Week 6 Flashcards

1
Q

Maternal-Fetal hormonal interplay

A

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

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2
Q

Human chorionic gonadotrophin hCG

A

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

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3
Q

Maternal recognition of pregnancy

A

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

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4
Q

Progesterone

A

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

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5
Q

Progesterone function

A

“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)

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6
Q

Progesterone as a substrate for steroidogenesis

A

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

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7
Q

Oestrogens

A

Oestrone E1: predominates after menopause
Oestradiol, E2: regulates menstruation
Oestriol E3: pregnancy-specific

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8
Q

Oestrogens 2

A

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

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9
Q

The role of oestrogens following implantation

A

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

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10
Q

Placental growth hormone PGH

A

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

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11
Q

Human placental lactogen hPL

A

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

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12
Q

Effects of hPL

A

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

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13
Q

Relaxin

A

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

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14
Q

Prolactin PRL

A

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)

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15
Q

3 stages of parturition

A

Contractions begin, dilation and shortening/effacement of cervix
Full dilation of cervix- delivery of baby
Delivery of placenta

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16
Q

NICE guidelines: intrapartum care

A

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)

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17
Q

Process of parturition

A

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

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18
Q

Myometrial contractility

A

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

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19
Q

Regulation of parturition

A

Progesterone suppresses myometrial contractions preventing birth
Balance between procontractile effects of E2 and pro relaxant effects of P4

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20
Q

Progesterone levels do not fall prior to human parturition

A

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>

21
Q

Corticotropin-releasing hormone CRH

A

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

22
Q

Fetal contribution to initiation of labour

A

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

23
Q

Prostaglandins

A

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

24
Q

Cervical ripening/softening

A

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

25
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
26
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
27
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
28
Parturition
Progesterone decreases myometrial oestrogen responsiveness by inhibiting oestrogen receptor-a expression Functional progesterone withdrawal removes the suppression on oestrogen receptor-a expression
29
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
30
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
31
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
32
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
33
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
34
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
35
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
36
Intrauterine insemination problems
Low success rates 10-20% per stimulated cycle Multiple pregnancy -10% Cost:~£500 no NHS funded Invasive
37
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
38
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
39
IVF timing egg collection
HCG 34-36 hours prior to egg collection
40
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
41
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
42
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
43
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
44
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
45
Donated oocytes
Ovarian failure Premature menopause Turner’s syndrome Surgical loss of ovaries Female partner carrier
46
Donated sperm
Azoospermia -testicular failure -obstructive- cystic fibrosis Klinefelters syndrome Microdeletions of Y Male partner carrier of inheritable disease
47
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
48
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
49
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