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