f.ube ampulla
what changes to the cervical mucus occur at ovulation
prog dom
decr mucin produced
loss hydration
prevent sperm entry
what some of the sperm defects seen in inferile males
globosoospermia - round head sperm/no acr cap/ mut in DRY 192 = cant fert
what factors influence male infertility
hormone imbalance
infection
morphology
problem with ejeaculation
what probelm arise from ICSI
bypass a natual selection point = no selection on good fertility genes
in mice = ageing and tumour incr and decr in offspring
what occurs as soon as sperm is deposited in the vagina an dwhy is this important?
forms fibrin like gel
which retians sperm and biffers against acidic cervical fluid
what is the function of human cervical mucus
protect cervix from hostil vaginal env
resticit sperm entry to the peri ovulatory period when the mucus is less viscous
restrict abnormal sperm entry
E ?
remove factors from sperm eg chol and anti capaacitation factors that prevent sperm occuring
(only when no Prog sperm can penetrate)
where does fertilisation occur?
at the ampulla of the fallopian tube 10*2 reach 2cm distance
how do sperm get to the fertilisation area?
own motility
uterine cillia dev a current?
but immotile isthmus of oviduct
what is capacitation?
acquire fertilisation competence
why is capacitation necessary?
alllow sperm to bind Zp
what drives capacatation?
sterol bp initaiate loss of chol incr mbn fluidity
needs external HCO3 = adenyl cyclase promotes cAMP dep tyrosine phosphy of specific pr
incr intracell ph = act ion channel in flagella (k entry= hyperpol=ca influx by catsper)
ion inlfux =motility change
what changes occur to sperm at capacitation?
hyperactivee motility detach from oviductal epi removal of seminal glycopr entry ca and rel from internal stores export proton cytoskel change expose rec for zp2 3
prior to fet what oocyte surrounded by
cumulus oophurus
what are the six stages of fert
zp bind acrosome reaction penetrate zp bind p mbn fusion nuc enter cplasm
what rec is necessary for zp binding
zp3
what are the two steps zp binding
= intial b1-4 GALT independent
SED1 sperm rec imp
firm sperm zp binding and induce aggregation of sperm rec GALT
=GALT dependent
binds ZP3
binding - cluster of rec on side of sperm head,
acrosome rel acrosin - digest whole through zp
zp2 imp for skeeping sperm and sp attach
in humans zp1-4 imp
what is the zona pellucida
glyco pr coat layer inc pr zp1-4 human
1-3 mice
what triggers acrosome reaction
GALT sperm rec bind ZP3
but observed in mice areaction before zp = no galt
what changes occur at acrosome reaction
p.mbn of spern and outer acrosom mbn multiple fusion
anterior sperm head enclosed by inner acrosomal mbn
what is acrosome reaction dependent on?
Ca
plc act ca influc
induce exocytosis of cap
and convert proacrosin to acrosin
how do sperm penetrate the zp
motility
proteases and glycosidase
where does the sperm binding to the p.mbn occur
at microvilli free region far from meta chr
how does sperm binding to the p.mbn occur?
by equatorial segment
(same pr that drive fusion?)
pot vitronectin rel at acrosome bidge helps other bind?
what pr are important for the fusion of the sperm and egg
CD9=
on ooocyte mbn in microvilli
KO no fusion
izumo = immunoglobin fam pr KO bind not fuse
what happens to the sperm tail at entry?
into egg
sperm bring centriole - form aster for first mitotic div
What activates the egg
series of intracellular calcium oscillatiion
ER rel 40-400nm Ca
occur one min after fert
one min duration and between 3-15 mins
need internal ca and doesnt occur in ca free external media
what how long do calcium oscillations continue for
pronuclear fromation
why calcium oscillation importnant?
cortical granule extension
resumption meiosis
pronuclear formation
how is polyspermy prevented
ca dependent fusion and exocytosis of cortical granules w enzymes at mbn
these inc protease which cleave ZP2
enz also induce crosslink of zp = no bind/entry
also strip sperm rec from mbn. and harden zona by peroxidase mediated oxidation
what occurs in the prelacunar phase?
trophoblast differnenitiates into two pops
what are the two populations of trophoblast cells at the prelacunar stage
cytotrophoblast = mono nuc/nearer embryonic disc/stem cells prlif and fuse
synctitrophoblast - syncital fusion of CT forms multinucleated ST/sgl cell continuous layer /terminally differentiated/inasive ptype/in contact w mat cells/expands and surrounds blastocyst
when does the lacunar phase occur?
8 days pc
what occurs at the lacunar stage
vacules appear in ST and coalescce= lacunae
llacunae sep by bits ST called trabaculae
blastocyst embedded
when the lacunar sytem has developed what layers of placecnta can be categorised
chorionic plate
lacunar system
trophoblastic shell- contacts endo and anchors
how does maternal blood enter the lacunar sytstem
ST pentrate interstitium of endo
contact mat capillaries and venous sytem of endo
erode vessels
=mat blood enters
how do primary villous trees form and when?
CT from priamry choironic plate invade downthrough the trabeculae down to the trophoblastic shell and contacts the lacunae.
d12-15 pc
how and when do secondary villous trees form?
mesenchymal cells penetrate the primary villous between days 15-21
when and how do tertiary villous trees form?
when the b vessels start to form from mesenchyme cells derived from hemangioblastic progenitor cells
vasularisation of the strucutre and occurs days 18-20
when and how does connection of maternal and fetal circulation occur
-5 weeks pc
fusion of the allantois with the choironic plate form = umbilical cord forms
choironic plate fuses with the villous cap
what are the four main step of villi development that continue though pregnancy
CT prolif
CT fuse
mesenchyme migr
formation of vascularised stromal core
what featres are there fo theird trimester villi?
stem villi
terminal villi = specialised fr transport
what ST specialised for
nutrient and gas exchange
what changes in morphology happen to placenta in 3rd trim to support dev fetus
decr diameter of villi
thinning ST
highly vascularised
vasculosynctial mbns = capillaries v close to ST
what the function of the placenta
nutrient gas exchange
hormone synth
protective barrier
what cells of placenta make hormones
ST
hcg and prog estradiol
role of the hormones prod by the placenta
hcg= save cl and essential for norm preg
prog=inh myometrial contraction/ strengthen connective tissue
oest= stim growth of brest tissue and myom layer/incr uterine b.flow
hwat metabolic adpatation occur in preg
1st trm = facilitate fat storage
3rd trim= mobilisation of fat stores by placental lactogen/gf make insulin res
how does the placenta act as a protective barrier?
cell surface transporters MDR! and BCRP , pump toxins out of placenta
why is there no immune reaction in pregnancy?
fetus allogenic
st dont have MHC class 1 antigen = hide
represed mat immune syst
what are hofbauer cells
fetla macrophages
derived from mesenchymal stem cells
promotes placenta angiogenesis
what change occurs to blood flow and how?
35-50% incr out put
by incr CO/sv/hr/ decr res
what changes in flow occur in the first 20 and last 20 weeks ?
incr in flow aar of incr flow ratte
incr in flow aar of incr diameter of UA
what stimulates the vascular chnages in preg?
metabolic
mechanical
hormonal
what signals do the endothelial cells of vessels release
prostaglycin
NO (oest effects, in primates incr oest incr no =dil)
EDHf
in the first 11 weeks what why is there no blood to placenta
extravillous trophoblast cells that invade the maternal spiral arterioles and accumulate to form plugs
also line and remodel the maternal SA to allow the blood to get to intervillous space and not dmaage
what are the two type of CT
extravillous trophoblast (imp in plugs) villous trophoblast (proliferate and fuse = the stem cells)
where are the two locations EVT invade
spiral arteries and uterine glands
aside from damage why trophoblast plugs important
hpoxic condtions in placenta imortant for DNA transcription
how and when do trophoblast plugs form
invade from implantation
but CT radiate away from shell to group of glands
these cells form the plugs of the SA (EVT)
what two components remodel the artieries
maternal leukocytes *unk and macrophages)
trophoblast
the steps of remodelling
1-leukocyte - vsmc interactio 2-leukocyte- ecm interaction 3-trophoblast - vsmc interaction 4-trophoblast - ecm interaction l
consequence of remodelling
loss of vsmc =insensitive to maternal constriction
loss of elastic lamina - loss of ealstic recoil and irreversible expansion of the arterial channel.
low res blood to intervillous space
when does remodelling occur
pre 11 weeks to 18 weeks
where does the trophoblast invasion continue until
reaches arterial segment sin the inner thrid of hte myometrium
difference in the remodelling in the myometrium
less lukocytes
mainly trophoblast
mosty in 2nd trim as takes times to get past functional zone
what happens do plugs after 11 weeks
displaced and intervillous space a shut oxygenated blood passes through at low pressure
% of coneptions reach= implantation]
recognised preg
live brith
75
60
50
effect of age on success getting preganat
decr due to oocyte quality
incr risk misarriage down
how successful is ivf
29% clinical preg
21% live birth
how common are chr abnomalites in oocyte/blastocyst/zygote
20
50
40
first trimester and chr abn
90% chr abn misscarry 1st trim
60% of all 1st trim miscarry chr abn
why is it difficult to determine embryo chr
genetic mosaicism
diff ways detect chr abn
fish
TE biopsy
comparative genomic hybridisation
other factors link to miscarriage
lif imp
poor decidulistion
SA not remodel
immune recog
what is pre eclampsia
complex heterogenous syndrome
what symptoms of pe
in 3rd trim hypertension/oedema/proteinerea someimtes fgr
what are risk factors of pe
hyper tension 20%
prev pe 23%
chronic renal disease 30%
diabetes
how to treat pe?
early delivery
is pe big porblem
yes 50000=70000 each yr die worldwide
causes and physiological links of pe
problems with placenta
remodelling failure -no incr b flow stll high pressure
severe early onset - fail to remodel in myometrial seg
result in shear stress in intervillous space = oxiddative stress?
release of microparticles = immune/vascular act result in decr atp
and decr uteroplacental perfusion
activation of endo cells = pedema/proteinurea/platelet act
how could transriptomics be used to treat PE
look at mrna levels
see if common gene inv
give idea of the molecular pathways inv
long term effect of pe
incr risk nearly by 2 of cardiovasc disease
incr pe risk again
how common is fgr
5-8% preg
75% missed antenatal
the consequence of fgr
iatrogenic preterm brith
neonatal morbidity
lifelong disabilities
stillbirth (more than 50% sill birthfgr)
what causes of fgr
placental dysfunction
placentla abnoramlities
what are the placental abnormalities that can cause fgr and how do they
abn dev
- decr villous tree/dec SA
- thicker ST
- cell turnover/less CT prolif and ST growth = less branched smaller placenta with limiting supply to fetus
Abn blood supply
- no remodel=decr supply
- no blood flow in diastole shwon by doppler
- decr mat perfusion
- werid cord placement
- plac arteries constrict
REduced Activity nutrient transporters
- syst A decr 50%
- ca x2 in st of fgr
Endocrine function
-lower conc of placentlal hormones in mat blood
hpl/pgh/pigf
how are placental probs currently detectted?
ultrasound/doppler utlrasound
future prospects of monitoring for fgr
placental ultrasound
measure conc of placental hormones in mat cric
similarities between human and mouse placenta
hemochorial - T cells bathed in mat blood
have decidua/evtchoironic plate and u cord
transport syst - glut1
dim diffusion characteristics
how is mouse differnet to human placenta
labyrinthe - T lined mat blood spaces interwoven w fetal capillaries in a labyrinthe
2 zones - spongiotrophoblast(for endocrien and labyrinthe
hemotrichorial - 3 layer t cekksbetween mat and fetal blood
have two types invasie T=giant cells and endovascular T
what is the effect of IGF 1 ko
IGF 2 ko
fgr
fgr and placental growth restr
ko igf2 in plac only via mut in prmoter
fgr and placenta growth rest= show reduced plac size a cause of fgr
ptype of no igf2 in placenta
decr i labyrinthe by 50%
decr spongiotrophoblast zone
thicker exchange barrier
effecton transport system of igf2ko
igf2 plac only
decr syst a at d19
no decr elevated at d16 (perhaps upreg to compensate for decr growth
when are Gc administered therapeutic
labour at les than 32 weeks to get lung dev
whats the role of 11b hsd2?
and role in fgr
converts cotrisol to cortisone
expr in st
decr in fgr
impact of gc on placenta dev
gc to preg rat = decr fetal and placental weight /decr syst a
ko 11bhsd2= model fgr supports expsure to cotrisol casue fgr
impact of gc on human cells
impairs angiogensis
decr igf1 expr
incr vasocon of arteris
what is the barker hypothesis
low weight at birth less than 5.5lb = increase risk of disease later in life
inc t2 diabetes every incr of 1kg in bw decr risk by 25%
obesity = both low and high weight maker more liekly (43/34)
studies shown the impact of stress and undernutrtion
sheep - pr rest 60 days b4 preg and 30 days after = preterm delivery and neonatal death
humans - dutch hunger winter, low mat bmi famine b4 or in early preg had early delivery
impact of stress at preimplantation
mice fed low pr diet at preimp
= blastocyst reduce cell no
both = acc postnantal growth /hypertension
female offspring- decr b weight
male offspring - incr systolic bp, abn org;mass ratio
do culture condtions effect mouse embryos?
yes decr in no of TE cells in ivf
decr in icm due to embryo culture
what genes effected by culture conditioNS
imprinting
example of an imprinted gene effcet by cuturie
h19 biallelic after culture
negative reg of igf2 - decr in igf2 expr
long term effects of culture onbehaviour in mice
elevated pllus maze test showed less anxiety and memory
effect of stress in preganancy
decr fetal growth
rats synthetic gd decr placental growth and bw
rats undernutrtion decr 11bhsd2
what is glycyrrhiz contain?
11b hsd2 inh
more than 500mg/week= earlier labour/cognitionve beahv diff/incr contrisol effecting brain dev
pot treatments of stress
omega 3 = blocks high bp
leptin - rescues mismatich ptype reset E homeostasis pathway
