Week 6 Flashcards
Maternal-Fetal hormonal interplay
From the point of fertilisation the early embryo starts to influence the mother
The embryo/fetus and mother both produce hormones as a means of communication
Endocrine ‘interplay’ allows maternal recognition and support of pregnancy
Human chorionic gonadotrophin hCG
Glycoprotein- a and b subunits. Alpha subunit identical to LH, FSH, and TSH
Acts on LH receptors present on corpus luteum
-maintains corpus luteum
-stimulates DHEA production in fetal adrenal
-in males- stimulates testosterone- masculinisation
In early pregnancy doubles every 48 hours
Used for monitoring pregnancy
-pregnancy test detects b-subunit in urine, positive days 8-12 after implantation
Maternal recognition of pregnancy
Human chorionic gonadotrophin hCG:
-synthesised by syncytiotrophoblast of implanting blastocyst 6-7 days post fertilisation
-released into maternal circulation; blood levels in women 8-12 days post- fertilisation
Useful hormone for monitoring pregnancy: in blood hCG is correlated with decrease in 17ahydroxyprogesterone from corpus luteum
Detectable throughout pregnancy
Progesterone
Absolute requirement for progesterone throughout pregnancy
-mifepristone RU486- anti progesterone used for termination
Initially produced from corpus luteum
Produced from cholesterol by syncytiotrophoblast- placenta takes over from corpus luteum ~6-8 weeks
Luteal-placental shift- progesterone stopped being produced by corpus luteum now placenta. Mismatch can lead miscarriage can take place
Progesterone function
“Progestin”- maintains pregnancy
Myometrium: reduces muscle excitability- decreases synthesis of proteins associated with contractility via progesterone B receptor
-gap junctions (connexin 43) reduce number
-oxytocin receptors -inhibits receptor expression
Endometrium/decidua:
-decidual transformation/maintenance
-immune modulation
Resets ‘respiratory centre’- increases ventilation rate decrease CO2 and increase O2
Thermogenic - +0.5C body temp rise
Increases protein breakdown amino acids get more readily transferred to foetus
Promotes breast alveolar cell proliferation- inhibits lactogenic effect of placental lactogen (hPL)
Progesterone as a substrate for steroidogenesis
Placenta lacks 17a-hydroxylase activity and so cannot convert progesterone to dehydroepiandrostenedione DHEA
Fetal adrenal gland lacks 3beta-hydroxysteroid dehydrogenase cannot convert pregnenolone to progesterone. These modifications result in an alternative pathway for oestrogen synthesis
Oestrogens
Oestrone E1: predominates after menopause
Oestradiol, E2: regulates menstruation
Oestriol E3: pregnancy-specific
Oestrogens 2
Rise throughout pregnancy
Oestriol production predominates (oestriol» oestrone and oestradiol)
Produced cooperatively by placenta and fetus
Progesterone (placenta)—conjugated sulphate-> androgen (fetal adrenal)—deconjugated—> oestrogen (placenta)
Conjugated= water soluble, inactive
The role of oestrogens following implantation
Maternal effects:
-vascular changes:
—vasodilation- increase uterine blood flow
—increase in prothrombotic mechanisms: activated protein C resistance increases, antithrombin III and protein S decrease
-increase contractile associated proteins:
—gap junctions (eg connexin 43)
—oxytocin and its receptors
—myometrial glycogen stores
—breast development (for lactation)
-metabolism:
—reduces peripheral glucose uptake
—increases cholesterol and triglycerides- decreases HDL
Oestrogen synthesis results predominantly in maternal physiological changes
Placental growth hormone PGH
Secretion starts from 15-20 weeks from syncytiotrophoblast and EVTs
Modifies receptors which transport glucose across to the fetal compartment
Levels correlate with placental size
Stimulates maternal gluconeogenesis and lipolysis
No functional growth hormone receptor until near term
Human placental lactogen hPL
Aka human chorionic somatomammotropin
85% AA homologous with GH and PRL
Produced by the syncytiotrophoblast
Rises as hCG falls
Large amounts in maternal blood- little reaches fetus
Development of acinar cells in mammary glands
Aids fetal nutrition:
-suppresses action of insulin in mother- “metabolic screwdriver”
—increases blood glucose levels- more available to fetus
—mobilises maternal FAs to meet fetal demand
Effects of hPL
Maternal compartment: lobuloalveolar development and maturation
IGF-1 increase—> insulin (resistance increases), lipolysis and gluconeogenesis increases
—glucose. Ketones (steroid synthesis)
Key message: placental GH and hPL result in increased maternal glucose for the fetus
Relaxin
Peptide hormone ~6kDa related to insulin
Primarily produced by corpus luteum in pregnant and non pregnant states plus small amounts from decidua and placenta
Levels rise in 1st trimester- peaks at ~14 weeks and again at delivery
Increases cardiac output and arterial compliance
Increases renal blood flow
Relaxes pelvic ligaments and is believed to soften pubic symphysis also promotes cervical ripening
Prolactin PRL
Homology with growth hormone and hPL- half life 5-10 min
Synthesised by lactotrophs in the anterior pituitary gland
Rises linearly during pregnancy
Oestrogen stimulates PRL release by lactotrophs cells in the anterior pituitary and low level PRL from decidua (dPRL- enters amniotic fluid)
3 stages of parturition
Contractions begin, dilation and shortening/effacement of cervix
Full dilation of cervix- delivery of baby
Delivery of placenta
NICE guidelines: intrapartum care
Nulliparous: a women who has never been pregnant
Parous: a woman who has previously been pregnant
Key message: labour consists of a latent phase where cervical changes precede regular rhythmic uterine activity that induced progressive cervical dilation (active phase)
Process of parturition
Key mediators of parturition:
-increase in oestrogen: progesterone activity ratio
-prostaglandins (PGF2a, PGE2)
-oxytocin
Parturition requires 3 key changes:
-initiating signal- increased maternal/fetal corticosteroids
-co-ordinated contraction of uterine myometrium smooth muscle
-cervical softening/ripening and dilatation- progressing from 0cm (closed cervix) to full dilatation at ~10cm and expulsion of the foetus
Myometrial contractility
Myometrium must remain quiescent during pregnancy- progesterone suppresses contractility by decreasing oxytocin receptor expression
At term, rising oestrogen: progesterone activity increases oxytocin receptor levels
Oxytocin synthesised in hypothalamus, secreted by posterior pituitary and decidual tissue- up regulated at term by oestrogen activity
Regulation of parturition
Progesterone suppresses myometrial contractions preventing birth
Balance between procontractile effects of E2 and pro relaxant effects of P4
Progesterone levels do not fall prior to human parturition
Parturition is preceded by a fall in progesterone levels in many mammals this does not occur in humans
Progesterone antagonist RU486 initiates myometrial contractility
“Functional progesterone withdrawal”
-changes in progesterone receptors (<PrB>PrA and C) at the feto-maternal interface
-increased progesterone degradation in myometrial cells</PrB>
Corticotropin-releasing hormone CRH
Precursor of ACTH/corticotropin- produced in response to stress
Stimulates corticosteroid production from the adrenals
CRH activity increases in primate pregnancies prior to parturition- most produced by placenta- not HPA
CRH and CRH receptor in the placenta/decidua increase at term- CRH binding protein decreases
Glucocorticoids/cortisol levels increase
-lung maturation- synthesis of surfactants
-promote oestrogen and prostaglandin production
Fetal contribution to initiation of labour
Placental CRH increases during gestation
DHEAS increases via fetal adrenal gland
Converted to oestradiol in the placenta
Oestradiol metabolised to DHEAS in the maternal liver
Pro contractile myometrial effects
Prostaglandins
Arachidonic acid is 6-8 fold higher in women during labour
At term- increasing oestrogen: progesterone activity ratio promotes:
-phospolipase A2 activation
-local arachidonic acid release
-prostaglandins PGF2a and PGE2
CRH promotes prostaglandin release
Cervical ripening/softening
Cervix starts to ripen days/weeks preceding birth
-prostaglandin E2 (PGE2), relaxin, NO
PGE2 used clinically in induction of labour (or abortion)
-also in semen
Cervical remodelling
Cervix- essential to retain the fetus
-rigid connective tissue- bundles of collagen fibres embedded in proteoglycan matrix (dermatan sulphate)
Cervical changes peripartum:
-loosening of collagen fibre bundles
—keratan sulphate which does not bind collagen replaces dermatan sulphate
-increased glycosaminoglycans- eg hyaluron
-increased matrix metalloproteinase production- eg collagenase
-increased inflammatory cells and cytokines
Oxytocin
Nonapeptide produced by neurohypophysis and released by posterior pituitary
Oestrogens main stimulators of oxytocin synthesis
Lowers the excitation threshold of the myometrial muscle cell at which spiking occurs
Released in response to tactile stimulation of the uterine cervix
Operates through a neuroendocrine pathway- Ferguson reflex
Oxytocin and uterine contractions
Neuroendocrine reflex:
-intramyometrial PGF2a increases uterine contractions and cervical distension
“Sensed” by neurones - stimulates oxytocin release
Oxytocin promotes further uterine contractions and release of PGs
Parturition
Progesterone decreases myometrial oestrogen responsiveness by inhibiting oestrogen receptor-a expression
Functional progesterone withdrawal removes the suppression on oestrogen receptor-a expression
Anatomy of the breast
15-20 lobes of glandular tissue interspaced with fibrous/adipose tissue
Lobes- lobules of alveoli, blood vessels and lactiferous ducts
Alveoli- epithelial “acinar” cells- synthesise milk
-myoepithelial cells- contract to move milk to lactiferous ducts for ejection
At birth- mostly lactiferous ducts, few alveoli
Puberty- oestrogen stimulates lactiferous ducts sprout and branch, alveoli start to develop, deposition of fat and connective tissue
Lactation/breast feeding
Oestrogen- increases size and number of ducts in the breast
Progesterone- increases the number of alveolar cells- but inhibits lactogenic effects of prolactin
HPL- stimulates the development of acinar glands
Prolactin- levels increase with gestation and promotes milk production
Oxytocin- promotes ‘let down’ or milk ejection reflex
Lactation and breast feeding summary
PRL and hPL contribute to breast development
PRL is responsible for milk production
Suckling increases:
-PRL release which maintains milk production
-oxytocin release which causes smooth muscle contraction and thus milk ejection
Maintenance of milk production
Somato-sensory pathway for prolactin release by “positive feedback”
Tuberoinfundibular dopamine TIDA neuron activity is modulated reducing dopamine (prolactin inhibitory factor/PIF) secretion
Dopamine agonists (eg Bromocriptine) inhibit prolactin secretion
Vasointestinal peptide VIP and TRH release promotes prolactin secretion
Milk ejection reflex (let down)
Neuroendocrine reflex:
-nipple stimulation by neonatal sucking leads to release of oxytocin
-oxytocin stimulates breast myoepithelial cell contractility
-results in release of milk from alveoli and increased ductal flow of milk to the nipples
-can promote uterine contractility
Breast feeding advantages
Baby:
-enhances development and intelligence
-protects against infection, illnesses, allergies
-long term health benefits
Mother:
-delays fertility
-reduce gynaecological cancer risk
-emotional health
-weight loss
-osteoporosis
Intrauterine insemination
Not NHS funded
Indications NICE
-inability to have sexual intercourse
-need sperm washing HIV
-same sex couples
Steps:
-with or without ovarian stimulation (FSH or clomiphene)
—aim with no more than 3 follicles
-with or without HCG triggering
-sperm preparation and sperm insemination
-pregnancy test 2 weeks later
Intrauterine insemination problems
Low success rates 10-20% per stimulated cycle
Multiple pregnancy -10%
Cost:~£500 no NHS funded
Invasive
In vitro fertilisation Indications
Tubal disease
Anovulatory (eg PCOS)
Unexplained
Male factor (with ICSI)
Endometriosis
Other failed Tx (eg IUI)
No eggs (egg donor IVF)
No uterus (host surrogacy)
PGD
IVF steps
Counselling and consenting
-aim: psychologically ready
Pituitary suppression (GnRHa: antagonist)
-aim: prevent premature LH surge
Ovarian stimulation (HMG, rFSH)
-aim: multi follicular development
HCG triggering (cf LH surge):
-aim: final egg maturation
IVF timing egg collection
HCG 34-36 hours prior to egg collection
IVF insemination
Insemination or ICSI
Embryo culturing (2,3 or 5 days)
Embryo transfer (number of embryos)
Luteal support (cf corpus luteal function)
Pregnancy test- 2 weeks after embryo transfer
Intracytoplasmic sperm injection
Used in cases of sperm dysfunction/failure of fertilisation in IVF
Problems with sperm concentration, morphology or motility
Surgical sperm retrieval
No demonstrable benefit to using ICSI if sperm parameters are normal
Blastocyst culture
Culture of embryos 5-6 days post oocyte collection
Development to the blastocyst passes significant hurdles:
-switching on of embryonic genome
-past stages of totipotency to first differentiation
Non invasive embryo selection
IVF problems
Multiple pregnancies- one at a time drive
OHSS
Oocyte collection risks: injury to bladder, bowel, blood vessels, infection
Long term maternal risks
Cost: £4000
Very invasive
Cryopreservation of gametes and embryos
Oocytes and sperm preserved using liquid nitrogen and cryoprotectant
Sperm, cyropreservation is very successful. Oocyte cyropreservation more difficult and less successful
Embryo storage of top quality embryos only means that further IVF stimulation not required
Donated oocytes
Ovarian failure
Premature menopause
Turner’s syndrome
Surgical loss of ovaries
Female partner carrier
Donated sperm
Azoospermia
-testicular failure
-obstructive- cystic fibrosis
Klinefelters syndrome
Microdeletions of Y
Male partner carrier of inheritable disease
Human fertilisation and embryology authority
UKs independent regulator overseeing fertility treatment and research
The HFEA licenses fertility clinics performing regular inspections
Success rates by clinics
Information provision for patients and professionals
“One at a time” drive
Pre implantation genetic diagnosis
Removal of one or two cells from the early embryo for genetic analysis
Single gene disorders and balanced translocations
CF
Huntingtons disease
Sickle cell disease
Muscular dystrophies
Moral and ethical arguments
Same sex couples
Donor treatment
Sex selection
Couples separating before embryo transfer
Fate of surplus embryos
Should NHS fund IVF treatment
Should NHS pick up the tab on multiples
Health tourism
Add on tests and treatments
PGD- designer babies, eye colour/height etc
Embryo research
