LECTURE 32 - endocrine control of pregnancy and parturition

Question 1

What is human chorionic gonadotrophin hormone?

Answer 1

• syncytiotrophoblast is the main synthetic unit of the placenta that produces most of the hormones
• first to be produced in hCG (6-7 days post fertilisation)
• glycoprotein - made of α and β subunits (α identical to LH, FSH and TSH)
• acts on LH receptors
• maintains corpus luteum
• stimulates DHEA production in fetal adrenal
• has a half life ~24 hours
• in early pregnancy doubles every 48hrs
• used for monitoring pregnancy (decrease in blood hCG correlated with decrease in 17a-OHP)
• pregnancy test detects β subunits in urine

Question 2

Where is progesterone produced both initially and subsequently?

Answer 2

• initially produced from corpus luteum
• produced from cholesterol by syncytiotrophoblast - placenta takes over from corpus luteum ~6-8 weeks
• mifepristone (RU486) = anti-progesterone, used for late stage contraception/ prevention of pregnancy

Question 3

How does progesterone maintain pregnancy?

Answer 3

• progestin
• reduces myometrial muscle excitability - decreases synthesis of proteins associated with contractility (suppresses oxytocin receptors and interferes with gap junctions)
• maintains the decidua
• resets respiratory centre (hyperventilation) - reduces [CO2] in maternal lungs
• thermogenic
• progesterone receptor B activity predominates
• increases protein breakdown
• promotes breast alveolar cell proliferation but inhibits lactogenic effect of placental lactogen (hPL)

Question 4

What are oestrogens?

Answer 4

• rise throughout pregnancy
• oestriol production predominates
• produced cooperatively by placenta and fetus
  progesterone (placenta) –> (conjugated sulphate) androgen (fetal adrenal) –> (deconjugated) oestrogen (placenta)
• oestriol > oestrone > oestradiol

Question 5

What does oestrogen do?

Answer 5

• increases uterine blood flow
• stimulatees release of prolactin from the ant. pit.
  Metabolism
• reduce peripheral glucose uptake
• increase cholesterol and triglycerides
• decrease HDL
• increase glycogen stores and muscle cell size in myometrium

Question 6

What is human placental lactogen (hPL)?

Answer 6

• hormone produced by the syncytiotrophoblast
• rises as hCG falls
• large amounts in maternal blood - little reaches fetus
• development of acinar glands in mammy glands
• aids fetal nutrition => suppresses action of insulin in mother
  
  • increases blood glucose levels so more is available for fetus
  • mobilizes FFAs - maternal nutrients to meet fetal demand

Question 7

What is prolactin (PRL)?

Answer 7

• homology with growth hormone and hPL (half life 5-10min)
• important for milk production
• -ve feedback effect on HPG axis
• rises linearly during pregnancy
• oestrogen stimulates PRL release by lactotroph cells in the ant. pit. and low level level PRL from decidua (dPRL enters amniotic fluid)

Question 8

What is the position of the fetus prior to birth?

Answer 8

• fetus lies very low
• lies within fetal membranes in the uterus retained by the cervix
• starts to engage with cervix
• important myometrium remains quiescent and also important cervix stays closed so that fetus doesn’t leave too early

Question 9

What are the 3 stages of parturition?

Answer 9

1. Contraction beings, dilation and shortening/effacement of cervix
2. Full dilation of cervix - delivery of baby
3. delivery of placenta

Question 10

What are the key mediators of parturition?

Answer 10

• increase in oestrogen:progesteorne activity ratio
• prostaglandins (PGF2α, PGE2)
• oxytocin

Question 11

What 3 key changes are required for parturition?

Answer 11

1. Initiating signal - increased maternal/fetal corticosteroids possibly
2. Co-ordinated contraction of uterine myometrium smooth muscle
3. Cervical softening/ripening & dilation - progression from 0cm (closed cervix) to full dilation at ~10cm & expulsion of the fetus

Question 12

What is myometrial contractility?

Answer 12

• 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 post. pit. + decimal tissue - up-regulated at term by oestrogen activity

Question 13

What happens to progesterone levels prior to human parturition?

Answer 13

• levels do not fall
• parturition is preceded by a fall in progesterone in many mammals but not in humans
• progesterone antagonist RU486 initiates myometrial contractility
• functional progesterone withdrawal
  
  • changes in progesterone receptors (PrB, PrA and PrC) at the feto-maternal interface

Question 14

How does the fetus contribute to the timing of parturition?

Answer 14

• maturation of fetal HPA axis
• fetal glucocorticoids and corticotropin releasing hormone (CRH) increase at term - promote oestrogen and prostaglandin production
• cortisol - lung maturation by synthesis of surfactants
  
  • dexamethasone given in pre-term labour

Question 15

What is corticotropin-releasing hormone (CRH) and what does it do?

Answer 15

• 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
• fetal glucocorticoids and CRH increase at term

Question 16

What does increasing oestrogen:progesterone activity ratio promote?

Answer 16

• phospholipase A2 activation
• local arachidonic acid release (6-8 fold higher during labour)
• prostaglandins (PGF2α)
• CRH promotes prostaglandin release

Question 17

What is cervix remodelling?

Answer 17

• cervix is essential to retain the fetus
• rigid connective tissue - bundles of collagen fibres embedded in proteoglycan matrix (dermatan sulphate)
• consistency changes throughout gestation

Question 18

What cervical changes occur preipartum?

Answer 18

• loosening of collagen fibre bundles
  
  • keratan sulphate which does not bind collagen replaces dermatan sulphate
• increased glycosaminoglycans e.g. Hyaluron
• increased matrix metalloproteinase production e.g. Collagenase
• increased inflammatory cells and cytokines

Question 19

What is cervical ripening/softening?

Answer 19

• cervix starts to ripen days/weeks preceding birth
• prostaglandin E2 (PGE2), relaxin, NO
• PGE2 used clinically in indication of labour (or abortion) - also in semen

Question 20

What is oxytocin?

Answer 20

• nonapeptide produced by neurohypophysis and released by post. pit.
• oestrogen maintains 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

Question 21

What is the neuroendocrine reflex?

Answer 21

intramyometrial PGF2α increases uterine contractions and cervical distention
–>
sensed by neurones - stimulates oxytocin release
–>
oxytocin promotes further uterine contractions and release of PGs

Question 22

How does the fetus contribute to the initiation of labour?

Answer 22

• placental CRH increases during gestation
• DHEAS (dehydroepiandrosterone) increases via fetal adrenal gland
• converted to oestradiol in the placenta
• oestradiol metabolised to DHEAS in the maternal liver
• pro-contractile myometrial effects

Question 23

Describe the anatomy of the breast

Answer 23

• 15-20 lobes of glandular tissue interspaced with fibrous/adipose tissue
• lobes = lobules of alveoli, blood vessels and lactiferous ducts
• alveoli = epithelial acinar cells - synthesis 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

Question 24

How do different hormones enable lactation/breast feeding?

Answer 24

Oestrogen = increases size and number of ducts in the breast
Progesterone = increases number of alveolar cells but inhibits lactogenic effects of hPL
hPL = stimulates the development of the acinar glands 
Prolactin = levels increase with gestation and promote milk production 
Oxytocin = promotes let-down or milk ejection reflex

Question 25

How is milk production maintained?

Answer 25

• need physical stimulation of nipple by suckling
• triggers neuronal response within nipple
• travel back through spinal column to neural secretory cells which are dopamine secretory cells
• secrete prolactin
• dopamine activity has -ve effect and to inhibit prolactin secretion dopamine antagonists can be used such as bromocriptine
• stimulation of nipple keeps prolactin being secreted

Question 26

What is the milk ejection reflex?

Answer 26

• aka let-down reflex
• nipple stimulation by neonatal suckling 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

Question 27

What are the advantages of breast feeding?

Answer 27

Baby

• enhances development and intelligence
• protects against infection, illnesses and allergies
• long term health benefits

Mother

• delays fertility
• reduces gynaecological cancer risk
• emotional health
• weight loss
• osteoporosis